Skip to main content
SpringerLink
Log in
Book cover

In vitro Environmental Toxicology - Concepts, Application and Assessment pp 1–58Cite as

Endocrine Disruption and In Vitro Ecotoxicology: Recent Advances and Approaches

  • Chapter
  • First Online:

Part of the book series: Advances in Biochemical Engineering/Biotechnology ((ABE,volume 157))

Abstract

Endocrine-disrupting chemicals (EDCs) are man-made compounds interfering with hormone signaling. Omnipresent in the environment, they can cause adverse effects in a wide range of wildlife. Accordingly, Endocrine Disruption is one focal area of ecotoxicology. Because EDCs induce complex response patterns in vivo via a wide range of mechanisms of action, in vitro techniques have been developed to reduce and understand endocrine toxicity. In this review we revisit the evidence for endocrine disruption in diverse species and the underlying molecular mechanisms. Based on this, we examine the battery of in vitro bioassays currently in use in ecotoxicological research and discuss the following key questions. Why do we use in vitro techniques? What endpoints are we looking at? Which applications are we using in vitro bioassays for? How can we put in vitro data into a broader context? And finally, what is the practical relevance of in vitro data? In critically examining these questions, we review the current state-of-the-art of in vitro (eco)toxicology, highlight important limitations and challenges, and discuss emerging trends and future research needs.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Notes

  1. 1.

    Imposex is defined as the imposition of male reproductive characteristics, for example, penis development, on female individuals.

  2. 2.

    For example, female testosterone levels might be increased by aromatase inhibition. See Fernandes et al. [369] for a comprehensive review on molluskan steroid biosynthesis.

  3. 3.

    Organotin compounds have been shown to be potent agonists of the retinoid receptors RXR and RAR.

  4. 4.

    BPA found to be estrogenic in the 1930s [370] but was abandoned as synthetic estrogen in favor of the more potent diethylstilbestrol (DES). Today, it is mainly used as building block of polycarbonate plastics to produce food and beverage containers [130].

  5. 5.

    Given the almost universal contamination of freshwater ecosystems with (treated) wastewater, the issue of feminization became the focal point for research on ED in fish and EDCs in wastewater.

  6. 6.

    VTG is an egg yolk protein precursor. Synthesized in the female liver, it is transported via the bloodstream for incorporation into oocytes. Its expression is estrogen-dependent [371]. Naturally only produced by mature females, its prevalence in juvenile or male fish is considered a biomarker of exposure to estrogenic substances.

  7. 7.

    Intersex males had increased VTG and estradiol levels, delayed spermatogenesis, and malformed reproductive ducts as well as reduced milt production, sperm motility, and fertilization rates.

  8. 8.

    A nominal concentration of 5 ng L−1 17α-ethinylestradiol (EE2), the synthetic estrogen from the birth-control pill, was dosed to a lake in Ontario, Canada [372, 373].

  9. 9.

    During the exposure period, VTG levels in male fathead minnow (short life cycle) were three orders of magnitude higher than in the reference. In addition, the testicular and ovarian development was arrested [372]. Similar effects have been observed in pearl dace. While in this longer-lived species a clear impact on population size has not yet been observed, population structure was affected as indicated by the loss of the 1-year-old size class [374]. In another species (rainbow trout), fertility was unaffected [375]. This highlights considerable species differences [376].

  10. 10.

    Polychlorinated biphenyls (PCBs) and p,p-dichlorodiphenyltrichloroethane (DDT).

  11. 11.

    Newer studies indicate that the pesticide levels have not appreciably decreased in the early 2000s [87, 377]. Interestingly, associations between organochlorine pesticides and reproductive performance have also been reported for caimans [378].

  12. 12.

    Similar effects can be induced by other endocrine disruptors, including 17β-estradiol, atrazine, and Bisphenol A [379].

  13. 13.

    Several reptilian estrogen receptors have been cloned and display a differential responsiveness to estrogens and pesticides [293, 380].

  14. 14.

    Interestingly, in ovo exposure to estrogenic chemicals feminizes the male gonad in birds [381] as it does in rodent models.

  15. 15.

    The exposure scenario was based on the levels of estrogen-like compounds detected in earthworms sampled at wastewater treatment plants. Morphologically, the brain area controlling song complexity was enlarged in exposed compared to control males [109].

  16. 16.

    In a more recent study, growth and immunocompetence was reduced in nestlings exposed similarly to the previous experiment [382].

  17. 17.

    Notably, polar bears contaminated with organohalogens had thyroid gland lesions [383].

  18. 18.

    Key aspects of the Wingspread Statement were published in the peer-reviewed literature [384] and formed the cornerstones of Colbourn’s ‘Our stolen future’ [385].

  19. 19.

    It has been suggested to replace “secondary” by “consequent” [124].

  20. 20.

    This includes intracrine (intracellular), autocrine (targeting the cell itself), juxtacrine (targeting adjacent cells), and paracrine (targeting cells in the vicinity) signaling.

  21. 21.

    Half of the human NRs are ‘orphan receptors’, i.e., its natural ligand is unknown or might not exist [127]. Here, ligand-independent mechanisms might exist.

  22. 22.

    NRs bind specific hormone response elements (HREs) within the regulatory region(s) of target genes either as monomers, homo-, or heterodimers. In case of cytosolic NRs, nuclear translocation precedes DNA-binding [128, 127].

  23. 23.

    AhR does not belong to the NR superfamily but to the basic helix-loop-helix transcription factors. It is included here because of its relevance to endocrine disruption.

  24. 24.

    Aromatase is a cytochrome P450 (CYP) enzyme converting C19 androgens into C18 estrogens.

  25. 25.

    Another example is prostaglandin synthesis. Several EDCs bind to cyclooxygenase enzymes and block the synthesis of prostaglandin precursors [386].

  26. 26.

    Similarly, phthalic acid blocks PXR degradation in the proteasome [387]. Vice versa, dioxin-activated AhR increases ERα degradation [388].

  27. 27.

    Here, EGF, ERK, MAPK, or Ras signaling might be involved. For example, short-chain fatty acids enhance ER and PR activity through activation of mitogen-activated protein kinase (MAPK) and inhibition of histone deacetylase [389]. Such compounds are termed ‘hormone sensitizers’.

  28. 28.

    Peroxisome proliferator-activated receptor (PPAR).

  29. 29.

    Thyroid hormone receptor-associated protein.

  30. 30.

    Interestingly, phthalates increased the binding of TRAP to ERα.

  31. 31.

    AhR nuclear translocator (ARNT) is the dimerization partner of AhR but also a coactivator of ERs [390]. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied [143].

  32. 32.

    These methods were later standardized by the OECD as Hershberger/Uterotrophic Bioassay in Rats (Guidelines 441 and 440).

  33. 33.

    Kanter et al. and others [391] developed fish assays for pregnancy testing. They proposed to standardize the animal model because “the results became so confusing that it was felt tests could not be conducted along scientific lines until the fish had been standardized.” This is a splendid reminder that the standardization of bioassays has been an issue from the very beginning.

  34. 34.

    A combined chronic toxicity/carcinogenicity study in rats according to the U.S. EPA’s Pesticide Assessment Guidelines costs approximately 2 million dollars and takes approximately 2 years [392].

  35. 35.

    An AOP is a conceptual framework that portrays existing knowledge concerning the linkage between two anchor points – the molecular initiating event, and an adverse outcome, connected by a chain of key events and the relationships between them (adopted from AOP-KB, https://aopkb.org).

  36. 36.

    So far, the cellular processes resulting in feminization are not well understood. VTG induction is here rather used as biomarker for estrogenic effects than causative.

  37. 37.

    With regard to receptor transactivation, one can argue that the interaction of a chemical with a receptor protein is under investigation (as in the case of LBAs). However, because the induction/repression of the receptor-mediated gene expression is studied, the organizational level under investigation is indeed transcription.

  38. 38.

    While this difference is obvious, it is worth stressing. In the experience of the authors, the level of biological organization is often neglected when discussing in vitro “endocrine activity.”

  39. 39.

    The first ligand binding assay (a radioimmunoassay for insulin) was presented by Yalow and Berson [393]. Yalow was rewarded with the Nobel prize for her discovery in 1977 [394].

  40. 40.

    An ISI Web of Science search for “ligand binding assay” returns 20 hits in the research area Environmental Science/Ecology (October 2, 2015).

  41. 41.

    Receptor dimerization or nuclear localization may precede this event. Hormone response elements are regulatory, palindromic DNA sequences. See Ruff et al. [395] for more details.

  42. 42.

    These included not only endocrine endpoints but also mutagenicity, genotoxicity, stress response, and cytotoxicity.

  43. 43.

    Multiple substrates are available. Often the cleavage of o-nitrophenyl-β-d-galactopyranosid (ONPG) or chlorophenol red-β-d-galactopyranoside (CPRG) is determined colorimetrically. The fluorescent methylumbelliferyl β-d-galactopyranoside (MUG) has also been used as substrate [396].

  44. 44.

    The cleavage product of CPRG, chlorophenol red, is estrogenic itself [397], as is phenol red used as pH indicator in cell culture media [398, 399].

  45. 45.

    Indeed, OHT is a partial agonist inducing a weak estrogenic response in the absence of a full agonist such as 17β-estradiol [173].

  46. 46.

    This assay has been developed by the German Leibniz Institute of Plant Genetics and Crop Plant Research and is now marketed by New Diagnostics (www.new-diagnostics.com).

  47. 47.

    This list is far from comprehensive given that ISI Web of Science lists 13,292 publications under the keywords “yeast” AND “assay” AND “receptor” (on October 22, 2015).

  48. 48.

    http://www.biodetectionsystems.com/products/bioassays/available-assays.html (last accessed October 23, 2015).

  49. 49.

    Mainly, the results of the DR-CALUX are compared to chemical analysis, especially of dioxin-like compounds.

  50. 50.

    BioDetection Systems BV, the company marketing the CALUX assays, is a 2001 spinoff founded by Prof. Abraham Brouwer of the Free University of Amsterdam.

  51. 51.

    According to an ISI Web of Science search (October 5, 2015).

  52. 52.

    Humans possess 48 nuclear receptors, Caenorhabditis elegans 284 [400].

  53. 53.

    A meta-analysis by Dang et al. [401] demonstrated that the EC50s of several EDCs at human and fish ERs correlate and concluded that “transactivation of ERs in one vertebrate species or one subtype of ERs could be extrapolated to other species or subtypes of ERs for the purpose of chemical screening.” However, the EC50s can differ by two orders of magnitude for many EDCs.

  54. 54.

    An interesting question remains as to why mollusks possess steroid hormones anyway [402, 403].

  55. 55.

    Notably, other mollusk receptors (e.g., RAR) also appear to be constitutively active [404]. If so, the mechanism of action mediating endocrine disruption in mollusks remains unknown.

  56. 56.

    Despite tremendous advances in analytical chemistry, they remain unknown in most cases.

  57. 57.

    In the U.S., the term toxicity identification evaluation (TIE) is used. However, TIE rather refers to in vivo effects [405].

  58. 58.

    For instance, had we attempted to identify DEHF by NMR, we would have needed to extract, fractionate, and test at least 1,000 L of bottled drinking water.

  59. 59.

    Interestingly, ex vivo data were not predictive.

  60. 60.

    This might be because of publication bias.

  61. 61.

    For instance, the total cell concentration or the dose at the molecular target (biologically effective dose).

  62. 62.

    More information at http://www.epa.gov/endocrine-disruption.

  63. 63.

    See COMMISSION REGULATION (EU) No 589/2014 of 2 June 2014 laying down methods of sampling and analysis for the control of levels of dioxins, dioxin-like PCBs, and non-dioxin-like PCBs in certain foodstuffs and repealing Regulation (EU) No 252/2012. Official Journal of the European Union L 164/18.

  64. 64.

    ISO Standards Catalogue. ISO/TC 147 – Water quality. Standards under development (see www.iso.org).

  65. 65.

    Annual-Average Environmental Quality Standards (AA-EQS) for EE2: 0.035 ng/L and for E2 of 0.4 ng/L. These concentrations should not be exceeded in order to protect the aquatic environment and human health.

References

  1. LaFont R (2000) The endocrinology of invertebrates. Ecotoxicology 9(1–2):41–57

    Article  CAS  Google Scholar 

  2. Kortenkamp A, Martin O, Faust M, Evans R, McKinlay R, Orton F, Rosivatz E (2011) State of the art assessment of endocrine disruptors, final report. European Commission, The Directorate-General for the Environment, p 433

    Google Scholar 

  3. Thornton JW (2001) Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc Natl Acad Sci U S A 98(10):5671–5676

    Article  CAS  Google Scholar 

  4. Thornton JW, Need E, Crews D (2003) Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling. Science 301(5640):1714–1717

    Article  CAS  Google Scholar 

  5. Edwards TM, Moore BC, Guillette LJ (2006) Reproductive dysgenesis in wildlife: a comparative view. Int J Androl 29(1):109–120

    Article  Google Scholar 

  6. Guillette LJ (2000) Contaminant-induced endocrine disruption in wildlife. Growth Horm IGF Res 10:45–50

    Article  Google Scholar 

  7. Guillette LJ Jr (2006) Endocrine disrupting contaminants: beyond the dogma. Environ Health Perspect 114:9–12

    Article  Google Scholar 

  8. Kloas W, Urbatzka R, Opitz R, Wuertz S, Behrends T, Hermelink B, Hofmann F, Jagnytsch O, Kroupova H, Lorenz C, Neumann N, Pietsch C, Trubiroha A, Van Ballegooy C, Wiedemann C, Lutz I (2009) Endocrine disruption in aquatic vertebrates. Trends Comp Endocrinol Neurobiol 1163:187–200

    CAS  Google Scholar 

  9. McLachlan JA (2001) Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals. Endocr Rev 22(3):319–341

    Article  CAS  Google Scholar 

  10. Milnes MR, Bermudez DS, Bryan TA, Edwards TM, Gunderson MP, Larkin ILV, Moore BC, Guillette LJ (2006) Contaminant-induced feminization and demasculinization of nonmammalian vertebrate males in aquatic environments. Environ Res 100(1):3–17

    Article  CAS  Google Scholar 

  11. Oehlmann J, Schulte-Oehlmann U, Kloas W, Jagnytsch O, Lutz I, Kusk KO, Wollenberger L, Santos EM, Paull GC, Van Look KJW, Tyler CR (2009) A critical analysis of the biological impacts of plasticizers on wildlife. Philos Trans R Soc B-Biol Sci 364(1526):2047–2062

    Article  CAS  Google Scholar 

  12. Sumpter JP (2005) Endocrine disrupters in the aquatic environment: an overview. Acta Hydrochim Hydrobiol 33(1):9–16

    Article  CAS  Google Scholar 

  13. Tyler CR, Jobling S, Sumpter JP (1998) Endocrine disruption in wildlife: a critical review of the evidence. Crit Rev Toxicol 28(4):319–361

    Article  CAS  Google Scholar 

  14. Vos JG, Dybing E, Greim HA, Ladefoged O, Lambre C, Tarazona JV, Brandt I, Vethaak AD (2000) Health effects of endocrine-disrupting chemicals on wildlife, with special reference to the European situation. Crit Rev Toxicol 30(1):71–133

    Article  CAS  Google Scholar 

  15. Oehlmann J, Di Benedetto P, Tillmann M, Duft M, Oetken M, Schulte-Oehlmann U (2007) Endocrine disruption in prosobranch molluscs: evidence and ecological relevance. Ecotoxicology 16(1):29–43

