Disclosure: The authors declared no conflict of interest.
An Integrated Approach to Assess the Role of Chemical Exposure in Obesity
Version of Record online: 26 JUL 2013
Copyright © 2013 The Obesity Society
Volume 21, Issue 6, pages 1084–1085, June 2013
How to Cite
Legler, J. (2013), An Integrated Approach to Assess the Role of Chemical Exposure in Obesity. Obesity, 21: 1084–1085. doi: 10.1002/oby.20478
Funding agencies: We acknowledge the contribution of the entire OBELIX team and funding from the European Community's Seventh Framework Programme [FP7/2007-2013] under grant agreement no. 227391.
- Issue online: 26 JUL 2013
- Version of Record online: 26 JUL 2013
- Accepted manuscript online: 17 APR 2013 01:05PM EST
- Manuscript Accepted: 1 APR 2013
- Manuscript Received: 16 JAN 2013
The evidence that developmental exposure of humans to chemicals plays a role in onset of obesity is convincing, yet controversial as it challenges traditional views on the etiology of obesity. OBELIX, one of the largest pan-European studies researching the obesogen hypothesis, is accruing experimental and epidemiologic data on major classes of endocrine disrupting chemicals (EDCs) in both laboratory animal and prospective human cohort studies. Though still underway, this integrated and multidisciplinary project is adding new insights to the weight of evidence for effects of EDCs on obesity. Animal studies indicate divergent sex-specific effects of perinatal exposure on the development of overweight. In vitro mechanistic studies have shown that EDCs enhance murine adipocyte differentiation, an effect that is accompanied by global DNA demethylation. Epidemiological studies have revealed an inverse relationship between prenatal polychlorinated biphenyl exposure and birth weight, and suggest differences in pre- and postnatal exposure on growth trajectories in children.
The OBELIX (“OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life”) project is an ongoing multidisciplinary research project which focuses on assessing exposure to major classes of EDCs found in food including dioxins and dioxin-like polychlorinated biphenyls (PCBs), nondioxin-like PCBs, brominated flame retardants (BFRs), organochlorine pesticides, phthalates and perfluorinated alkyl acids, as well as bisphenol A (BPA) . A series of five long-term animal studies are underway, in which mice are exposed to EDCs through the diet during gestation and lactation. Offspring are monitored up to adulthood. Doses in animal experiments reflect human exposure and levels are below no adverse effect levels for developmental toxicity. Epidemiological studies involve mother-child cohorts from four European countries in which perinatal EDC exposure is determined in cord blood and milk samples, and growth and health status are followed up to 8 years. The strength of our approach is that we study the same chemicals in an integrated toxicological and epidemiological approach which we believe will allow for improved risk assessment.
Animal studies in OBELIX have revealed clearly divergent sex-specific effects of perinatal exposure to BPA, with male offspring showing body weight gain and females showing the opposite effect in adulthood, weeks after the exposure has ceased, with associated changes in serum lipids, hormones and related metabolic parameters (van Esterik et al, 2013, in preparation). Sex-specific effects of BPA have been shown before, both for obesity related and neurodevelopmental outcomes . These data indicate that gender stratification is essential when examining the role of chemical exposure in obesity development. Cross-sectional epidemiologic studies with phthalates, for example, have shown marked sex-specific differences in waist circumference and body mass index, based on the phthalate metabolite studied . Sex specific disease trajectories have also been noted for nutritional studies, as studies from the Dutch Hunger Winter show the association between prenatal famine and late life increase in BMI particularly in women, a sex-specific effect that is reflected in the sex-specific DNA methylation of genes . Recent studies have also shown that maternal diet triggers sex-specific transcriptomic and epigenomic responses in mouse placenta .
EDC-mediated changes in epigenetic processes such as DNA methylation, histone modifications, and microRNAs are proposed to play a role in the developmental origins of obesity. Animal studies showing irreversible effects of developmental EDC exposure on obesity have been attributed to epigenetic transgenerational inheritance . In OBELIX, mechanistic studies focus on understanding the role of changes in DNA methylation after developmental EDC exposure. We, and others, have demonstrated that exposure of the murine 3T3-L1 preadipocyte cell line to a variety of EDCs results in enhanced differentiation of adipocytes. Importantly, our work has also shown that 3T3 differentiation by EDCs is generally accompanied by global DNA hypomethylation  and specific changes in gene expression and promoter methylation of PPARγ, the master regulator of adipocyte differentiation (Kamstra et al, in preparation). Confirmation of the predictability of this in vitro model for humans remains a daunting task. For some EDCs, such as tributyltin and BPA, adipogenic responses in 3T3-L1 cells correlate with obesogenic effects in vivo following prenatal exposure in rodents. Recent studies, however, show considerable differences between the 3T3-L1 and human adipocyte transcriptome and epigenome. While transcription factors critical for adipocyte differentiation are shared, including PPARγ and genes associated with lipid metabolism, there are differences in expression of other genes such as the androgen receptor shown recently to be important for human adipocyte differentiation . These differences highlight the importance of using of human in vitro models for predicting effects in humans.
Prospective cohort studies in OBELIX are still underway. Our first published study has indicated an inverse relationship between PCB 153 (a marker of PCB exposure) and birth weight in a meta-analysis of 12 European birth cohorts . Decreases in birth weight of 150 g with each 1 μg L−1 increase of PCB 153 in cord serum were observed. The birth weight decreases related to PCB exposure are reminiscent of the changes found in birth weight in Dutch Hunger Winter babies, and the association is comparable to what known for smoking during pregnancy, a known risk factor for low birth weight as well as childhood obesity. Interestingly, no association of 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE), the breakdown product of the organochlorine pesticide DDT, and birth weight was found in the meta-analysis, though at an individual cohort level, some cohorts did also observe a significant inverse relationship . We are currently examining the growth trajectories in our children, and differentiating between pre- and postnatal exposure to EDCs. It is clear that postnatal exposure, i.e., breastfeeding, is a major source of exposure in the developing infant that has largely been overlooked in epidemiological studies, certainly those studying chemical-obesity links. We have developed a novel toxicokinetic model to simulate levels of persistent organic pollutants (POP) in children's blood that accurately estimates POP levels at 6 months and later based on maternal or cord blood levels . Using this model, preliminary analyses indicate divergent effects of pre- and postnatal exposure to POPs on growth trajectories in children.
OBELIX is tackling this controversial issue of the role of chemical exposure in obesity development with an open mind and by using sound science, with a multidisciplinary team of toxicologists, molecular biologists, chemists, epidemiologists, pediatricians and risk assessors. We have added to the weight of evidence that specific chemicals influence health outcomes related to obesity, while for other chemicals, the jury is still out. Many questions remain, such as what is role of exposure to the complex mixtures of chemicals we encounter in everyday life? Do chemicals play a role in other novel, putative mechanisms of obesity, such as circadian rhythms, inflammation or composition of gut microbiota? And what is the combined effect of chemical exposure and an adverse fetal environment, such as under or overnutrition? There is clearly much work still to be done in this field that calls for diverse expertise and an integrated approach.
- 7Effects of endocrine disrupting chemicals on in vitro global DNA methylation and adipocyte differentiation. Toxicol In vitro (in press)., , , et al.