Persistent organic pollutant exposure and celiac disease: A pilot study
Introduction
Celiac disease is a chronic immune-mediated disease characterized by enteropathy and nutrient malabsorption in the presence of the protein peptide gliadin, a component of gluten (Chou et al., 2017; Leonard et al., 2017; J. F. Ludvigsson et al., 2013a, Ludvigsson et al., 2013b). Epidemiologic studies have observed increases in celiac disease incidence for reasons that remain unknown. The most recent estimates report the disease prevalence at approximately 1% of the population worldwide and 0.71% of the United States population (Fasano et al., 2003; Hoffenberg et al., 2003; Liu et al., 2017; Jonas F. Ludvigsson et al., 2013a, Ludvigsson et al., 2013b; Rubio-Tapia et al., 2009; Rubio-Tapia et al., 2012; Tursi et al., 2010). These numbers may be underestimates of the actual prevalence, however, given the disease's historically vague definition and its broad range of symptoms (Ludvigsson et al., 2014; J. F. Ludvigsson et al., 2013).
The pathophysiology of celiac disease involves the adaptive and innate immune systems. Once in the small intestine, gliadin has increased binding affinity for antigen-presenting cells (APCs) expressing the HLA (human leukocyte antigen) -DQ2 or -DQ8 receptors, which are subsequently recognized and bound by CD4+ T cells (Lebwohl et al., 2015; Lundin et al., 1993; Meresse et al., 2012). For this reason, the degree to which an individual is susceptible to celiac disease depends primarily on their having either the HLA-DQ2 and/or HLA-DQ8 genotype (Black et al., 2002; Leonard et al., 2017; Megiorni et al., 2009; Sollid et al., 1989). The innate immune system responds to gliadin through increased production of intraepithelial lymphocytes (IELs), which express CD8+ T cell receptors NKG2D and CD9/NKG2A. The resulting CD4+ and CD8+ T cell activation by these two pathways causes cytokine and metalloproteinase production in the small intestine and the ensuing epithelial tissue damage characteristic of celiac disease (Lebwohl et al., 2015). Although HLA-DQ2/8 plays a clear and important role in celiac disease pathology, evidence from mouse models suggests that genetic predisposition and gluten exposure are not the only factors contributing to celiac disease (Black et al., 2002; Du Pre et al., 2011; Marietta et al., 2004). Identifying these missing links may help to explain why some children with genetic susceptibility develop celiac disease while others remain disease-free.
Synthetic chemicals have long been associated with adverse health outcomes in humans (VanDoren, 1996). Persistent organic pollutants (POPs) are halogenated, synthetic organic compounds that have been used in manufacturing and industrial processes. Polybrominated diphenyl ethers (PBDEs) are known for their use as flame retardants in upholstered furniture, mattresses, and electronic products. PBDEs are additive flame retardants and can leach out of these products quite easily (Darnerud et al., 2001). Perfluoroalkyl substances (PFASs) are commonly used as surfactants and polymers for consumer products and building materials (Buck et al., 2011; Lau et al., 2007). P,p’-dichlorodiphenyldichloroethylene (DDE) is the main metabolite of dichlorodiphenyltrichloroethane (DDT), which was predominately used as an insecticide until it's U.S. ban in 1972 (Cetkovic-Cvrlje et al., 2016; Fischer-Kowalski et al., 2011). Although many of these POPs have been or are currently being phased out of use, these chemicals remain in the environment, as they are resistant to degradation and tend to accumulate in animal and human tissue (ATSDR, 2015, 2016; EPA, 2009).