    Article  CAS  Google Scholar 

  16. Mills LJ, Chichester C (2005) Review of evidence: are endocrine-disrupting chemicals in the aquatic environment impacting fish populations? Sci Total Environ 343(1–3):1–34

    Article  CAS  Google Scholar 

  17. Hayes TB, Case P, Chui S, Chung D, Haeffele C, Haston K, Lee M, Mai VP, Marjuoa Y, Parker J, Tsui M (2006) Pesticide mixtures, endocrine disruption, and amphibian declines: are we underestimating the impact? Environ Health Perspect 114:40–50

    Article  Google Scholar 

  18. Milnes MR, Guillette LJ Jr (2008) Alligator tales: new lessons about environmental contaminants from a sentinel species. Bioscience 58(11):1027–1036

    Article  Google Scholar 

  19. Ottinger MA, Lauoie E, Thompson N, Barton A, Whitehouse K, Barton M, Abdelnabi M, Quinn M Jr, Panzica G, Viglietti-Panzica C (2008) Neuroendocrine and behavioral effects of embryonic exposure to endocrine disrupting chemicals in birds. Brain Res Rev 57(2):376–385

    Article  CAS  Google Scholar 

  20. Iguchi T, Watanabe H, Katsu Y (2006) Application of ecotoxicogenomics for studying endocrine disruption in vertebrates and invertebrates. Environ Health Perspect 114:101–105

    Article  Google Scholar 

  21. Hamlin HJ, Guillette LJ Jr (2011) Embryos as targets of endocrine disrupting contaminants in wildlife. Birth Defects Res C: Embryo Today 93(1):19–33

    Article  CAS  Google Scholar 

  22. Rhind SM (2009) Anthropogenic pollutants: a threat to ecosystem sustainability? Philos Trans R Soc B-Biol Sci 364(1534):3391–3401

    Article  CAS  Google Scholar 

  23. Acevedo-Whitehouse K, Duffus ALJ (2009) Effects of environmental change on wildlife health. Philos Trans R Soc B-Biol Sci 364(1534):3429–3438

    Article  Google Scholar 

  24. Jenssen BM (2006) Endocrine-disrupting chemicals and climate change: a worst-case combination for arctic marine mammals and seabirds? Environ Health Perspect 114:76–80

    Article  Google Scholar 

  25. Matthiessen P, Gibbs PE (1998) Critical appraisal of the evidence for tributyltin-mediated endocrine disruption in mollusks. Environ Toxicol Chem 17(1):37–43

    Article  CAS  Google Scholar 

  26. Blaber SJM (1970) The occurrence of a penis-like out-growth behind the right tentacle in spent females of Nucella lapillus (L.). Proc Malacol Soc Lond 39:231–232

    Google Scholar 

  27. Smith BS (1971) Sexuality in the American mud snail, Nassarius obsoletus SAY. Proc Malacol Soc Lond 39:377–378

    Google Scholar 

  28. Smith BS (1981) Male characteristics on female mud snails caused by antifouling bottom paints. J Appl Toxicol 1(1):22–25

    Article  CAS  Google Scholar 

  29. Smith BS (1981) Reproductive anomalies in stenoglossan snails related to pollution from marinas. J Appl Toxicol 1(1):15–21

    Article  CAS  Google Scholar 

  30. Titley-O’Neal CP, Munkittrick KR, MacDonald BA (2011) The effects of organotin on female gastropods. J Environ Monit 13(9):2360–2388

    Article  CAS  Google Scholar 

  31. Oetken M, Bachmann J, Schulte-Oehlmann U, Oehlmann J (2004) Evidence for endocrine disruption in invertebrates. Int Rev Cytol 236:1–44

    Article  CAS  Google Scholar 

  32. Galante-Oliveira S, Oliveira I, Ferreira N, Santos JA, Pacheco M, Barroso C (2011) Nucella lapillus L. imposex levels after legislation prohibiting TBT antifoulants: temporal trends from 2003 to 2008 along the Portuguese coast. J Environ Monit 13(2):304–312

    Article  CAS  Google Scholar 

  33. Guomundsdottir LO, Ho KKY, Lam JCW, Svavarsson J, Leung KMY (2011) Long-term temporal trends (1992–2008) of imposex status associated with organotin contamination in the dogwhelk Nucella lapillus along the Icelandic coast. Mar Pollut Bull 63(5–12):500–507

    Article  CAS  Google Scholar 

  34. Nicolaus EE, Barry J (2015) Imposex in the dogwhelk (Nucella lapillus): 22-year monitoring around England and Wales. Environ Monit Assess 187(12):736

    Article  CAS  Google Scholar 

  35. Santos JA, Galante-Oliveira S, Barroso C (2011) An innovative statistical approach for analysing non-continuous variables in environmental monitoring: assessing temporal trends of TBT pollution. J Environ Monit 13(3):673–680

    Article  CAS  Google Scholar 

  36. Titley-O’Neal CP, MacDonald BA, Pelletier E, Saint-Louis R (2011) Using Nucella lapillus (L.) as a bioindicator of tributyltin (TBT) pollution in eastern Canada: a historical perspective. Water Qual Res J Can 46(1):74–86

    Article  CAS  Google Scholar 

  37. Sternberg RM, Gooding MP, Hotchkiss AK, LeBlanc GA (2010) Environmental-endocrine control of reproductive maturation in gastropods: implications for the mechanism of tributyltin-induced imposex in prosobranchs. Ecotoxicology 19(1):4–23

    Article  CAS  Google Scholar 

  38. Bettin C, Oehlmann J, Stroben E (1996) TBT-induced imposex in marine neogastropods is mediated by an increasing androgen level. Helgoländer Meeresun 50(3):299–317

    Article  Google Scholar 

  39. Oehlmann J, Stroben E, Schulte-Oehlmann U, Bauer B, Fioroni P, Markert B (1996) Tributyltin biomonitoring using prosobranchs as sentinel organisms. Fresenius J Anal Chem 354(5–6):540–545

    CAS  Google Scholar 

  40. Spooner N, Gibbs PE, Bryan GW, Goad LJ (1991) The effect of tributyltin upon steroid titers in the female dogwhelk, Nucella lapillus, and the development of imposex. Mar Environ Res 32(1–4):37–49

    Article  CAS  Google Scholar 

  41. Schulte-Oehlmann U, Tillmann M, Markert B, Oehlmann J, Watermann B, Scherf S (2000) Effects of endocrine disruptors on prosobranch snails (Mollusca: Gastropoda) in the laboratory. Part II: Triphenyltin as a xeno-androgen. Ecotoxicology 9(6):399–412

    Article  CAS  Google Scholar 

  42. Abidli S, Santos MM, Lahbib Y, Costa Castro LF, Reis-Henriques MA, El Menif NT (2012) Tributyltin (TBT) effects on Hexaplex trunculus and Bolinus brandaris (Gastropoda: Muricidae): imposex induction and sex hormone levels insights. Ecol Indic 13(1):13–21

    Article  CAS  Google Scholar 

  43. Castro LFC, Lima D, Machado A, Melo C, Hiromori Y, Nishikawa J, Nakanishi T, Reis-Henriques MA, Santos MM (2007) Imposex induction is mediated through the retinoid X receptor signalling pathway in the neogastropod Nucella lapillus. Aquat Toxicol 85(1):57–66

    Article  CAS  Google Scholar 

  44. Horiguchi T, Nishikawa T, Ohta Y, Shiraishi H, Morita M (2010) Time course of expression of the retinoid X receptor gene and induction of imposex in the rock shell, Thais clavigera, exposed to triphenyltin chloride. Anal Bioanal Chem 396(2):597–607

    Article  CAS  Google Scholar 

  45. Horiguchi T, Ohta Y, Nishikawa T, Shiraishi F, Shiraishi H, Morita M (2008) Exposure to 9-cis retinoic acid induces penis and vas deferens development in the female rock shell, Thais clavigera. Cell Biol Toxicol 24(6):553–562

    Article  Google Scholar 

  46. Nakanishi T (2008) Endocrine disruption induced by organotin compounds; organotins function as a powerful agonist for nuclear receptors rather than an aromatase inhibitor. J Toxicol Sci 33(3):269–276

    Article  CAS  Google Scholar 

  47. Nishikawa J (2006) Imposex in marine gastropods may be caused by binding of organotins to retinoid X receptor. Mar Biol 149(1):117–124

    Article  CAS  Google Scholar 

  48. Nishikawa J, Mamiya S, Kanayama T, Nishikawa T, Shiraishi F, Horiguchi T (2004) Involvement of the retinoid X receptor in the development of imposex caused by organotins in gastropods. Environ Sci Technol 38(23):6271–6276

    Article  CAS  Google Scholar 

  49. Urushitani H, Katsu Y, Ohta Y, Shiraishi H, Iguchi T, Horiguchi T (2011) Cloning and characterization of retinoid X receptor (RXR) isoforms in the rock shell, Thais clavigera. Aquat Toxicol 103(1–2):101–111

    Article  CAS  Google Scholar 

  50. Stange D, Sieratowicz A, Oehlmann J (2012) Imposex development in Nucella lapillus: evidence for the involvement of retinoid X receptor and androgen signalling pathways in vivo. Aquat Toxicol 106–107:20–24

    Article  CAS  Google Scholar 

  51. Oehlmann J, Schulte-Oehlmann U, Tillmann M, Markert B (2000) Effects of endocrine disruptors on prosobranch snails (Mollusca: Gastropoda) in the laboratory. Part I: Bisphenol A and octylphenol as xeno-estrogens. Ecotoxicology 9(6):383–397

    Article  CAS  Google Scholar 

  52. Schulte-Oehlmann U, Tillmann M, Casey D, Duft M, Markert B, Oehlmann J (2001) Östrogenartige Wirkungen von Bisphenol A auf Vorderkiemenschnecken (Mollusca: Gastropoda: Prosobranchia). Umweltwiss Schadst Forsch 13(6):319–333

    Article  CAS  Google Scholar 

  53. Staples CA, Woodburn K, Caspers N, Hall AT, Klecka GM (2002) A weight of evidence approach to the aquatic hazard assessment of bisphenol A. Hum Ecol Risk Assess 8(5):1083–1105

    Article  Google Scholar 

  54. Oehlmann J, Schulte-Oehlmann U, Bachmann J, Oetken M, Lutz I, Kloas W, Ternes TA (2006) Bisphenol A induces superfeminization in the ramshorn snail Marisa cornuarietis (Gastropoda: Prosobranchia) at environmentally relevant concentrations. Environ Health Perspect 114:127–133

    Article  Google Scholar 

  55. Forbes VE, Aufderheide J, Warbritton R, van der Hoevene N, Caspers N (2007) Does bisphenol A induce superfeminization in Marisa cornuarietis? Part II: Toxicity test results and requirements for statistical power analyses. Ecotoxicol Environ Saf 66(3):319–325

    Article  CAS  Google Scholar 

  56. Forbes VE, Selck H, Palmqvist A, Aufderheide J, Warbritton R, Pounds N, Thompson R, van der Hoeven N, Caspers N (2007) Does bisphenol A induce superfeminization in Marisa cornuarietis? Part I: Intra- and inter-laboratory variability in test endpoints. Ecotoxicol Environ Saf 66(3):309–318

    Article  CAS  Google Scholar 

  57. Bortone SA, Davis WP (1994) Fish intersexuality as indicator of environmental-stress. Bioscience 44(3):165–172

    Article  Google Scholar 

  58. Tyler CR, Jobling S (2008) Roach, sex, and gender-bending chemicals: the feminization of wild fish in English rivers. Bioscience 58(11):1051–1059

    Article  Google Scholar 

  59. Purdom CE (1994) Estrogenic effects of effluents from sewage treatment works. Chem Ecol 8:275–285

    Article  CAS  Google Scholar 

  60. Desforges J-PW, Peachey BDL, Sanderson PM, White PA, Blais JM (2010) Plasma vitellogenin in male teleost fish from 43 rivers worldwide is correlated with upstream human population size. Environ Pollut 158(10):3279–3284

    Article  CAS  Google Scholar 

  61. Jobling S, Beresford N, Nolan M, Rodgers-Gray T, Brighty GC, Sumpter JP, Tyler CR (2002) Altered sexual maturation and gamete production in wild roach (Rutilus rutilus) living in rivers that receive treated sewage effluents. Biol Reprod 66(2):272–281

    Article  CAS  Google Scholar 

  62. Jobling S, Coey S, Whitmore JG, Kime DE, Van Look KJW, McAllister BG, Beresford N, Henshaw AC, Brighty G, Tyler CR, Sumpter JP (2002) Wild intersex roach (Rutilus rutilus) have reduced fertility. Biol Reprod 67(2):515–524

    Article  CAS  Google Scholar 

  63. Harris CA, Hamilton PB, Runnalls TJ, Vinciotti V, Henshaw A, Hodgson D, Coe TS, Jobling S, Tyler CR, Sumpter JP (2011) The consequences of feminization in breeding groups of wild fish. Environ Health Perspect 119(3):306–311

    Article  Google Scholar 

  64. Lange A, Paull GC, Hamilton PB, Iguchi T, Tyler CR (2011) Implications of persistent exposure to treated wastewater effluent for breeding in wild roach (Rutilus rutilus) populations. Environ Sci Technol 45(4):1673–1679

    Article  CAS  Google Scholar 

  65. Kidd KA, Blanchfield PJ, Mills KH, Palace VP, Evans RE, Lazorchak JM, Flick RW (2007) Collapse of a fish population after exposure to a synthetic estrogen. Proc Natl Acad Sci U S A 104(21):8897–8901

    Article  CAS  Google Scholar 

  66. Blanchfield PJ, Kidd KA, Docker MF, Palace VP, Park BJ, Postma LD (2015) Recovery of a wild fish population from whole-lake additions of a synthetic estrogen. Environ Sci Technol 49(5):3136–3144

    Article  CAS  Google Scholar 

  67. Filby AL, Thorpe KL, Maack G, Tyler CR (2007) Gene expression profiles revealing the mechanisms of anti-androgen-and estrogen-induced feminization in fish. Aquat Toxicol 81(2):219–231

    Article  CAS  Google Scholar 

  68. Jobling S, Burn RW, Thorpe K, Williams R, Tyler C (2009) Statistical modeling suggests that antiandrogens in effluents from wastewater treatment works contribute to widespread sexual disruption in fish living in English rivers. Environ Health Perspect 117(5):797–802

    Article  CAS  Google Scholar 

  69. Hill EM, Evans KL, Horwood J, Rostkowski P, Oladapo FO, Gibson R, Shears JA, Tyler CR (2010) Profiles and some initial identifications of (anti)androgenic compounds in fish exposed to wastewater treatment works effluents. Environ Sci Technol 44(3):1137–1143

    Article  CAS  Google Scholar 

  70. Rostkowski P, Horwood J, Shears JA, Lange A, Oladapo FO, Besselink HT, Tyler CR, Hill EM (2011) Bioassay-directed identification of novel antiandrogenic compounds in bile of fish exposed to wastewater effluents. Environ Sci Technol 45(24):10660–10667

    Article  CAS  Google Scholar 

  71. Schriks M, van Leerdam JA, van der Linden SC, van der Burg B, van Wezel AP, de Voogt P (2010) High-resolution mass spectrometric identification and quantification of glucocorticoid compounds in various wastewaters in the Netherlands. Environ Sci Technol 44(12):4766–4774

    Article  CAS  Google Scholar 

  72. Suzuki G, Tue NM, van der Linden S, Brouwer A, van der Burg B, van Velzen M, Lamoree M, Someya M, Takahashi S, Isobe T, Tajima Y, Yamada TK, Takigami H, Tanabe S (2011) Identification of major dioxin-like compounds and androgen receptor antagonist in acid-treated tissue extracts of high trophic-level animals. Environ Sci Technol 45(23):10203–10211

