Elsevier

NeuroToxicology

Volume 24, Issue 3, June 2003, Pages 449-462
NeuroToxicology

Polybrominated Diphenyl Ethers: Neurobehavioral Effects Following Developmental Exposure

https://doi.org/10.1016/S0161-813X(03)00020-2Get rights and content

Abstract

Polybrominated diphenyl ethers (PBDEs), a class of widely used flame retardants, are becoming widespread environmental pollutants, as indicated by studies on sentinel animal species, as well as humans. Of particular concern are the reported increasingly high levels of PBDEs in human milk, as should be given that almost no information is available on their potential effects on developing organisms. In order to address this issue, studies have been conducted in mice and rats to assess the potential neurotoxic effects of perinatal exposure to PBDEs (congeners 47, 99, 153 and the penta-BDE mixture DE-71). Characteristic endpoints of PBDE neurotoxicity are, among others, endocrine disruption (e.g. decreased thyroid hormone levels), alteration in cholinergic system activity (behavioral hyporesponsivity to nicotine challenge), as well as alterations of several behavioral parameters. In particular, the main hallmark of PBDE neurotoxicity is a marked hyperactivity at adulthood. Furthermore, a deficit in learning and memory processes has been found at adulthood in neonatally exposed animals. Some of neurotoxic effects of PBDEs are comparable to those of polychlorinated biphenyls (PCBs), though the latter class of compounds seems to exert a stronger toxic effect. Available information on PBDE neurotoxicity obtained from animal studies and the possibility of neonatal exposure to PBDEs via the mother’s milk suggest that these compounds may represent a potential risk for neurobehavioral development in humans.

Section snippets

INTRODUCTION

Polybrominated diphenyl ethers (PBDEs), are an important group of flame retardants, used worldwide in large quantities in polymers, especially in ready-made plastic products. They are persistent compounds that appear to have an environmental dispersion similar to that of polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT). In contrast to the well studied developmental neurotoxicity of PCBs, there is almost no information on the potential neurotoxicity of PBDEs. Their

CHEMICAL AND PHYSICAL PROPERTIES OF PBDEs

The general chemical formula of PBDEs is C12H(0–9)Br(1–10)O and the theoretical number of possible congeners is 209 (Fig. 1), though the number of PBDE congeners used in commercial products is limited. For instance, PBDE compounds with less than four bromine atoms are not found in commercial products (Darnerud et al., 2001). PBDEs are numbered using the IUPAC numbering system (Ballschmiter et al., 1993), and are divided into 10 congener groups (mono- to decabromodiphenyl ethers). PBDEs, as

HUMAN EXPOSURE

The fully brominated deca-BDE congeners are poorly absorbed and rapidly eliminated, thus their bio-accumulative potential is low (el Dareer et al., 1987, Norris et al., 1975). Extensive testing of these compounds has indicated their toxicity, which appears to be different from that of other classes of PBDEs (Darnerud et al., 2001, Hardy, 2002, McDonald, 2002). In contrast, lower molecular weight congeners, tetra- to hexa-BDEs, appear to be almost completely absorbed, slowly eliminated and

THE POTENTIAL RISKS OF PBDEs FOR HUMAN HEALTH

Evidence from animal models suggest that exposure to some PBDEs results in induction/down-regulation of liver enzyme and increase in liver weight (Darnerud et al., 2001, Hardy, 2002, McDonald, 2002). Moreover, treatment-related changes were reported in rodent reproductive performances (Branchi et al., 2002, Darnerud et al., 2001) and gestational exposure to PBDEs significantly increase incidence of resorption and subcutaneous edema and delayed ossification of normally developed bones of the

ANIMAL MODELS TO INVESTIGATE NEUROBEHAVIORAL TOXICITY

The study of behavioral changes following developmental exposure to possible neurotoxic agents employs animal models for both practical reasons and obvious ethical constraints of human experimentation. This approach consists of monitoring the development of the nervous system through the assessment of selected neurobehavioral endpoints appropriate for each maturational phase (Branchi and Ricceri, 2002, Cory-Slechta et al., 2001, Cuomo et al., 1996, Spear, 1990). Animal models allow one to

Reproductive Parameters

Studies in either rats or mice have not shown important adverse consequences on reproductive parameters upon exposure to PBDEs in utero and/or immediately after birth. Body weight gain of pregnant females, pregnancy duration, proportion of successful deliveries and pup sex-ratio were not affected by perinatal PBDE treatment (DE-71 or BDE 99) in either mice or rats (Branchi et al., 2002, Zhou et al., 2002). However, in a mouse study, litter viability was found to be slightly affected perinatal

Activity Profile

The data collected so far show that the main behavioral effect of perinatal PBDE exposure is a marked alteration of activity profile at adulthood. Prolonged perinatal PBDE administration (congener 99) to dams, as well as neonatal single-day (PND 10) administration (congeners 47 or 99), induced hyperactivity in young-adult mice. At 2 months of age, BDE 99 treated animals showed high levels of locomotor activity, especially in the last 40 min of a 60 min activity test, with a reduced habituation

PBDEs AND PCBs: COMPARABLE STRUCTURES LEAD TO SIMILAR EFFECTS?

PBDEs and PCBs have a comparable structure (Fig. 1) and their effects on neurobehavioural profile show similarities but also important differences, suggesting that their actions do not always overlap.

In adult animals, these two classes of polyhalogenated aromatic hydrocarbons exert in some cases similar toxicities. For example, both the PBDE mixture Bromkal 70-5 DE (constituted by penta- and tetra-BDEs), and the PCB mixture Aroclor 1254, cause an induction of cytochrome P-450 (Hanberg et al.,

CONCLUSIONS

Because of the high production volume of PBDEs and their accumulation in the environment, and the still limited knowledge of their potential neurotoxic/behavioral teratogenic effects (alone or in combination), more investigations are indeed warranted. In particular, more extensive studies using animal models are required in order to better characterize the neurotoxic effects of perinatal administration to PBDEs. In particular, learning and motor function should be assessed, since these

Acknowledgements

Authors thank the anonymous reviewers who greatly helped in improving the quality of the manuscript. Work by the authors was supported by EU, Contract no. QLK4-CT-1999-01562 (L.G.C.) and by ISS Project N 1103/RI-2001/2002 “Neurotrophins and neurobehavioral plasticity: animal models” (E.A.).

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