POPs are well-known endocrine disruptors that can have lasting effects on human health (Calafat et al., 2007; Perez et al., 2013; WHO, 2010). Their interference with endocrine homeostasis can stimulate immune system dysregulation, suggesting that exposure to POPs may increase the risk for immune-related disorders in addition to, or in conjunction with, their effects on endocrine processes (Ansar Ahmed et al., 1985; Khan and Ansar Ahmed, 2015; Kiess and Belohradsky, 1986; Paavonen, 1994). Evidence from mouse and rat models indicates that exposure to POPs, including PBDEs, PFASs, and DDE, can induce immunotoxicity (Banerjee et al., 1996; Dewitt et al., 2008; DeWitt et al., 2012; Lv et al., 2015). PBDEs have been associated with increased thyroid antibodies, typically considered to be a precursor for some autoimmune diseases (Turyk et al., 2008), while PFASs are shown to decrease antibody levels to immunization toxoids (Grandjean et al., 2012). A recent study in bottlenose dolphins found that exposure to perfluorooctane sulfonic acid (PFOS), a PFAS, increased T cell activation, indicating autoimmune dysregulation (Soloff et al., 2017). A study in Atlantic walruses revealed higher plasma PFAS concentrations were associated with increased blood transcript levels of T and B cells, again suggesting immune dysregulation (Routti et al., 2019). Another study showed that DDE was associated with increased risk of autoimmune Type 1 diabetes in mice (Cetkovic-Cvrlje et al., 2016). Despite our growing understanding of how POPs affect immune and autoimmune function, little information exists on the potential effects of PBDEs, PFASs, or DDE on celiac disease (Ansar Ahmed et al., 1985; Khan and Ansar Ahmed, 2015; Kiess and Belohradsky, 1986; Paavonen, 1994).
In this pilot study, we analyzed the serum concentrations of several PBDEs, PFASs, and DDE in a cohort of 88 patients presenting with gastrointestinal complaints. We identified the HLA genotype of the children to gain a better understanding of how chemical exposures and genetics interact in the development of celiac disease.
Section snippets
Study sample and recruitment
Patients were recruited from NYU Langone's Hassenfeld Children's Hospital outpatient pediatric gastroenterology clinic in New York City. Initial outpatients with gastrointestinal complaints were eligible for the study if they were routinely having blood tests to evaluate for possible celiac disease, were on a gluten-containing diet, and were no older than 21 years of age (n = 111). Height and weight were measured for each participant and used to calculate Body Mass Index (BMI) using the Centers
Results
Fig. 1 outlines the patient flow diagram for this pilot study. Among the children with newly diagnosed celiac disease, 29 had elevated tissue transglutaminase immunoglobulin A (tTG IgA). The remaining child had IgA deficiency and elevated tTG immunoglobulin G (IgG). All patients diagnosed with celiac disease had abnormal duodenal biopsies, with 26 biopsies classified as Marsh IIIa or greater and four biopsies classified as Marsh II. The children with Marsh II biopsies had elevated tTG IgA two
Discussion
This is the first study, to our knowledge, that has identified the effects of synthetic chemicals as possible risk factors for celiac disease in children and adolescents. After adjusting for genetic predisposition, age, race, BMI, and albumin (for PFASs) we found a statistically significant association of DDE with celiac disease. We also saw sex-specific associations, predominately among females (PFOS, PFOA, PFHxS) but also among males (BDE153). However, the sex-stratified analyses had low
Conclusions
The purpose of this pilot study was to identify whether POPs could be potential risk factors in the manifestation and development of celiac disease. Despite our small sample size, we did find increased odds of celiac disease associated with specific POPs, and in particular DDE, although these estimates lacked precision. However, this research raises several questions about the potential role of POPs in celiac disease development. It is possible that POPs play a role in the differentiation of
Funding source
This work was supported by the KiDS of NYU Foundation.
Role of funding source
The study sponsor was not involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
IRB approval
This study involves human subjects and was approved by the Institutional Review Board of New York University's School of Medicine.
Financial disclosure
The authors declare they have no potential conflicts relevant to the manuscript.
CRediT authorship contribution statement
Abigail Gaylord: Methodology, Software, Validation, Formal analysis, Writing - original draft, Writing - review & editing, Visualization. Leonardo Trasande: Conceptualization, Methodology, Investigation, Writing - review & editing, Supervision, Project administration, Funding acquisition. Kurunthachalam Kannan: Validation, Investigation, Resources, Writing - review & editing, Supervision. Kristen M. Thomas: Investigation, Resources. Mengling Liu: Methodology. Jeremiah Levine: Conceptualization,
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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