    Article  CAS  Google Scholar 

  73. Thomas KV, Langford K, Petersen K, Smith AJ, Tollefsen KE (2009) Effect-directed identification of naphthenic acids as important in vitro xeno-estrogens and anti-androgens in North sea offshore produced water discharges. Environ Sci Technol 43(21):8066–8071

    Article  CAS  Google Scholar 

  74. Weiss JM, Hamers T, Thomas KV, van der Linden S, Leonards PEG, Lamoree MH (2009) Masking effect of anti-androgens on androgenic activity in European river sediment unveiled by effect-directed analysis. Anal Bioanal Chem 394(5):1385–1397

    Article  CAS  Google Scholar 

  75. Weiss JM, Simon E, Stroomberg GJ, de Boer R, de Boer J, van der Linden SC, Leonards PEG, Lamoree MH (2011) Identification strategy for unknown pollutants using high-resolution mass spectrometry: androgen-disrupting compounds identified through effect-directed analysis. Anal Bioanal Chem 400(9):3141–3149

    Article  CAS  Google Scholar 

  76. Alford RA, Richards SJ (1999) Global amphibian declines: a problem in applied ecology. Annu Rev Ecol Syst 30:133–165

    Article  Google Scholar 

  77. Stuart SN, Chanson JS, Cox NA, Young BE, Rodrigues ASL, Fischman DL, Waller RW (2004) Status and trends of amphibian declines and extinctions worldwide. Science 306(5702):1783–1786

    Article  CAS  Google Scholar 

  78. Pounds JA, Bustamante MR, Coloma LA, Consuegra JA, Fogden MPL, Foster PN, La Marca E, Masters KL, Merino-Viteri A, Puschendorf R, Ron SR, Sanchez-Azofeifa GA, Still CJ, Young BE (2006) Widespread amphibian extinctions from epidemic disease driven by global warming. Nature 439(7073):161–167

    Article  CAS  Google Scholar 

  79. Sodhi NS, Bickford D, Diesmos AC, Lee TM, Koh LP, Brook BW, Sekercioglu CH, Bradshaw CJA (2008) Measuring the meltdown: drivers of global amphibian extinction and decline. PLoS One 3(2)

    Google Scholar 

  80. Mann RM, Hyne RV, Choung CB, Wilson SP (2009) Amphibians and agricultural chemicals: review of the risks in a complex environment. Environ Pollut 157(11):2903–2927

    Article  CAS  Google Scholar 

  81. Reeder AL, Ruiz MO, Pessier A, Brown LE, Levengood JM, Phillips CA, Wheeler MB, Warner RE, Beasley VR (2005) Intersexuality and the cricket frog decline: historic and geographic trends. Environ Health Perspect 113(3):261–265

    Article  Google Scholar 

  82. Hayes TB, Anderson LL, Beasley VR, de Solla SR, Iguchi T, Ingraham H, Kestemont P, Kniewald J, Kniewald Z, Langlois VS, Luque EH, McCoy KA, Munoz-de-Toro M, Oka T, Oliveira CA, Orton F, Ruby S, Suzawa M, Tavera-Mendoza LE, Trudeau VL, Victor-Costa AB, Willingham E (2011) Demasculinization and feminization of male gonads by atrazine: consistent effects across vertebrate classes. J Steroid Biochem Mol Biol 127(1–2):64–73

    Article  CAS  Google Scholar 

  83. Hayes TB, Khoury V, Narayan A, Nazir M, Park A, Brown T, Adame L, Chan E, Buchholz D, Stueve T, Gallipeau S (2010) Atrazine induces complete feminization and chemical castration in male African clawed frogs (Xenopus laevis). Proc Natl Acad Sci U S A 107(10):4612–4617

    Article  CAS  Google Scholar 

  84. Woodward AR, Percival HF, Jennings ML, Clinton TM (1993) Low clutch viability of American alligators. Fla Sci 56(1):52–63

    Google Scholar 

  85. Guillette LJ, Brock JW, Rooney AA, Woodward AR (1999) Serum concentrations of various environmental contaminants and their relationship to sex steroid concentrations and phallus size in juvenile American alligators. Arch Environ Contam Toxicol 36(4):447–455

    Article  CAS  Google Scholar 

  86. Heinz GH, Percival HF, Jennings ML (1991) Contaminants in American alligator eggs from Lake Apopka, Lake Griffin, and Lake Okeechobee, Florida. Environ Monit Assess 16(3):277–285

    Article  CAS  Google Scholar 

  87. Rauschenberger RH, Wiebe JJ, Sepulveda MS, Scarborough JE, Gross TS (2007) Parental exposure to pesticides and poor clutch viability in American alligators. Environ Sci Technol 41(15):5559–5563

    Article  CAS  Google Scholar 

  88. Guillette LJ, Gross TS, Masson GR, Matter JM, Percival HF, Woodward AR (1994) Developmental abnormalities of the gonad and abnormal sex-hormone concentrations in juvenile alligators from contaminated and control lakes in Florida. Environ Health Perspect 102(8):680–688

    Article  CAS  Google Scholar 

  89. Crain DA, Guillette LJ, Pickford DB, Percival HF, Woodward AR (1998) Sex-steroid and thyroid hormone concentrations in juvenile alligators (Alligator mississippiensis) from contaminated and reference lakes in Florida, USA. Environ Toxicol Chem 17(3):446–452

    Article  CAS  Google Scholar 

  90. Guillette LJ, Pickford DB, Crain DA, Rooney AA, Percival HF (1996) Reduction in penis size and plasma testosterone concentrations in juvenile alligators living in a contaminated environment. Gen Comp Endocrinol 101(1):32–42

    Article  CAS  Google Scholar 

  91. Crain DA, Guillette LJ (1998) Reptiles as models of contaminant-induced endocrine disruption. Anim Reprod Sci 53(1–4):77–86

    Article  CAS  Google Scholar 

  92. Guillette LJ Jr, Edwards TM, Moore BC (2007) Alligators, contaminants and steroid hormones. Environ Sci 14(6):331–347

    CAS  Google Scholar 

  93. Moore BC, Hamlin HJ, Botteri NL, Guillette LJ Jr (2010) Gonadal mRNA expression levels of TGF beta superfamily signaling factors correspond with post-hatching morphological development in American alligators. Sex Dev 4(1–2):62–72

    Article  CAS  Google Scholar 

  94. Moore BC, Milnes MR, Kohno S, Katsu Y, Iguchi T, Woodruff TK, Guillette LJ Jr (2011) Altered gonadal expression of TGF-beta superfamily signaling factors in environmental contaminant-exposed juvenile alligators. J Steroid Biochem Mol Biol 127(1–2):58–63

    Article  CAS  Google Scholar 

  95. Ratcliffe DA (1967) Decrease in eggshell weight in certain birds of prey. Nature 215(5097):208–210

    Article  CAS  Google Scholar 

  96. Bowerman WW, Giesy JP, Best DA, Kramer VJ (1995) A review of factors affecting productivity of bald eagles in the Great-lakes region - implications for recovery. Environ Health Perspect 103:51–59

    Article  CAS  Google Scholar 

  97. Fry DM (1995) Reproductive effects in birds exposed to pesticides and industrial-chemicals. Environ Health Perspect 103:165–171

    Article  CAS  Google Scholar 

  98. Ratcliffe DA (1970) Changes attributable to pesticides in egg breakage frequency and eggshell thickness in some British birds. J Appl Ecol 7(1):67–107

    Article  Google Scholar 

  99. Best DA, Elliott KH, Bowerman WW, Shieldcastle M, Postupalsky S, Kubiak TJ, Tillitt DE, Elliott JE (2010) Productivity, embryo and eggshell characteristics, and contaminants in bald eagles from the Great Lakes, USA, 1986 to 2000. Environ Toxicol Chem 29(7):1581–1592

    Article  CAS  Google Scholar 

  100. Bruggeman V, Swennen Q, De Ketelaere B, Onagbesan O, Tona K, Decuypere E (2003) Embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in chickens: effects of dose and embryonic stage on hatchability and growth. Comp Biochem Physiol Part C: Toxicol Pharmacol 136(1):17–28

    Article  CAS  Google Scholar 

  101. Fernie KJ, Shutt JL, Mayne G, Hoffman D, Letcher RJ, Drouillard KG, Ritchie IJ (2005) Exposure to polybrominated diphenyl ethers (PBDEs): changes in thyroid, vitamin A, glutathione homeostasis, and oxidative stress in American kestrels (Falco sparverius). Toxicol Sci 88(2):375–383

    Article  CAS  Google Scholar 

  102. Holm L, Blomqvist A, Brandt I, Brunstrom B, Ridderstrale Y, Berg C (2006) Embryonic exposure to o, p’-DDT causes eggshell thinning and altered shell gland carbonic anhydrase expression in the domestic hen. Environ Toxicol Chem 25(10):2787–2793

    Article  CAS  Google Scholar 

  103. Hoogesteijn AL, DeVoogd TJ, Quimby FW, De Caprio T, Kollias GV (2005) Reproductive impairment in zebra finches (Taeniopygia guttata). Environ Toxicol Chem 24(1):219–223

    Article  CAS  Google Scholar 

  104. Lundholm CE (1997) DDE-induced eggshell thinning in birds: effects of p, p’-DDE on the calcium and prostaglandin metabolism of the eggshell gland. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 118(2):113–128

    Article  CAS  Google Scholar 

  105. Quaglino AE, Craig-Veit CB, Viant MR, Erichsen AL, Fry DM, Millam JR (2002) Oral estrogen masculinizes female zebra finch song system. Horm Behav 41(2):236–241

    Article  CAS  Google Scholar 

  106. Rochester JR, Heiblum R, Rozenboim I, Millam JR (2008) Post-hatch oral estrogen exposure reduces oviduct and egg mass and alters nest-building behavior in adult zebra finches (Taeniopygia guttata). Physiol Behav 95(3):370–380

    Article  CAS  Google Scholar 

  107. Millam JR, Craig-Veit CB, Quaglino AE, Erichsen AL, Famula TR, Fry DM (2001) Posthatch oral estrogen exposure impairs adult reproductive performance of zebra finch in a sex-specific manner. Horm Behav 40(4):542–549

    Article  CAS  Google Scholar 

  108. Rochester JR, Forstmeier W, Millam JR (2010) Post-hatch oral estrogen in zebra finches (Taeniopygia guttata): is infertility due to disrupted testes morphology or reduced copulatory behavior? Physiol Behav 101(1):13–21

    Article  CAS  Google Scholar 

  109. Markman S, Leitner S, Catchpole C, Barnsley S, Mueller CT, Pascoe D, Buchanan KL (2008) Pollutants increase song complexity and the volume of the brain area HVC in a songbird. PLoS One 3(2)

    Google Scholar 

  110. Braune BM, Outridge PM, Fisk AT, Muir DCG, Helm PA, Hobbs K, Hoekstra PF, Kuzyk ZA, Kwan M, Letcher RJ, Lockhart WL, Norstrom RJ, Stern GA, Stirling I (2005) Persistent organic pollutants and mercury in marine biota of the Canadian Arctic: an overview of spatial and temporal trends. Sci Total Environ 351:4–56

    Article  CAS  Google Scholar 

  111. Letcher RJ, Bustnes JO, Dietz R, Jenssen BM, Jorgensen EH, Sonne C, Verreault J, Vijayan MM, Gabrielsen GW (2010) Exposure and effects assessment of persistent organohalogen contaminants in arctic wildlife and fish. Sci Total Environ 408(15):2995–3043

    Article  CAS  Google Scholar 

  112. Tanabe S (2002) Contamination and toxic effects of persistent endocrine disrupters in marine mammals and birds. Mar Pollut Bull 45(1–12):69–77

    Article  CAS  Google Scholar 

  113. Buckman AH, Veldhoen N, Ellis G, Ford JKB, Helbing CC, Ross PS (2011) PCB-associated changes in mRNA expression in killer whales (Orcinus orca) from the NE Pacific Ocean. Environ Sci Technol 45(23):10194–10202

    Article  CAS  Google Scholar 

  114. Routti H, Arukwe A, Jenssen BM, Letcher RJ, Nyman M, Backman C, Gabrielsen GW (2010) Comparative endocrine disruptive effects of contaminants in ringed seals (Phoca hispida) from Svalbard and the Baltic Sea. Comp Biochem Physiol Part C: Toxicol Pharmacol 152(3):306–312

    Google Scholar 

  115. Schwacke LH, Zolman ES, Balmer BC, De Guise S, George RC, Hoguet J, Hohn AA, Kucklick JR, Lamb S, Levin M, Litz JA, McFee WE, Place NJ, Townsend FI, Wells RS, Rowles TK (2012) Anaemia, hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus). Proc R Soc B Biol Sci 279(1726):48–57

    Article  CAS  Google Scholar 

  116. Villanger GD, Lydersen C, Kovacs KM, Lie E, Skaare JU, Jenssen BM (2011) Disruptive effects of persistent organohalogen contaminants on thyroid function in white whales (Delphinapterus leucas) from Svalbard. Sci Total Environ 409(13):2511–2524

    Article  CAS  Google Scholar 

  117. Van den Berg KJ, Zurcher C, Brouwer A, Vanbekkum DW (1988) Chronic toxicity of 3,4,3’,4’-tetrachlorobiphenyl in the marmoset monkey (Callithrix jacchus). Toxicology 48(2):209–224

    Article  Google Scholar 

  118. Iguchi T, Katsu Y (2008) Commonality in signaling of endocrine disruption from snail to human. Bioscience 58(11):1061–1067

    Article  Google Scholar 

  119. Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, Lee D-H, Shioda T, Soto AM, vom Saal FS, Welshons WV, Zoeller RT, Myers JP (2012) Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endoc Rev 33(3):378–455

    Google Scholar 

  120. Barouki R, Gluckman PD, Grandjean P, Hanson M, Heindel JJ (2012) Developmental origins of non-communicable disease: implications for research and public health. Environ Health 11:1–9, http://www.ehjournal.net/content/11/1/42

  121. Kortenkamp A (2007) Ten years of mixing cocktails: a review of combination effects of endocrine-disrupting chemicals. Environ Health Perspect 115:98–105

    Article  Google Scholar 

  122. Bern HA, Blair P, Brasseur S, Colborn T, Cunha GR, Davis W, Döhler KD, Fox G, Fry M, Gray LE, Green R, Hines MJKT, McLachlan J, Myers JP, Peterson RW, Reijnders PJH, Soto AM, Van Der Kraak G, vom Saal FS, Whitten P (1992) Statement from the work session on chemically-induced alterations in sexual development: the wildlife/human connection. In: Colborn T, Clement C (eds) Chemically-induced alterations in sexual and functional development: the wildlife/human connection. Advances in modern environmental toxicology, vol. xxi. Princeton Scientific Pub, Princeton, NJ, p 403

    Google Scholar 

  123. Kavlock RJ, Daston GP, DeRosa C, Fenner-Crisp P, Gray LE, Kaattari S, Lucier G, Luster M, Mac MJ, Maczka C, Miller R, Moore J, Rolland R, Scott G, Sheehan DM, Sinks T, Tilson HA (1996) Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. Environ Health Perspect 104(Suppl 4):715–740

    Google Scholar 

  124. European Commission (1996) Report of Proceedings: European Workshop on the Impact of Endocrine Disrupters on Human Health and Wildlife, Weybridge, UK, EUR 17549, European Commission, Environment and Climate Research Programme of DG XII, 2–4 December 1996

    Google Scholar 

  125. WHO/IPCS (2002) Global assessment of the state-of-the-science of endocrine disruptors. WHO publication no. WHO/PCS/EDC/02.2. International Programme on Chemical Safety, World Health Organisation, Geneva, Switzerland

    Google Scholar 

  126. Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, Woodruff TJ, Vom Saal FS (2012) Endocrine-disrupting chemicals and public health protection: a statement of principles from the Endocrine Society. Endocrinology

    Google Scholar 

  127. Germain P, Staels B, Dacquet C, Spedding M, Laudet V (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58(4):685–704

    Article  CAS  Google Scholar 

  128. Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3(11):950–964

    Article  CAS  Google Scholar 

  129. Rubin BS (2011) Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol 127(1–2):27–34

    Article  CAS  Google Scholar 

  130. Vandenberg LN, Maffini MV, Sonnenschein C, Rubin BS, Soto AM (2009) Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev 30(1):75–95

    Article  CAS  Google Scholar 

  131. Tabb MM, Blumberg B (2006) New modes of action for endocrine-disrupting chemicals. Mol Endocrinol 20(3):475–482

    Article  CAS  Google Scholar 

  132. Masuyama H, Hiramatsu Y, Kunitomi M, Kudo T, MacDonald PN (2000) Endocrine disrupting chemicals, phthalic acid and nonylphenol, activate Pregnane X receptor-mediated transcription. Mol Endocrinol 14(3):421–428

    Article  CAS  Google Scholar 

  133. Takeshita A, Igarashi-Migitaka J, Nishiyama K, Takahashi H, Takeuchi Y, Koibuchi N (2011) Acetyl tributyl citrate, the most widely used phthalate substitute plasticizer, induces cytochrome P450 3A through steroid and xenobiotic receptor. Toxicol Sci 123(2):460–470

    Article  CAS  Google Scholar 

  134. Takeshita A, Koibuchi N, Oka J, Taguchi M, Shishiba Y, Ozawa Y (2001) Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur J Endocrinol 145(4):513–517

    Article  CAS  Google Scholar 

  135. Mendiola J, Jorgensen N, Andersson A-M, Calafat AM, Ye X, Redmon JB, Drobnis EZ, Wang C, Sparks A, Thurston SW, Liu F, Swan SH (2010) Are environmental levels of bisphenol A associated with reproductive function in fertile men? Environ Health Perspect 118(9):1286–1291

    Article  CAS  Google Scholar 

  136. Aldad TS, Rahmani N, Leranth C, Taylor HS (2011) Bisphenol-A exposure alters endometrial progesterone receptor expression in the nonhuman primate. Fertil Steril 96(1):175–179

    Article  CAS  Google Scholar 

  137. Masuyama H, Hiramatsu Y (2004) Involvement of suppressor for Gal 1 in the ubiquitin/proteasome-mediated degradation of estrogen receptors. J Biol Chem 279(13):12020–12026

    Article  CAS  Google Scholar 

  138. Weigel NL, Moore NL (2007) Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol Endocrinol 21(10):2311–2319

    Article  CAS  Google Scholar 

  139. Gillesby BE, Zacharewski TR (1998) Exoestrogens: mechanisms of action and strategies for identification and assessment. Environ Toxicol Chem 17(1):3–14

    Article  CAS  Google Scholar 

  140. Zsarnovszky A, Le HH, Wang HS, Belcher SM (2005) Ontogeny of rapid estrogen-mediated extracellular signal-regulated kinase signaling in the rat cerebellar cortex: potent nongenomic agonist and endocrine disrupting activity of the xenoestrogen bisphenol A. Endocrinology 146(12):5388–5396

    Article  CAS  Google Scholar 

  141. le Maire A, Grimaldi M, Roecklin D, Dagnino S, Vivat-Hannah V, Balaguer P, Bourguet W (2009) Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors. EMBO Rep 10(4):367–373

    Article  CAS  Google Scholar 

  142. Inoshita H, Masuyama H, Hiramatsu Y (2003) The different effects of endocrine-disrupting chemicals on estrogen receptor-mediated transcription through interaction with coactivator TRAP220 in uterine tissue. J Mol Endocrinol 31(3):551–561

    Article  CAS  Google Scholar 

  143. Rüegg J, Swedenborg E, Wahlstroem D, Escande A, Balaguer P, Pettersson K, Pongratz I (2008) The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen receptor beta-selective coactivator, and its recruitment to alternative pathways mediates antiestrogenic effects of dioxin. Mol Endocrinol 22(2):304–316

    Article  CAS  Google Scholar 

  144. Safe S, Wormke M (2003) Inhibitory aryl hydrocarbon receptor-estrogen receptor a cross-talk and mechanisms of action. Chem Res Toxicol 16(7):807–816

    Article  CAS  Google Scholar 

  145. Swedenborg E, Ruegg J, Makela S, Pongratz I (2009) Endocrine disruptive chemicals: mechanisms of action and involvement in metabolic disorders. J Mol Endocrinol 43(1–2):1–10

    Article  CAS  Google Scholar 

  146. Crews D, Gillette R, Scarpino SV, Manikkam M, Savenkova MI, Skinner MK (2012) Epigenetic transgenerational inheritance of altered stress responses. Proc Natl Acad Sci U S A 109(23):9143–9148

    Article  CAS  Google Scholar 

  147. Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK (2013) Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One 8(1):e55387

    Google Scholar 

  148. Bjornstrom L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19(4):833–842

    Article  CAS  Google Scholar 

  149. Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M (2000) Multiple actions of steroid hormones: a focus on rapid, nongenomic effects. Pharmacol Rev 52(4):513–555

    CAS  Google Scholar 

  150. Watson CS, Jeng Y-J, Guptarak J (2011) Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways. J Steroid Biochem Mol Biol 127(1–2):44–50

    Article  CAS  Google Scholar 

  151. Mainini CG (1947) Pregnancy test using the male toad. J Clin Endocrinol Metab 7(9):653–658

    Article  Google Scholar 

  152. Bulbring E, Burn JH (1935) The estimation of oestrin and of male hormone in oily solution. J Physiol-Lond 85(3):320–333

    Article  CAS  Google Scholar 

  153. Korenchevsky V (1932) The assay of testicular hormone preparations. Biochem J 26:413–422

    Article  CAS  Google Scholar 

  154. Kanter AE, Bauer CP, Klawans AH (1934) A new biologic test for hormones in pregnancy urine: preliminary report. JAMA 103(26):2026–2027

    Article  Google Scholar 

  155. National Research Council (2007) Toxicity testing in the 21st century: a vision and a strategy, vol xvii. National Academies Press, Washington, DC, p 196

    Google Scholar 

  156. Langley G, Austin CP, Balapure AK, Birnbaum LS, Bucher JR, Fentem J, Fitzpatrick SC, Fowle JR III, Kavlock RJ, Kitano H, Lidbury BA, Muotri AR, Peng SQ, Sakharov D, Seidle T, Trez T, Tonevitsky A, van de Stolpe A, Whelan M, Willett C (2015) Lessons from toxicology: developing a 21st-century paradigm for medical research. Environ Health Perspect 123:A268–A272

    Article  Google Scholar 

  157. Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR, Nichols JW, Russom CL, Schmieder PK, Serrrano JA, Tietge JE, Villeneuve DL (2010) Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29(3):730–741

    Article  CAS  Google Scholar 

  158. Hultman MT, Rundberget JT, Tollefsen KE (2015) Evaluation of the sensitivity, responsiveness and reproducibility of primary rainbow trout hepatocyte vitellogenin expression as a screening assay for estrogen mimics. Aquat Toxicol 159:233–244

    Article  CAS  Google Scholar 

  159. Scrimshaw MD, Lester JN (2004) In-vitro assays for determination of oestrogenic activity. Anal Bioanal Chem 378(3):576–581

    Article  CAS  Google Scholar 

  160. Zacharewski T (1997) In vitro bioassays for assessing estrogenic substances. Environ Sci Technol 31(3):613–623

    Article  CAS  Google Scholar 

  161. de Jong LAA, Uges DRA, Franke JP, Bischoff R (2005) Receptor-ligand binding assays: technologies and applications. J Chromatogr B Analyt Technol Biomed Life Sci 829(1–2):1–25

    Article  CAS  Google Scholar 

  162. Hulme EC, Trevethick MA (2010) Ligand binding assays at equilibrium: validation and interpretation. Br J Pharmacol 161(6):1219–1237

    Article  CAS  Google Scholar 

  163. Chae K, Albro PW, Luster MI, Mckinney JD (1984) A screening assay for the tetrachlorodibenzo-para-dioxin receptor using the [iodovaleramide-i-125 derivative of trichlorodibenzo-para-dioxin as the binding ligand. Int J Environ Anal Chem 17(3–4):267–274

    Article  CAS  Google Scholar 

  164. Poland A, Glover E, Kende AS (1976) Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-para-dioxin by hepatic cytosol: evidence that binding species is receptor for induction of aryl-hydrocarbon hydroxylase. J Biol Chem 251(16):4936–4946

    CAS  Google Scholar 

  165. Yost EE, Pow CL, Hawkins MB, Kullman SW (2014) Bridging the gap from screening assays to estrogenic effects in fish: potential roles of multiple estrogen receptor subtypes. Environ Sci Technol 48(9):5211–5219

    Article  CAS  Google Scholar 

  166. Fang ML, Webster TF, Ferguson PL, Stapleton HM (2015) Characterizing the peroxisome proliferator-activated receptor (PPAR gamma) ligand binding potential of several major flame retardants, their metabolites, and chemical mixtures in house dust. Environ Health Perspect 123(2):166–172

    CAS  Google Scholar 

  167. Wagner M, Vermeirssen ELM, Buchinger S, Behr M, Magdeburg A, Oehlmann J (2013) Deriving bio-equivalents from in vitro bioassays: assessment of existing uncertainties and strategies to improve accuracy and reporting. Environ Toxicol Chem 32(8):1906–1917

    Article  CAS  Google Scholar 

  168. Martin MT, Dix DJ, Judson RS, Kavlock RJ, Reif DM, Richard AM, Rotroff DM, Romanov S, Medvedev A, Poltoratskaya N, Gambarian M, Moeser M, Makarov SS, Houck KA (2010) Impact of environmental chemicals on key transcription regulators and correlation to toxicity end points within EPA’s ToxCast program. Chem Res Toxicol 23(3):578–590

    Article  CAS  Google Scholar 

  169. Escher BI, Allinson M, Altenburger R, Bain PA, Balaguer P, Busch W, Crago J, Denslow ND, Dopp E, Hilscherova K, Humpage AR, Kumar A, Grimaldi M, Jayasinghe BS, Jarosova B, Jia A, Makarov S, Maruya KA, Medvedev A, Mehinto AC, Mendez JE, Poulsen A, Prochazka E, Richard J, Schifferli A, Schlenk D, Scholz S, Shiraish F, Snyder S, Su GY, Tang JYM, van der Burg B, van der Linden SC, Werner I, Westerheide SD, Wong CKC, Yang M, Yeung BHY, Zhang XW, Leusch FDL (2014) Benchmarking organic micropollutants in wastewater, recycled water and drinking water with in vitro bioassays. Environ Sci Technol 48(3):1940–1956

    Article  CAS  Google Scholar 

  170. Purvis IJ, Chotai D, Dykes CW, Lubahn DB, French FS, Wilson EM, Hobden AN (1991) An androgen-inducible expression system for Saccharomyces cerevisiae. Gene 106(1):35–42

    Article  CAS  Google Scholar 

  171. Routledge EJ, Sumpter JP (1996) Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen. Environ Toxicol Chem 15(3):241–248

    Article  CAS  Google Scholar 

  172. Sohoni P, Sumpter JP (1998) Several environmental oestrogens are also anti-androgens. J Endocrinol 158(3):327–339

    Article  CAS  Google Scholar 

  173. Beresford N, Routledge EJ, Harris CA, Sumpter JP (2000) Issues arising when interpreting results from an in vitro assay for estrogenic activity. Toxicol Appl Pharmacol 162(1):22–33

    Article  CAS  Google Scholar 

  174. Dhooge W, Arijs K, D’Haese I, Stuyvaert S, Versonnen B, Janssen C, Verstraete W, Comhaire F (2006) Experimental parameters affecting sensitivity and specificity of a yeast assay for estrogenic compounds: results of an interlaboratory validation exercise. Anal Bioanal Chem 386(5):1419–1428

    Article  CAS  Google Scholar 

  175. Murk AJ, Legler J, van Lipzig MMH, Meerman JHN, Belfroid AC, Spenkelink A, van der Burg B, Rijs GBJ, Vethaak D (2002) Detection of estrogenic potency in wastewater and surface water with three in vitro bioassays. Environ Toxicol Chem 21(1):16–23

    Article  CAS  Google Scholar 

  176. Wagner M, Oehlmann J (2011) Endocrine disruptors in bottled mineral water: estrogenic activity in the E-Screen. J Steroid Biochem Mol Biol 127(1–2):128–135

    Article  CAS  Google Scholar 

  177. Wagner M, Schlusener MP, Ternes TA, Oehlmann J (2013) Identification of putative steroid receptor antagonists in bottled water: combining bioassays and high-resolution mass spectrometry. PLoS One 8(8), e72472

    Article  CAS  Google Scholar 

  178. De Boever P, Demare W, Vanderperren E, Cooreman K, Bossier P, Verstraete W (2001) Optimization of a yeast estrogen screen and its applicability to study the release of estrogenic isoflavones from a soygerm powder. Environ Health Perspect 109(7):691–697

    Article  Google Scholar 

  179. Schultis T, Metzger JW (2004) Determination of estrogenic activity by LYES-assay (yeast estrogen screen-assay assisted by enzymatic digestion with lyticase). Chemosphere 57(11):1649–1655

    Article  CAS  Google Scholar 

  180. Routledge EJ, Parker J, Odum J, Ashby J, Sumpter JP (1998) Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicol Appl Pharmacol 153(1):12–19

    Article  CAS  Google Scholar 

  181. Lyttle CR, Damianmatsumura P, Juul H, Butt TR (1992) Human estrogen-receptor regulation in a yeast model system and studies on receptor agonists and antagonists. J Steroid Biochem Mol Biol 42(7):677–685

    Article  CAS  Google Scholar 

  182. Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, Omalley BW, McGuire WL (1991) Variant human breast-tumor estrogen-receptor with constitutive transcriptional activity. Cancer Res 51(1):105–109

    CAS  Google Scholar 

  183. McDonnell DP, Nawaz Z, Densmore C, Weigel NL, Pham TA, Clark JH, Omalley BW (1991) High-level expression of biologically-active estrogen-receptor in Saccharomyces cerevisiae. J Steroid Biochem Mol Biol 39(3):291–297

    Article  CAS  Google Scholar 

  184. McDonnell DP, Nawaz Z, Omalley BW (1991) In situ distinction between steroid-receptor binding and transactivation at a target gene. Mol Cell Biol 11(9):4350–4355

    Article  CAS  Google Scholar 

  185. Inoue D, Nakama K, Matsui H, Sei K, Ike M (2009) Detection of agonistic activities against five human nuclear receptors in river environments of Japan using a yeast two-hybrid assay. Bull Environ Contam Toxicol 82(4):399–404

    Article  CAS  Google Scholar 

  186. Miller CA, Tan XB, Wilson M, Bhattacharyya S, Ludwig S (2010) Single plasmids expressing human steroid hormone receptors and a reporter gene for use in yeast signaling assays. Plasmid 63(2):73–78

    Article  CAS  Google Scholar 

  187. Hahn T, Tag K, Riedel K, Uhlig S, Baronian K, Gellissen G, Kunze G (2006) A novel estrogen sensor based on recombinant Arxula adeninivorans cells. Biosens Bioelectron 21(11):2078–2085

    Article  CAS  Google Scholar 

  188. Bovee TFH, Helsdingen RJR, Hamers ARM, van Duursen MBM, Nielen MWF, Hoogenboom RLAP (2007) A new highly specific and robust yeast androgen bioassay for the detection of agonists and antagonists. Anal Bioanal Chem 389(5):1549–1558

    Article  CAS  Google Scholar 

  189. Kamata R, Shiraishi F, Nakajima D, Takigami H, Shiraishi H (2009) Mono-hydroxylated polychlorinated biphenyls are potent aryl hydrocarbon receptor ligands in recombinant yeast cells. Toxicol in Vitro 23(4):736–743

    Article  CAS  Google Scholar 

  190. Lee HJ, Lee YS, Kwon HB, Lee K (2003) Novel yeast bioassay system for detection of androgenic and antiandrogenic compounds. Toxicol in Vitro 17(2):237–244

    Article  CAS  Google Scholar 

  191. Leskinen P, Michelini E, Picard D, Karp M, Virta M (2005) Bioluminescent yeast assays for detecting estrogenic and androgenic activity in different matrices. Chemosphere 61(2):259–266

    Article  CAS  Google Scholar 

  192. Miller CA (1997) Expression of the human aryl hydrocarbon receptor complex in yeast: activation of transcription by indole compounds. J Biol Chem 272(52):32824–32829

    Article  CAS  Google Scholar 

  193. Miller CA, Martinat MA, Hyman LE (1998) Assessment of aryl hydrocarbon receptor complex interactions using pBEVY plasmids: expression vectors with bi-directional promoters for use in Saccharomyces cerevisiae. Nucleic Acids Res 26(15):3577–3583

    Article  CAS  Google Scholar 

  194. Bovee TFH, Helsdingen RJR, Hamers ARM, Brouwer BA, Nielen MWF (2011) Recombinant cell bioassays for the detection of (gluco)corticosteroids and endocrine-disrupting potencies of several environmental PCB contaminants. Anal Bioanal Chem 401(3):873–882

    Article  CAS  Google Scholar 

  195. Gaido KW, Leonard LS, Lovell S, Gould JC, Babai D, Portier CJ, McDonnell DP (1997) Evaluation of chemicals with endocrine modulating activity in a yeast-based steroid hormone receptor gene transcription assay. Toxicol Appl Pharmacol 143(1):205–212

    Article  CAS  Google Scholar 

  196. Garcia-Reyero N, Grau E, Castillo M, De Alda MJL, Barcelo D, Pina B (2001) Monitoring of endocrine disruptors in surface waters by the yeast recombinant assay. Environ Toxicol Chem 20(6):1152–1158

    Article  CAS  Google Scholar 

  197. Ito-Harashima S, Shiizaki K, Kawanishi M, Kakiuchi K, Onishi K, Yamaji R, Yagi T (2015) Construction of sensitive reporter assay yeasts for comprehensive detection of ligand activities of human corticosteroid receptors through inactivation of CWP and PDR genes. J Pharmacol Toxicol Methods 74:41–52

    Article  CAS  Google Scholar 

  198. Inoue D, Nakama K, Sawada K, Watanabe T, Takagi M, Sei K, Yang M, Hirotsuji J, Hu J, Nishikawa J-I, Nakanishi T, Ike M (2010) Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan. Water Res 44(8):2409–2418

    Article  CAS  Google Scholar 

  199. Kamata R, Shiraishi F, Nishikawa J-I, Yonemoto J, Shiraishi H (2008) Screening and detection of the in vitro agonistic activity of xenobiotics on the retinoic acid receptor. Toxicol in Vitro 22(4):1050–1061

    Article  CAS  Google Scholar 

  200. Li J, Ma M, Wang ZJ (2008) A two-hybrid yeast assay to quantify the effects of xenobiotics on retinoid X receptor-mediated gene expression. Toxicol Lett 176(3):198–206

    Article  CAS  Google Scholar 

  201. Zhen H, Wu X, Hu J, Xiao Y, Yang M, Hirotsuji J, Nishikawa J-I, Nakanishi T, Ike M (2009) Identification of retinoic acid receptor agonists in sewage treatment plants. Environ Sci Technol 43(17):6611–6616

    Article  CAS  Google Scholar 

  202. Kitagawa Y, Takatori S, Oda H, Nishikawa J, Nishihara T, Nakazawa H, Hori S (2003) Detection of thyroid hormone receptor-binding activities of chemicals using a yeast two-hybrid assay. J Health Sci 49(2):99–104

    Article  CAS  Google Scholar 

  203. Shiraishi F, Okumura T, Nomachi M, Serizawa S, Nishikawa J, Edmonds JS, Shiraishi H, Morita M (2003) Estrogenic and thyroid hormone activity of a series of hydroxy-polychlorinated biphenyls. Chemosphere 52(1):33–42

    Article  CAS  Google Scholar 

  204. Rajasarkka J, Hakkila K, Virta M (2011) Developing a compound-specific receptor for bisphenol A by directed evolution of human estrogen receptor alpha. Biotechnol Bioeng 108(11):2526–2534

    Article  CAS  Google Scholar 

  205. Rajasarkka J, Virta M (2013) Characterization of a bisphenol A specific yeast bioreporter utilizing the bisphenol A-targeted receptor. Anal Chem 85(21):10067–10074

    Article  CAS  Google Scholar 

  206. Rajasarkka J, Koponen J, Airaksinen R, Kiviranta H, Virta M (2014) Monitoring bisphenol A and estrogenic chemicals in thermal paper with yeast-based bioreporter assay. Anal Bioanal Chem 406(23):5695–5702

    Article  CAS  Google Scholar 

  207. Murk AJ, Legler J, Denison MS, Giesy JP, van de Guchte C, Brouwer A (1996) Chemical-activated luciferase gene expression (CALUX): a novel in vitro bioassay for Ah receptor active compounds in sediments and pore water. Fundam Appl Toxicol 33(1):149–160

    Article  CAS  Google Scholar 

  208. Aarts JMMJG, Denison MS, Cox MA, Schalk MAC, Garrison PM, Tullis K, Dehaan LHJ, Brouwer A (1995) Species-specific antagonism of Ah receptor action by 2,2’,5,5’-tetrachlorobiphenyl and 2,2’,3,3’,4,4’-hexachlorobiphenyl. Eur J Pharmacol Environ Toxicol Pharmacol 293(4):463–474

    Article  CAS  Google Scholar 

  209. Garrison PM, Tullis K, Aarts JMMJG, Brouwer A, Giesy JP, Denison MS (1996) Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals. Fundam Appl Toxicol 30(2):194–203

    Article  CAS  Google Scholar 

  210. Legler J, van den Brink CE, Brouwer A, Murk AJ, van der Saag PT, Vethaak AD, van der Burg P (1999) Development of a stably transfected estrogen receptor-mediated luciferase reporter gene assay in the human T47D breast cancer cell line. Toxicol Sci 48(1):55–66

    Article  CAS  Google Scholar 

  211. Sonneveld E, Jansen HJ, Riteco JAC, Brouwer A, van der Burg B (2005) Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Toxicol Sci 83(1):136–148

    Article  CAS  Google Scholar 

  212. Gijsbers L, Man H-Y, Kloet SK, de Haan LHJ, Keijer J, Rietjens IMCM, van der Burg B, Aarts JMMJG (2011) Stable reporter cell lines for peroxisome proliferator-activated receptor gamma (PPAR gamma)-mediated modulation of gene expression. Anal Biochem 414(1):77–83

    Article  CAS  Google Scholar 

  213. Piersma AH, Bosgra S, van Duursen MBM, Hermsen SAB, Jonker LRA, Kroese ED, van der Linden SC, Man H, Roelofs MJE, Schulpen SHW, Schwarz M, Uibel F, van Vugt-Lussenburg BMA, Westerhout J, Wolterbeek APM, van der Burg B (2013) Evaluation of an alternative in vitro test battery for detecting reproductive toxicants. Reprod Toxicol 38:53–64

    Article  CAS  Google Scholar 

  214. van der Burg B, van der Linden S, Man H-Y, Winter R, Jonker L, van Vugt-Lussenburg B, Brouwer A (2013) A panel of quantitative calux® reporter gene assays for reliable high-throughput toxicity screening of chemicals and complex mixtures, p 532

    Google Scholar 

  215. Brennan JC, He G, Tsutsumi T, Zhao J, Wirth E, Fulton MH, Denison MS (2015) Development of species-specific Ah receptor-responsive third generation CALUX cell lines with enhanced responsiveness and improved detection limits. Environ Sci Technol 49(19):11903–11912

    Article  CAS  Google Scholar 

  216. Gizzi G, Hoogenboom LAP, Von Holst C, Rose M, Anklam E (2005) Determination of dioxins (PCDDs/PCDFs) and PCBs in food and feed using the DR CALUX (R) bioassay: results of an international validation study. Food Addit Contam 22(5):472–481

    Article  CAS  Google Scholar 

  217. He G, Tsutsumi T, Zhao B, Baston DS, Zhao J, Heath-Pagliuso S, Denison MS (2011) Third-generation Ah receptor-responsive luciferase reporter plasmids: amplification of dioxin-responsive elements dramatically increases CALUX bioassay sensitivity and responsiveness. Toxicol Sci 123(2):511–522

    Article  CAS  Google Scholar 

  218. Pieterse B, Felzel E, Winter R, van der Burg B, Brouwer A (2013) PAH-CALUX, an optimized bioassay for AhR-mediated hazard identification of polycyclic aromatic hydrocarbons (PAHs) as individual compounds and in complex mixtures. Environ Sci Technol 47(20):11651–11659

    Article  CAS  Google Scholar 

  219. van der Burg B, Winter R, Man H-Y, Vangenechten C, Berckmans P, Weimer M, Witters H, van der Linden S (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reproductive Toxicology 30(1):18–24

    Article  CAS  Google Scholar 

  220. van der Burg B, Winter R, Weimer M, Berckmans P, Suzuki G, Gijsbers L, Jonas A, van der Linden S, Witters H, Aarts J, Legler J, Kopp-Schneider A, Bremer S (2010) Optimization and prevalidation of the in vitro ER alpha CALUX method to test estrogenic and antiestrogenic activity of compounds. Reprod Toxicol 30(1):73–80

    Article  CAS  Google Scholar 

  221. Van Loco J, Van Leeuwen SPJ, Roos P, Carbonnelle S, de Boer J, Goeyens L, Beernaert H (2004) The international validation of bio- and chemical-analytical screening methods for dioxins and dioxin-like PCBs: the DIFFERENCE project rounds 1 and 2. Talanta 63(5):1169–1182

    Article  CAS  Google Scholar 

  222. Windal I, Denison MS, Birnbaum LS, Van Wouwe N, Baeyens W, Goeyens L (2005) Chemically activated luciferase gene expression (CALUX) cell bioassay analysis for the estimation of dioxin-like activity: critical parameters of the CALUX procedure that impact assay results. Environ Sci Technol 39(19):7357–7364

    Article  CAS  Google Scholar 

  223. Anezaki K, Yamaguchi K, Takeuchi S, Iida M, Jin K, Kojima H (2009) Application of a bioassay using DR-Ecoscreen cells to the determination of dioxins in ambient air: a comparative study with HRGC-HRMS analysis. Environ Sci Technol 43(19):7478–7483

    Article  CAS  Google Scholar 

  224. Besselink HT, Schipper C, Klamer H, Leonards P, Verhaar H, Felzel E, Murk AJ, Thain J, Hosoe K, Schoeters G, Legler J, Brouwer B (2004) Intra- and interlaboratory calibration of the DR Calux (R) bioassay for the analysis of dioxins and dioxin-like chemicals in sediments. Environ Toxicol Chem 23(12):2781–2789

    Article  Google Scholar 

  225. Bovee TFH, Heskamp HH, Helsdingen RJR, Hamers ARM, Brouwer BA, Nielen MWF (2013) Validation of a recombinant cell bioassay for the detection of (gluco)corticosteroids in feed. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 30(2):264–271

    Article  CAS  Google Scholar 

  226. Bovee TFH, Hoogenboom LAP, Hamers ARM, Traag WA, Zuidema T, Aarts J, Brouwer A, Kuiper HA (1998) Validation and use of the CALUX-bioassay for the determination of dioxins and PCBs in bovine milk. Food Addit Contam 15(8):863–875

    Article  CAS  Google Scholar 

  227. Chou IC, Lee W-J, Wang L-C, Chang-Chien G-P, Lee W-S, Lee H (2008) Validation of the CALUX bioassay as a screening and semi-quantitative method for PCDD/F levels in cow’s milk. J Hazard Mater 154(1–3):1166–1172

    Article  CAS  Google Scholar 

  228. Sonneveld E, Pieterse B, Schoonen WG, van der Burg B (2011) Validation of in vitro screening models for progestagenic activities: inter-assay comparison and correlation with in vivo activity in rabbits. Toxicol in Vitro 25(2):545–554

    Article  CAS  Google Scholar 

  229. Tsutsumi T, Amakura Y, Nakamura M, Brown DJ, Clark GC, Sasaki K, Toyoda M, Maitani T (2003) Validation of the CALUX bioassay for the screening of PCDD/Fs and dioxin-like PCBs in retail fish. Analyst 128(5):486–492

    Article  CAS  Google Scholar 

  230. Windal I, Van Wouwe N, Eppe G, Xhrouet C, Debacker V, Baeyens W, De Pauw E, Goeyens L (2005) Validation and interpretation of CALUX as a tool for the estimation of dioxin-like activity in marine biological matrixes. Environ Sci Technol 39(6):1741–1748

    Article  CAS  Google Scholar 

  231. Wilson VS, Bobseine K, Gray LE (2004) Development and characterization of a cell line that stably expresses an estrogen-responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicol Sci 81(1):69–77

    Article  CAS  Google Scholar 

  232. Balaguer P, Francois F, Comunale F, Fenet H, Boussioux AM, Pons M, Nicolas JC, Casellas C (1999) Reporter cell lines to study the estrogenic effects of xenoestrogens. Sci Total Environ 233(1–3):47–56

    Article  CAS  Google Scholar 

  233. Jugan ML, Oziol L, Bimbot M, Huteau V, Tamisier-Karolak S, Blondeau JP, Levi Y (2009) In vitro assessment of thyroid and estrogenic endocrine disruptors in wastewater treatment plants, rivers and drinking water supplies in the greater Paris area (France). Sci Total Environ 407(11):3579–3587

    Article  CAS  Google Scholar 

  234. Wehmas LC, Cavallin JE, Durhan EJ, Kahl MD, Martinovic D, Mayasich J, Tuominen T, Villeneuve DL, Ankley GT (2011) Screening complex effluents for estrogenic activity with the T47D-kbluc cell bioassay: assay optimization and comparison with in vivo responses in fish. Environ Toxicol Chem 30(2):439–445

    Article  CAS  Google Scholar 

  235. Grimaldi M, Boulahtouf A, Delfosse V, Thouennon E, Bourguet W, Balaguer P (2015) Reporter cell lines for the characterization of the interactions between human nuclear receptors and endocrine disruptors. Front Endocrinol 6:62–62

    Article  Google Scholar 

  236. Nguyen LP, Bradfield CA (2008) The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21(1):102–116

    Article  CAS  Google Scholar 

  237. Tian J, Feng Y, Fu H, Xie HQ, Jiang JX, Zhao B (2015) The aryl hydrocarbon receptor: a key bridging molecule of external and internal chemical signals. Environ Sci Technol 49(16):9518–9531

    Article  CAS  Google Scholar 

  238. Fritsche E, Schaefer C, Calles C, Bernsmann T, Bernshausen T, Wurm M, Huebenthal U, Cline JE, Hajimiragha H, Schroeder P, Klotz L-O, Rannug A, Fuerst P, Hanenberg H, Abel J, Krutmann J (2007) Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci U S A 104(21):8851–8856

    Article  CAS  Google Scholar 

  239. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478(7368):197–203

    Article  CAS  Google Scholar 

  240. Beischlag TV, Morales JL, Hollingshead BD, Perdew GH (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 18(3):207–250

    Article  CAS  Google Scholar 

  241. Tijet N, Boutros PC, Moffat ID, Okey AB, Tuomisto J, Pohjanvirta R (2006) Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries. Mol Pharmacol 69(1):140–153

    CAS  Google Scholar 

  242. Mandal PK (2005) Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J Comp Physiol B 175(4):221–230

    Article  CAS  Google Scholar 

  243. Doolittle DJ, Newton JF, Goodman JI (1983) Quantitative studies on metabolic-activation in vitro employing benzo[a]pyrene as the test compound. Mutat Res 108(1–3):29–44

    Article  CAS  Google Scholar 

  244. Doolittle DJ, Goodman JI (1984) Quantitative studies on the in vitro metabolic-activation of dimethylnitrosamine by rat-liver postmitochondrial supernatant. Environ Health Perspect 57(Aug):327–332

    Article  CAS  Google Scholar 

  245. Mason G, Farrell K, Keys B, Piskorskapliszczynska J, Safe L, Safe S (1986) Polychlorinated dibenzo-para-dioxins: quantitative in vitro and in vivo structure-activity-relationships. Toxicology 41(1):21–31

    Article  CAS  Google Scholar 

  246. Piskorska-Pliszczynska J, Keys B, Safe S, Newman MS (1986) The cytosolic receptor-binding affinities and AHH induction potencies of 29 polynuclear aromatic-hydrocarbons. Toxicol Lett 34(1):67–74

    Article  CAS  Google Scholar 

  247. Safe S (1987) Determination of 2,3,7,8-Tcdd toxic equivalent factors (TEFs): support for the use of the in vitro AHH induction assay. Chemosphere 16(4):791–802

    Article  CAS  Google Scholar 

  248. Van den Berg M, Birnbaum L, Bosveld ATC, Brunstrom B, Cook P, Feeley M, Giesy JP, Hanberg A, Hasegawa R, Kennedy SW, Kubiak T, Larsen JC, van Leeuwen FXR, Liem AKD, Nolt C, Peterson RE, Poellinger L, Safe S, Schrenk D, Tillitt D, Tysklind M, Younes M, Waern F, Zacharewski T (1998) Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect 106(12):775–792

    Article  Google Scholar 

  249. Van den Berg M, Birnbaum LS, Denison M, De Vito M, Farland W, Feeley M, Fiedler H, Hakansson H, Hanberg A, Haws L, Rose M, Safe S, Schrenk D, Tohyama C, Tritscher A, Tuomisto J, Tysklind M, Walker N, Peterson RE (2006) The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicol Sci 93(2):223–241

    Article  CAS  Google Scholar 

  250. Soto AM, Chung KL, Sonnenschein C (1994) The pesticides endosulfan, toxaphene, and dieldrin have estrogenic effects on human estrogen-sensitive cells. Environ Health Perspect 102(4):380–383

    Article  CAS  Google Scholar 

  251. Soto AM, Sonnenschein C (1985) The role of estrogens on the proliferation of human breast tumor cells (MCF-7). J Steroid Biochem Mol Biol 23(1):87–94

    Article  CAS  Google Scholar 

  252. Soto AM, Sonnenschein C, Chung KL, Fernandez MF, Olea N, Serrano FO (1995) The E-Screen assay as a tool to identify estrogens: an update on estrogenic environmental-pollutants. Environ Health Perspect 103:113–122

    Article  CAS  Google Scholar 

  253. Villalobos M, Olea N, Brotons JA, Oleaserrano MF, Dealmodovar JMR, Pedraza V (1995) The E-Screen assay: a comparison of different MCF7 cell stocks. Environ Health Perspect 103(9):844–850

    Article  CAS  Google Scholar 

  254. Desaulniers D, Leingartner K, Zacharewski T, Foster WG (1998) Optimization of an MCF7-E3 cell proliferation assay and effects of environmental pollutants and industrial chemicals. Toxicol in Vitro 12(4):409–422

    Article  CAS  Google Scholar 

  255. Korner W, Hanf V, Schuller W, Kempter C, Metzger J, Hagenmaier H (1999) Development of a sensitive E-screen assay for quantitative analysis of estrogenic activity in municipal sewage plant effluents. Sci Total Environ 225(1–2):33–48

    Article  CAS  Google Scholar 

  256. Rasmussen TH, Nielsen JB (2002) Critical parameters in the MCF-7 cell proliferation bioassay (E-Screen). Biomarkers 7(4):322–336

    Article  CAS  Google Scholar 

  257. Vanparys C, Maras M, Lenjou M, Robbens J, Van Bockstaele D, Blust R, De Coen W (2006) Flow cytometric cell cycle analysis allows for rapid screening of estrogenicity in MCF-7 breast cancer cells. Toxicol in Vitro 20(7):1238–1248

    Article  CAS  Google Scholar 

  258. Riverso M, Kortenkamp A, Silva E (2014) Non-tumorigenic epithelial cells secrete MCP-1 and other cytokines that promote cell division in breast cancer cells by activating ER alpha via PI3K/Akt/mTOR signaling. Int J Biochem Cell Biol 53:281–294

    Article  CAS  Google Scholar 

  259. Gutleb AC, Meerts I, Bergsma JH, Schriks M, Murk AJ (2005) T-Screen as a tool to identify thyroid hormone receptor active compounds. Environ Toxicol Pharmacol 19(2):231–238

    Article  CAS  Google Scholar 

  260. Schriks M, Vrabie CM, Gutleb AC, Faassen EJ, Rietjens I, Murk AJ (2006) T-screen to quantify functional potentiating, antagonistic and thyroid hormone-like activities of poly halogenated aromatic hydrocarbons (PHAHs). Toxicol in Vitro 20(4):490–498

    Article  CAS  Google Scholar 

  261. Gutleb AC, Mossink L, Schriks M, van den Berg HJH, Murk AJ (2007) Delayed effects of environmentally relevant concentrations of 3,3’,4,4’-tetrachlorobiphenyl (PCB-77) and non-polar sediment extracts detected in the prolonged-FETAX. Sci Total Environ 381(1–3):307–315

    Article  CAS  Google Scholar 

  262. Taxvig C, Vinggaard AM, Hass U, Axelstad M, Boberg J, Hansen PR, Frederiksen H, Nellemann C (2008) Do parabens have the ability to interfere with steroidogenesis? Toxicol Sci 106(1):206–213

    Article  CAS  Google Scholar 

  263. Ghisari M, Bonefeld-Jorgensen EC (2009) Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol Lett 189(1):67–77

    Article  CAS  Google Scholar 

  264. Long M, Kruger T, Ghisari M, Bonefeld-Jorgensen EC (2012) Effects of selected phytoestrogens and their mixtures on the function of the thyroid hormone and the aryl hydrocarbon receptor. Nutr Cancer 64(7):1008–1019

    Article  CAS  Google Scholar 

  265. Long M, Ghisari M, Bonefeld-Jorgensen EC (2013) Effects of perfluoroalkyl acids on the function of the thyroid hormone and the aryl hydrocarbon receptor. Environ Sci Pollut Res 20(11):8045–8056

    Article  CAS  Google Scholar 

  266. Ghisari M, Long M, Tabbo A, Bonefeld-Jorgensen EC (2015) Effects of currently used pesticides and their mixtures on the function of thyroid hormone and aryl hydrocarbon receptor in cell culture. Toxicol Appl Pharmacol 284(3):292–303

    Article  CAS  Google Scholar 

  267. Sanderson JT (2006) The steroid hormone biosynthesis pathway as a target for endocrine-disrupting chemicals. Toxicol Sci 94(1):3–21

    Article  CAS  Google Scholar 

  268. Connolly L, Ropstad E, Verhaegen S (2011) In vitro bioassays for the study of endocrine-disrupting food additives and contaminants. TrAC Trends Anal Chem 30(2):227–238

    Article  CAS  Google Scholar 

  269. OECD (2011) Test no. 456: H295R steroidogenesis assay. OECD, Paris. doi: 10.1787/9789264122642-en

  270. US EPA (2009) Endocrine disruptor screening program test guidelines. OPPTS 890.1550: steroidogenesis (human cell line – H295R). Office of Prevention, Pesticides and Toxic Substances, United States Environmental Protection Agency

    Google Scholar 

  271. Harvey PW, Everett DJ, Springall CJ (2007) Adrenal toxicology: a strategy for assessment of functional toxicity to the adrenal cortex and steroidogenesis. J Appl Toxicol 27(2):103–115

    Article  CAS  Google Scholar 

  272. Zhang XW, Yu RMK, Jones PD, Lam GKW, Newsted JL, Gracia T, Hecker M, Hilscherova K, Sanderson JT, Wu RSS, Giesy JP (2005) Quantitative RT-PCR methods for evaluating toxicant-induced effects on steroidogenesis using the H295R cell line. Environ Sci Technol 39(8):2777–2785

    Article  CAS  Google Scholar 

  273. Hecker M, Hollert H, Cooper R, Vinggaard AM, Akahori Y, Murphy M, Nellemann C, Higley E, Newsted J, Laskey J, Buckalew A, Grund S, Maletz S, Giesy J, Timm G (2011) The OECD validation program of the H295R steroidogenesis assay: phase 3. Final inter-laboratory validation study. Environ Sci Pollut Res 18(3):503–515

    Article  CAS  Google Scholar 

  274. Hilscherova K, Jones PD, Gracia T, Newsted JL, Zhang XW, Sanderson JT, Yu RMK, Wu RSS, Giesy JP (2004) Assessment of the effects of chemicals on the expression of ten steroidogenic genes in the H295R cell line using real-time PCR. Toxicol Sci 81(1):78–89

    Article  CAS  Google Scholar 

  275. Maglich JM, Kuhn M, Chapin RE, Pletcher MT (2014) More than just hormones: H295R cells as predictors of reproductive toxicity. Reprod Toxicol 45:77–86

    Article  CAS  Google Scholar 

  276. Antczak P, Jo HJ, Woo S, Scanlan L, Poynton H, Loguinov A, Chan S, Falciani F, Vulpe C (2013) Molecular toxicity identification evaluation (mTIE) approach predicts chemical exposure in Daphnia magna. Environ Sci Technol 47(20):11747–11756

    Article  CAS  Google Scholar 

  277. Bundy JG, Davey MP, Viant MR (2009) Environmental metabolomics: a critical review and future perspectives. Metabolomics 5(1):3–21

    Article  CAS  Google Scholar 

  278. Iguchi T, Watanabe H, Katsu Y (2007) Toxicogenomics and ecotoxicogenomics for studying endocrine disruption and basic biology. Gen Comp Endocrinol 153(1–3):25–29

    Article  CAS  Google Scholar 

  279. Grun F, Blumberg B (2006) Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling. Endocrinology 147(6, Suppl. S):S50–S55

    Google Scholar 

  280. Jordao R, Casas J, Fabrias G, Campos B, Pina B, Lemos MFL, Soares AMVM, Tauler R, Barata C (2015) Obesogens beyond vertebrates: lipid perturbation by tributyltin in the crustacean Daphnia magna. Environ Health Perspect 123(8):813–819

    Google Scholar 

  281. Alsop DH, Brown SB, van der Kraak GJ (2004) Dietary retinoic acid induces hindlimb and eye deformities in Xenopus laevis. Environ Sci Technol 38(23):6290–6299

    Article  CAS  Google Scholar 

  282. Chen C-H, Chou P-H, Kawanishi M, Yagi T (2014) Occurrence of xenobiotic ligands for retinoid X receptors and thyroid hormone receptors in the aquatic environment of Taiwan. Mar Pollut Bull 85(2):613–618

    Article  CAS  Google Scholar 

  283. Inoue D, Nakama K, Sawada K, Watanabe T, Matsui H, Sei K, Nakanishi T, Ike M (2011) Screening of agonistic activities against four nuclear receptors in wastewater treatment plants in Japan using a yeast two-hybrid assay. J Environ Sci (China) 23(1):125–132

    Article  CAS  Google Scholar 

  284. Inoue D, Sawada K, Wada Y, Sei K, Ike M (2013) Removal characteristics of retinoic acids and 4-oxo-retinoic acids in wastewater by activated sludge treatment. Water Sci Technol 67(12):2868–2874

    Article  CAS  Google Scholar 

  285. Sawada K, Inoue D, Wada Y, Sei K, Nakanishi T, Ike M (2012) Detection of retinoic acid receptor agonistic activity and identification of causative compounds in municipal wastewater treatment plants in Japan. Environ Toxicol Chem 31(2):307–315

    Article  CAS  Google Scholar 

  286. Miyagawa S, Lange A, Hirakawa I, Tohyama S, Ogino Y, Mizutani T, Kagami Y, Kusano T, Ihara M, Tanaka H, Tatarazako N, Ohta Y, Katsu Y, Tyler CR, Iguchi T (2014) Differing species responsiveness of estrogenic contaminants in fish is conferred by the ligand binding domain of the estrogen receptor. Environ Sci Technol 48(9):5254–5263

    Article  CAS  Google Scholar 

  287. Kunz PY, Fent K (2006) Estrogenic activity of UV filter mixtures. Toxicol Appl Pharmacol 217(1):86–99

    Article  CAS  Google Scholar 

  288. Legler J, Zeinstra LM, Schuitemaker F, Lanser PH, Bogerd J, Brouwer A, Vethaak AD, De Voogt P, Murk AJ, Van der Burg B (2002) Comparison of in vivo and in vitro reporter gene assays for short-term screening of estrogenic activity. Environ Sci Technol 36(20):4410–4415

    Article  CAS  Google Scholar 

  289. Simmons DB, Marlatt VL, Trudeau VL, Sherry JP, Metcalfe CD (2010) Interaction of Galaxolide(R) with the human and trout estrogen receptor-alpha. Sci Total Environ 408(24):6158–6164

    Article  CAS  Google Scholar 

  290. Ihara M, Kitamura T, Kumar V, Park C-B, Ihara MO, Lee S-J, Yamashita N, Miyagawa S, Iguchi T, Okamoto S, Suzuki Y, Tanaka H (2015) Evaluation of estrogenic activity of wastewater: comparison among in vitro er alpha reporter gene assay, in vivo vitellogenin induction, and chemical analysis. Environ Sci Technol 49(10):6319–6326

    Article  CAS  Google Scholar 

  291. Kohno S, Katsu Y, Iguchi T, Guillette LJ Jr (2008) Novel approaches for the study of vertebrate steroid hormone receptors. Integr Comp Biol 48(4):527–534

    Article  CAS  Google Scholar 

  292. Hultin CL, Hallgren P, Persson A, Hansson MC (2014) Identification of an estrogen receptor gene in the natural freshwater snail Bithynia tentaculata. Gene 540(1):26–31

    Article  CAS  Google Scholar 

  293. Katsu Y, Matsubara K, Kohno S, Matsuda Y, Toriba M, Oka K, Guillette LJ Jr, Ohta Y, Iguchi T (2010) Molecular cloning, characterization, and chromosome mapping of reptilian estrogen receptors. Endocrinology 151(12):5710–5720

    Article  CAS  Google Scholar 

  294. Kaur S, Jobling S, Jones CS, Noble LR, Routledge EJ, Lockyer AE (2015) The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: implications for developing new model organisms. PLoS One 10(4)

    Google Scholar 

  295. Nagasawa K, Treen N, Kondo R, Otoki Y, Itoh N, Rotchell JM, Osada M (2015) Molecular characterization of an estrogen receptor and estrogen-related receptor and their autoregulatory capabilities in two Mytilus species. Gene 564(2):153–159

    Article  CAS  Google Scholar 

  296. Vogeler S, Galloway TS, Lyons BP, Bean TP (2014) The nuclear receptor gene family in the Pacific oyster, Crassostrea gigas, contains a novel subfamily group. BMC Genomics 15

    Google Scholar 

  297. Bannister R, Beresford N, Granger DW, Pounds NA, Rand-Weaver M, White R, Jobling S, Routledge EJ (2013) No substantial changes in estrogen receptor and estrogen-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals. Aquat Toxicol 140:19–26

    Article  CAS  Google Scholar 

  298. Bridgham JT, Keay J, Ortlund EA, Thornton JW (2014) Vestigialization of an allosteric switch: genetic and structural mechanisms for the evolution of constitutive activity in a steroid hormone receptor. PLoS Genet 10(1)

    Google Scholar 

  299. Grun F, Watanabe H, Zamanian Z, Maeda L, Arima K, Cubacha R, Gardiner DM, Kanno J, Iguchi T, Blumberg B (2006) Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Mol Endocrinol 20(9):2141–2155

    Article  CAS  Google Scholar 

  300. Kanayama T, Kobayashi N, Mamiya S, Nakanishi T, Nishikawa J (2005) Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor gamma/retinoid X receptor pathway. Mol Pharmacol 67(3):766–774

    Article  CAS  Google Scholar 

  301. Watson CS, Bulayeva NN, Wozniak AL, Alyea RA (2007) Xenoestrogens are potent activators of nongenomic estrogenic responses. Steroids 72(2):124–134

    Article  CAS  Google Scholar 

  302. Rajapakse N, Silva E, Kortenkamp A (2002) Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Environ Health Perspect 110(9):917–921

    Article  CAS  Google Scholar 

  303. Silva E, Rajapakse N, Kortenkamp A (2002) Something from “nothing”: eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol 36(8):1751–1756

    Article  CAS  Google Scholar 

  304. Kortenkamp A (2014) Low dose mixture effects of endocrine disrupters and their implications for regulatory thresholds in chemical risk assessment. Curr Opin Pharmacol 19:105–111

    Article  CAS  Google Scholar 

  305. Christiansen S, Kortenkamp A, Axelstad M, Boberg J, Scholze M, Jacobsen PR, Faust M, Lichtensteiger W, Schlumpf M, Burdorf A, Hass U (2012) Mixtures of endocrine disrupting contaminants modelled on human high end exposures: an exploratory study in rats. Int J Androl 35(3):303–316

    Article  CAS  Google Scholar 

  306. Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M, Kortenkamp A, Hass U (2009) Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. Environ Health Perspect 117(12):1839–1846

    Article  CAS  Google Scholar 

  307. Hass U, Scholze M, Christiansen S, Dalgaard M, Vinggaard AM, Axelstad M, Metzdorff SB, Kortenkamp A (2007) Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. Environ Health Perspect 115:122–128

    Article  Google Scholar 

  308. Jarošová B, Erseková A, Hilscherová K, Loos R, Gawlik BM, Giesy JP, Bláha L (2014) Europe-wide survey of estrogenicity in wastewater treatment plant effluents: the need for the effect-based monitoring. Environ Sci Pollut Res 21(18):10970–10982

    Article  CAS  Google Scholar 

  309. Behr M, Oehlmann J, Wagner M (2011) Estrogens in the daily diet: in vitro analysis indicates that estrogenic activity is omnipresent in foodstuff and infant formula. Food Chem Toxicol 49(10):2681–2688

    Article  CAS  Google Scholar 

  310. Wagner M, Oehlmann J (2009) Endocrine disruptors in bottled mineral water: total estrogenic burden and migration from plastic bottles. Environ Sci Pollut Res 16(3):278–286

    Article  CAS  Google Scholar 

  311. Yang CZ, Yaniger SI, Jordan VC, Klein DJ, Bittner GD (2011) Most plastic products release estrogenic chemicals: a potential health problem that can be solved. Environ Health Perspect 119(7):989–996

    Article  CAS  Google Scholar 

  312. Brack W (2003) Effect-directed analysis: a promising tool for the identification of organic toxicants in complex mixtures? Anal Bioanal Chem 377(3):397–407

    Article  CAS  Google Scholar 

  313. Buchinger S, Spira D, Broder K, Schlusener M, Ternes T, Reifferscheid G (2013) Direct coupling of thin-layer chromatography with a bioassay for the detection of estrogenic compounds: applications for effect-directed analysis. Anal Chem 85(15):7248–7256

    Article  CAS  Google Scholar 

  314. Jonker W, Lamoree MH, Houtman CJ, Hamers T, Somsen GW, Kool J (2015) Rapid activity-directed screening of estrogens by parallel coupling of liquid chromatography with a functional gene reporter assay and mass spectrometry. J Chromatogr A 1406:165–174

    Article  CAS  Google Scholar 

  315. Reemtsma T (2001) Prospects of toxicity-directed wastewater analysis. Anal Chim Acta 426(2):279–287

    Article  CAS  Google Scholar 

  316. Schmitt S, Reifferscheid G, Claus E, Schluesener M, Buchinger S (2012) Effect directed analysis and mixture effects of estrogenic compounds in a sediment of the river Elbe. Environ Sci Pollut Res 19(8):3350–3361

    Article  CAS  Google Scholar 

  317. Creusot N, Budzinski H, Balaguer P, Kinani S, Porcher J-M, Ait-Aissa S (2013) Effect-directed analysis of endocrine-disrupting compounds in multi-contaminated sediment: identification of novel ligands of estrogen and pregnane X receptors. Anal Bioanal Chem 405(8):2553–2566

    Article  CAS  Google Scholar 

  318. Simon E, van Velzen M, Brandsma SH, Lie E, Loken K, de Boer J, Bytingsvik J, Jenssen BM, Aars J, Hamers T, Lamoree MH (2013) Effect-directed analysis to explore the polar bear exposome: identification of thyroid hormone disrupting compounds in plasma. Environ Sci Technol 47(15):8902–8912

    Article  CAS  Google Scholar 

  319. Weiss JM, Andersson PL, Zhang J, Simon E, Leonards PEG, Hamers T, Lamoree MH (2015) Tracing thyroid hormone-disrupting compounds: database compilation and structure-activity evaluation for an effect-directed analysis of sediment. Anal Bioanal Chem 407(19):5625–5634

    Article  CAS  Google Scholar 

  320. Alvarez-Munoz D, Indiveri P, Rostkowski P, Horwood J, Greer E, Minier C, Pope N, Langston WJ, Hill EM (2015) Widespread contamination of coastal sediments in the Transmanche Channel with anti-androgenic compounds. Mar Pollut Bull 95(2):590–597

    Article  CAS  Google Scholar 

  321. Berger E, Potouridis T, Haeger A, Puettmann W, Wagner M (2015) Effect-directed identification of endocrine disruptors in plastic baby teethers. J Appl Toxicol 35(11):1254–1261

    Article  CAS  Google Scholar 

  322. Fang H, Tong W, Perkins R, Soto AM, Prechtl NV, Sheehan DM (2000) Quantitative comparisons of in vitro assays for estrogenic activities. Environ Health Perspect 108(8):723–729

    Article  CAS  Google Scholar 

  323. Leusch FD, de Jager C, Levi Y, Lim R, Puijker L, Sacher F, Tremblay LA, Wilson VS, Chapman HF (2010) Comparison of five in vitro bioassays to measure estrogenic activity in environmental waters. Environ Sci Technol 44(10):3853–3860

    Article  CAS  Google Scholar 

  324. Dreier DA, Connors KA, Brooks BW (2015) Comparative endpoint sensitivity of in vitro estrogen agonist assays. Regul Toxicol Pharmacol 72(2):185–193

    Article  CAS  Google Scholar 

  325. Akahori Y, Nakai M, Yamasaki K, Takatsuki M, Shimohigashi Y, Ohtaki M (2008) Relationship between the results of in vitro receptor binding assay to human estrogen receptor alpha and in vivo uterotrophic assay: comparative study with 65 selected chemicals. Toxicol in Vitro 22(1):225–231

    Article  CAS  Google Scholar 

  326. Coldham NG, Dave M, Sivapathasundaram S, McDonnell DP, Connor C, Sauer MJ (1997) Evaluation of a recombinant yeast cell estrogen screening assay. Environ Health Perspect 105(7):734–742

    Article  CAS  Google Scholar 

  327. Rotroff DM, Martin MT, Dix DJ, Filer DL, Houck KA, Knudsen TB, Sipes NS, Reif DM, Xia M, Huang R, Judson RS (2014) Predictive endocrine testing in the 21st century using in vitro assays of estrogen receptor signaling responses. Environ Sci Technol 48(15):8706–8716

    Article  CAS  Google Scholar 

  328. Rotroff DM, Dix DJ, Houck KA, Knudsen TB, Martin MT, McLaurin KW, Reif DM, Crofton KM, Singh AV, Xia M, Huang R, Judson RS (2013) Using in vitro high throughput screening assays to identify potential endocrine-disrupting chemicals. Environ Health Perspect 121(1):7–14

    Google Scholar 

  329. Blaauboer BJ (2015) The long and winding road of progress in the use of in vitro data for risk assessment purposes: from “carnation test” to integrated testing strategies. Toxicology 332:4–7

    Article  CAS  Google Scholar 

  330. Meek ME, Lipscomb JC (2015) Gaining acceptance for the use of in vitro toxicity assays and QIVIVE in regulatory risk assessment. Toxicology 332:112–123

    Article  CAS  Google Scholar 

  331. Villeneuve DL, Ankley GT, Makynen EA, Blake LS, Greene KJ, Higley EB, Newsted JL, Giesy JP, Hecker M (2007) Comparison of fathead minnow ovary explant and H295R cell-based steroidogenesis assays for identifying endocrine-active chemicals. Ecotoxicol Environ Saf 68(1):20–32

    Article  CAS  Google Scholar 

  332. Puy-Azurmendi E, Olivares A, Vallejo A, Ortiz-Zarragoitia M, Pina B, Zuloaga O, Cajaraville MP (2014) Estrogenic effects of nonylphenol and octylphenol isomers in vitro by recombinant yeast assay (RYA) and in vivo with early life stages of zebrafish. Sci Total Environ 466:1–10

    Article  CAS  Google Scholar 

  333. Hornung MW, Kosian PA, Haselman JT, Korte JJ, Challis K, Macherla C, Nevalainen E, Degitz SJ (2015) In vitro, ex vivo, and in vivo determination of thyroid hormone modulating activity of benzothiazoles. Toxicol Sci 146(2):254–264

    Article  CAS  Google Scholar 

  334. Leusch FDL, Khan SJ, Gagnon MM, Quayle P, Trinh T, Coleman H, Rawson C, Chapman HF, Blair P, Nice H, Reitsema T (2014) Assessment of wastewater and recycled water quality: a comparison of lines of evidence from in vitro, in vivo and chemical analyses. Water Res 50:420–431

    Article  CAS  Google Scholar 

  335. Vermeirssen ELM, Burki R, Joris C, Peter A, Segner H, Suter MJF, Burkhardt-Holm P (2005) Characterization of the estrogenicity of swiss midland rivers using a recombinant yeast bioassay and plasma vitellogenin concentrations in feral male brown trout. Environ Toxicol Chem 24(9):2226–2233

    Article  CAS  Google Scholar 

  336. Henneberg A, Bender K, Blaha L, Giebner S, Kuch B, Koehler H-R, Maier D, Oehlmann J, Richter D, Scheurer M, Schulte-Oehlmann U, Sieratowicz A, Ziebart S, Triebskorn R (2014) Are in vitro methods for the detection of endocrine potentials in the aquatic environment predictive for in vivo effects? Outcomes of the projects SchussenAktiv and SchussenAktiv plus in the Lake Constance area, Germany. PLoS One 9(6)

    Google Scholar 

  337. Groothuis FA, Heringa MB, Nicol B, Hermens JL, Blaauboer BJ, Kramer NI (2015) Dose metric considerations in in vitro assays to improve quantitative in vitro-in vivo dose extrapolations. Toxicology 332:30–40

    Article  CAS  Google Scholar 

  338. Brinkmann M, Maletz S, Krauss M, Bluhm K, Schiwy S, Kuckelkorn J, Tiehm A, Brack W, Hollert H (2014) Heterocyclic aromatic hydrocarbons show estrogenic activity upon metabolization in a recombinant transactivation assay. Environ Sci Technol 48(10):5892–5901

    Article  CAS  Google Scholar 

  339. Louisse J, Bosgra S, Blaauboer BJ, Rietjens IM, Verwei M (2015) Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling. Arch Toxicol 89(7):1135–1148

    Article  CAS  Google Scholar 

  340. Yoon M, Campbell JL, Andersen ME, Clewell HJ (2012) Quantitative in vitro to in vivo extrapolation of cell-based toxicity assay results. Crit Rev Toxicol 42(8):633–652

    Article  CAS  Google Scholar 

  341. Wetmore BA (2015) Quantitative in vitro-to-in vivo extrapolation in a high-throughput environment. Toxicology 332:94–101

    Article  CAS  Google Scholar 

  342. Wilk-Zasadna I, Bernasconi C, Pelkonen O, Coecke S (2015) Biotransformation in vitro: an essential consideration in the quantitative in vitro-to-in vivo extrapolation (QIVIVE) of toxicity data. Toxicology 332:8–19

    Article  CAS  Google Scholar 

  343. Burden N, Sewell F, Andersen ME, Boobis A, Chipman JK, Cronin MTD, Hutchinson TH, Kimber I, Whelan M (2015) Adverse outcome pathways can drive non-animal approaches for safety assessment. J Appl Toxicol 35(9):971–975

    Article  CAS  Google Scholar 

  344. Lee JW, Won E-J, Raisuddin S, Lee J-S (2015) Significance of adverse outcome pathways in biomarker-based environmental risk assessment in aquatic organisms. J Environ Sci 35:115–127

    Article  Google Scholar 

  345. Plant NJ (2015) An introduction to systems toxicology. Toxicol Res 4(1):9–22

    Article  CAS  Google Scholar 

  346. Simmons DBD, Benskin JP, Cosgrove JR, Duncker BP, Ekman DR, Martyniuk CJ, Sherry JP (2015) Omics for aquatic ecotoxicology: control of extraneous variability to enhance the analysis of environmental effects. Environ Toxicol Chem 34(8):1693–1704

    Article  CAS  Google Scholar 

  347. Spurgeon DJ, Jones OAH, Dorne J-LCM, Svendsen C, Swain S, Stuerzenbaum SR (2010) Systems toxicology approaches for understanding the joint effects of environmental chemical mixtures. Sci Total Environ 408(18):3725–3734

    Article  CAS  Google Scholar 

  348. Waters MD, Fostel JM (2004) Toxicogenomics and systems toxicology: aims and prospects. Nat Rev Genet 5(12):936–948

    Article  CAS  Google Scholar 

  349. Yoon K, Kwack SJ, Kim HS, Lee B-M (2014) Estrogenic endocrine-disrupting chemicals: molecular mechanisms of actions on putative human diseases. J Toxicol Environ Health B Crit Rev 17(3):127–174

    Article  CAS  Google Scholar 

  350. Escher B, Leusch F (2012) Bioanalytical tools in water quality assessment. International Water Association, London

    Google Scholar 

  351. Kunz PY, Kienle C, Carere M, Homazava N, Kase R (2015) In vitro bioassays to screen for endocrine active pharmaceuticals in surface and waste waters. J Pharm Biomed Anal 106:107–115

    Article  CAS  Google Scholar 

  352. Loos R (2012) Analytical methods relevant to the European Commission’s 2012 proposal on priority substances under the water framework directive. Publications Office of the European Union

    Google Scholar 

  353. OECD (2012) OECD Series on Testing and Assessment Number 178. Detailed review paper on the state of the science on novel in vitro and in vivo screening and testing methods and endpoints for evaluating endocrine disruptors. ENV/JM/MONO(2012)23

    Google Scholar 

  354. EU (2008) DIRECTIVE 2008/105/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 2008 on environmental quality standards in the field of water policy, amending and subsequently repealing Council Directives 82/176/EEC, 83/513/EEC, 84/156/EEC, 84/491/EEC, 86/280/EEC and amending Directive 2000/60/EC of the European Parliament and of the Council. Off J Eur Union L 348/84

    Google Scholar 

  355. ANZECC, ARMCANZ (2000) Australian and New Zealand guidelines for fresh and marine water quality. Aquatic ecosystems: Rationale and background information, vol. 2. Australian Water Association, Artarmon, AU

    Google Scholar 

  356. EU Council (2009) Council conclusions on combination effects of chemicals Brussels, Belgium. 2988th Environment Council meeting, Council of the European Union, 22 Dec 2009

    Google Scholar 

  357. Epa U (2002) Guidance on cumulative risk assessment of pesticide chemicals that have a common mechanism of toxicity, federal register. U.S. Environmental Protection Agency. Office of Pesticide Programs, Washington, DC

    Google Scholar 

  358. OSPAR Commission (2007) Practical guidance document on whole effluent assessment, No. 316/2007. OSPAR Commission, London

    Google Scholar 

  359. OECD (2005) OECD Series on Testing and Assessment Number 34. Guidance document on the validation and international acceptance of new or updated test methods for hazard assessment. ENV/JM/MONO(2005)14

    Google Scholar 

  360. Tang JYM, McCarty S, Glenn E, Neale PA, Warne MSJ, Escher BI (2013) Mixture effects of organic micropollutants present in water: towards the development of effect-based water quality trigger values for baseline toxicity. Water Res 47(10):3300–3314

    Article  CAS  Google Scholar 

  361. EU (2013) DIRECTIVE 2013/39/EU OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 12 August 2013 amending Directives 2000/60/EC and 2008/105/EC as regards priority substances in the field of water policy. Off J Eur Union L226/1

    Google Scholar 

  362. Brand W, de Jongh CM, van der Linden SC, Mennes W, Puijker LM, van Leeuwen CJ, van Wezel AP, Schriks M, Heringa MB (2013) Trigger values for investigation of hormonal activity in drinking water and its sources using CALUX bioassays. Environ Int 55:109–118

    Article  CAS  Google Scholar 

  363. Jarošová B, Bláha L, Giesy JP, Hilscherová K (2014) What level of estrogenic activity determined by in vitro assays in municipal waste waters can be considered as safe? Environ Int 64:98–109

    Article  CAS  Google Scholar 

  364. Escher BI, Neale PA, Leusch FDL (2015) Effect-based trigger values for in vitro bioassays: reading across from existing water quality guideline values. Water Res 81:137–148

    Article  CAS  Google Scholar 

  365. Langston WJ, Burt GR, Chesman BS (2007) Feminisation of male clams Scrobicularia plana from estuaries in Southwest UK and its induction by endocrine-disrupting chemicals. Mar Ecol Prog Ser 333:173–184

    Article  CAS  Google Scholar 

  366. De Solla SR, Martin PA, Fernie KJ, Park BJ, Mayne G (2006) Effects of environmentally relevant concentrations of atrazine on gonadal development of snapping turtles (Chelydra serpentina). Environ Toxicol Chem 25(2):520–526

    Article  Google Scholar 

  367. Mattsson A, Olsson JA, Brunstrom B (2008) Selective estrogen receptor alpha activation disrupts sex organ differentiation and induces expression of vitellogenin II and very low-density apolipoprotein II in Japanese quail embryos. Reproduction 136(2):175–186

    Article  CAS  Google Scholar 

  368. Wagner M (2012) Endocrine disruptors in bottled water and foodstuff: a bioassay-based approach. Dr. Phil. Nat., Faculty of Biological Sciences, Goethe University, Frankfurt, p 206

    Google Scholar 

  369. Fernandes D, Loi B, Porte C (2011) Biosynthesis and metabolism of steroids in molluscs. J Steroid Biochem Mol Biol 127(3–5):189–195

    Article  CAS  Google Scholar 

  370. Dodds EC, Lawson W (1936) Synthetic oestrogenic agents without the phenanthrene nucleus. Nature 137:996

    Article  CAS  Google Scholar 

  371. Vanbohemen CG, Lambert JGD, Goos HJT, Vanoordt P (1982) Estrone and estradiol participation during exogenous vitallogenesis in the female rainbow-trout, Salmo gairdneri. Gen Comp Endocrinol 46(1):81–92

    Article  CAS  Google Scholar 

  372. Palace VP, Evans RE, Wautier K, Baron C, Vandenbyllardt L, Vandersteen W, Kidd K (2002) Induction of vitellogenin and histological effects in wild fathead minnows from a lake experimentally treated with the synthetic estrogen, ethynylestradiol. Water Qual Res J Can 37(3):637–650

    CAS  Google Scholar 

  373. Park BJ, Kidd K (2005) Effects of the synthetic estrogen ethinylestradiol on early life stages of mink frogs and green frogs in the wild and in situ. Environ Toxicol Chem 24(8):2027–2036

    Article  CAS  Google Scholar 

  374. Palace VP, Wautier KG, Evans RE, Blanchfield PJ, Mills KH, Chalanchuk SM, Godard D, McMaster ME, Tetreault GR, Peters LE, Vandenbyllaardt L, Kidd KA (2006) Biochemical and histopathological effects in pearl dace (Margariscus margarita) chronically exposed to a synthetic estrogen in a whole lake experiment. Environ Toxicol Chem 25(4):1114–1125

    Article  CAS  Google Scholar 

  375. Werner J, Palace VP, Wautier KG, Mills KH, Chalanchuk SM, Kidd KA (2006) Reproductive fitness of lake trout (Salvelinus namaycush) exposed to environmentally relevant concentrations of the potent estrogen ethynylestradiol (EE2) in a whole lake exposure experiment. Sci Mar 70:59–66

    Article  Google Scholar 

  376. Palace VP, Evans RE, Wautier KG, Mills KH, Blanchfield PJ, Park BJ, Baron CL, Kidd KA (2009) Interspecies differences in biochemical, histopathological, and population responses in four wild fish species exposed to ethynylestradiol added to a whole lake. Can J Fish Aquat Sci 66(11):1920–1935

    Article  CAS  Google Scholar 

  377. Milnes MR, Bryan TA, Katsu Y, Kohno S, Moore BC, Iguchi T, Guillette LJ Jr (2008) Increased posthatching mortality and loss of sexually dimorphic gene expression in alligators (Alligator mississippiensis) from a contaminated environment. Biol Reprod 78(5):932–938

    Article  CAS  Google Scholar 

  378. Stoker C, Repetti MR, Garcia SR, Zayas MA, Galoppo GH, Beldomenico HR, Loque EH, Munoz-de-Toro M (2011) Organochlorine compound residues in the eggs of broad-snouted caimans (Caiman latirostris) and correlation with measures of reproductive performance. Chemosphere 84(3):311–317

    Article  CAS  Google Scholar 

  379. Stoker C, Beldomenico PM, Bosquiazzo VL, Zayas MA, Rey F, Rodriguez H, Munoz-de-Toro M, Luque EH (2008) Developmental exposure to endocrine disruptor chemicals alters follicular dynamics and steroid levels in Caiman latirostris. Gen Comp Endocrinol 156(3):603–612

    Article  CAS  Google Scholar 

  380. Rider CV, Hartig PC, Cardon MC, Lambright CR, Bobseine KL, Guillette LJ Jr, Gray LE Jr, Wilson VS (2010) Differences in sensitivity but not selectivity of xenoestrogen binding to alligator versus human estrogen receptor alpha. Environ Toxicol Chem 29(9):2064–2071

    Article  CAS  Google Scholar 

  381. Fry DM, Toone CK (1981) DDT-induced feminization of gull embryos. Science 213(4510):922–924

    Article  CAS  Google Scholar 

  382. Markman S, Mueller CT, Pascoe D, Dawson A, Buchanan KL (2011) Pollutants affect development in nestling starlings Sturnus vulgaris. J Appl Ecol 48(2):391–397

    Article  Google Scholar 

  383. Sonne C, Iburg T, Leifsson PS, Born EW, Letcher RJ, Dietz R (2011) Thyroid gland lesions in organohalogen contaminated East Greenland polar bears (Ursus maritimus). Toxicol Environ Chem 93(4):789–805

    Article  CAS  Google Scholar 

  384. Colborn T, vom Saal FS, Soto AM (1993) Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect 101(5):378–384

    Article  CAS  Google Scholar 

  385. Colborn T, Dumanoski D, Myers JP (1996) Our stolen future: are we threatening our fertility, intelligence, and survival? A scientific detective story. Dutton, New York

    Google Scholar 

  386. Kristensen DM, Skalkam ML, Audouze K, Lesne L, Desdoits-Lethimonier C, Frederiksen H, Brunak S, Skakkebaek NE, Jegou B, Hansen JB, Junker S, Leffers H (2011) Many putative endocrine disruptors inhibit prostaglandin synthesis. Environ Health Perspect 119(4):534–541

    Article  CAS  Google Scholar 

  387. Masuyama H, Inoshita H, Hiramatsu Y, Kudo T (2002) Ligands have various potential effects on the degradation of pregnane X receptor by proteasome. Endocrinology 143(1):55–61

    Article  CAS  Google Scholar 

  388. Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S (2003) The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. Mol Cell Biol 23(6):1843–1855

    Article  CAS  Google Scholar 

  389. Jansen MS, Nagel SC, Miranda PJ, Lobenhofer EK, Afshari CA, McDonnell DP (2004) Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci U S A 101(18):7199–7204

    Article  CAS  Google Scholar 

  390. Brunnberg S, Pettersson K, Rydin E, Matthews J, Hanberg A, Pongratz I (2003) The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription. Proc Natl Acad Sci U S A 100(11):6517–6522

    Article  CAS  Google Scholar 

  391. Kleiner IS, Weisman AI, Barowsky H (1935) An investigation of the new biologic test for hormones in pregnancy urine: preliminary report. JAMA 104:1318–1319

    Article  Google Scholar 

  392. Klaassen CD, Casarett LJ, Doull J (2013) Casarett and Doull’s toxicology: the basic science of poisons. McGraw-Hill, New York

    Google Scholar 

  393. Yalow RS, Berson SA (1960) Immunoassay of endogenous plasma insulin in man. J Clin Invest 39(7):1157–1175

    Article  CAS  Google Scholar 

  394. Khan MN, Findlay JWA (2010) Ligand-binding assays: development, validation, and implementation in the drug development arena. Wiley, Hoboken, NJ

    Google Scholar 

  395. Ruff M, Gangloff M, Wurtz JM, Moras D (2000) Estrogen receptor transcription and transactivation: structure-function relationship in DNA- and ligand-binding domains of estrogen receptors. Breast Cancer Res 2(5):353–359

    Article  CAS  Google Scholar 

  396. Muller MB, Dausend C, Weins C, Frimmel FH (2004) A new bioautographic screening method for the detection of estrogenic compounds. Chromatographia 60(3–4):207–211

    Google Scholar 

  397. Vanderperren E, Demare W, Blust R, Cooreman K, Bossier P (2001) Oestrogenic activity of CPRG (chlorophenol red-beta-D-galactopyranoside), a beta-galactosidase substrate commonly used in recombinant yeast oestrogenic assays. Biomarkers 6(5):375–380

    Article  CAS  Google Scholar 

  398. Berthois Y, Katzenellenbogen JA, Katzenellenbogen BS (1986) Phenol red in tissue-culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci U S A 83(8):2496–2500

    Article  CAS  Google Scholar 

  399. Welshons WV, Wolf MF, Murphy CS, Jordan VC (1988) Estrogenic activity of phenol red. Mol Cell Endocrinol 57(3):169–178

    Article  CAS  Google Scholar 

  400. Antebi A (2006) Nuclear hormone receptors in C. elegans. In: WormBook (ed). The C. elegans Research Community, WormBook. doi:10.1895/wormbook.1.64.1. http://www.wormbook.org

  401. Dang Z, Ru S, Wang W, Rorije E, Hakkert B, Vermeire T (2011) Comparison of chemical-induced transcriptional activation of fish and human estrogen receptors: regulatory implications. Toxicol Lett 201(2):152–175

    Article  CAS  Google Scholar 

  402. Scott AP (2012) Do mollusks use vertebrate sex steroids as reproductive hormones? Part I: Critical appraisal of the evidence for the presence, biosynthesis and uptake of steroids. Steroids 77(13):1450–1468

    Article  CAS  Google Scholar 

  403. Scott AP (2013) Do mollusks use vertebrate sex steroids as reproductive hormones? II. Critical review of the evidence that steroids have biological effects. Steroids 78(2):268–281

    Article  CAS  Google Scholar 

  404. Gutierrez-Mazariegos J, Nadendla EK, Lima D, Pierzchalski K, Jones JW, Kane M, Nishikawa J-I, Hiromori Y, Nakanishi T, Santos MM, Castro LFC, Bourguet W, Schubert M, Laudet V (2014) A mollusk retinoic acid receptor (RAR) ortholog sheds light on the evolution of ligand binding. Endocrinology 155(11):4275–4286

    Article  CAS  Google Scholar 

  405. Burgess RM, Ho KT, Brack W, Lamoree M (2013) Effects-directed analysis (EDA) and toxicity identification evaluation (TIE): complementary but different approaches for diagnosing causes of environmental toxicity. Environ Toxicol Chem 32(9):1935–1945

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department Aquatic Ecotoxicology, Goethe University Frankfurt, Max-von-Laue-Str. 13, Frankfurt, 60438, Germany

    Martin Wagner & Jörg Oehlmann

  2. Swiss Centre for Applied Ecotoxicology, Eawag-EPFL, Dübendorf, Switzerland

    Cornelia Kienle & Etiënne L. M. Vermeirssen

Authors
  1. Martin Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cornelia Kienle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Etiënne L. M. Vermeirssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jörg Oehlmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Wagner .

Editor information

Editors and Affiliations

  1. Federal Institute of Hydrology, Koblenz, Germany

    Georg Reifferscheid

  2. Federal Institute of Hydrology, Koblenz, Germany

    Sebastian Buchinger

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Wagner, M., Kienle, C., Vermeirssen, E.L.M., Oehlmann, J. (2017). Endocrine Disruption and In Vitro Ecotoxicology: Recent Advances and Approaches. In: Reifferscheid, G., Buchinger, S. (eds) In vitro Environmental Toxicology - Concepts, Application and Assessment. Advances in Biochemical Engineering/Biotechnology, vol 157. Springer, Cham. https://doi.org/10.1007/10_2016_2

Download citation

Publish with us

Policies and ethics

Search

Navigation