by Kirsten Hartil
The increasing prevalence of obesity has major health and economic implications. Childhood obesity is of particular concern because obese children are more likely to become obese adults and they have increased risk of high blood pressure, high cholesterol, heart disease and type 2 diabetes. Identifying obesogens, environmental contaminants that contribute to obesity, and elucidating their mechanism are areas of clinical, basic and public health research.
Exposure to bisphenol A (BPA), a synthetic chemical used in the production of certain plastics, is linked to developmental, behavioral and reproductive problems in the fetus, infants and young children. Governments around the world (including the United States, Canada and members of the European Union) have banned its use in baby pacifiers, infant bottles, canned food and sippy cups.
A number of studies have also reported associations between BPA levels in urine (the current gold standard for estimating BPA exposure) and obesity (Wang; Carwile; Trasande; Eng; Harley; and Li). These publications have received widespread media attention in the Huffington Post, abcNEWS, NPR, USA TODAY and The New York Times. However, these studies were all cross-sectional in design limiting their interpretation.
During the Epidemiology class I took as part of the Masters of Public Health (MPH) program at Einstein, we covered Bradford Hill’s nine criteria for determining causation, the most important being temporality (exposure, in this case BPA, must precede the outcome – obesity). A caveat of cross-sectional studies is the simultaneous assessment of exposure and outcome, which precludes temporality being determined.
The gold-standard for determining causation is a randomized controlled trial (RCT), common in clinical studies, for ethical reasons, it is not possible in environmental health research to deliberately expose one group to something considered to cause an adverse outcome. Determining causality in this field relies on costly longitudinal prospective studies.
In another class, Environmental Health Sciences, our final assessment was to choose an environmental factor and its health outcome and present the route(s) of exposure, the biologically effective dose and the mode(s) of action by which the factor elicits its outcome. Given the media attention given to BPA and obesity, I thought this would be a straightforward choice and set about to demonstrate a biologically plausible mechanism, another of Hill’s criteria.
BPA is present in food and soda cans, water bottles, water supply pipes, sports equipment, medical and dental devices, dental filling sealants, CDs and DVDs, carbonless copy paper and thermal paper (i.e. sales receipts). As a result of its ubiquitous presence in everyday materials, human exposure to BPA is widespread, as it has been detected in the urine of greater than 90 percent of individuals.
BPA is an endocrine disruptor, similar to diethylstilbestrol (DES) historically given to pregnant women to alleviate morning sickness and prevent miscarriage. It was later discovered to increase vaginal cancers and to have other adverse reproductive health outcomes in female offspring. Perhaps because of this and because of the effect that endocrine disruptors can exert during periods of rapid cell growth and differentiation1 many peer-reviewed studies investigating BPA exposure have looked at in utero and perinatal exposure. The importance of the unterine environment and maternal exposure to endocrine disruptors on health and disease is well established, contributing to the Developmental Origins of Health and Disease (DOHaD) hypothesis.
Perinatal exposure to BPA, and other endocrine disruptors, in rodents are associated with obesity. In vivo and in vitro studies have demonstrated that exposure to endocrine disruptors alters estrogen receptor signaling, epigenetic modifications and changes in expression of genes that regulate fat cell number and mass 2-10.
However, less is known about the pharmacokinetics of BPA in humans including whether it is excreted before exerting a biological effect and whether obesity alters its metabolism in a way that may cause it to be excreted at higher levels.
So why might obese children have higher levels of BPA in their urine?
One possibility is that obese children are consuming more BPA-containing food and beverages. Obesity is more prevalent in individuals of lower socioeconomic status and in minorities, populations known to consume high amounts of soda and other sugar sweetened beverages. Additionally, people living in or near poverty are more likely to live in neighborhoods with reduced access to affordable fresh produce and consume high amounts of calorie dense processed foods. Both of these are well known to contribute to obesity and data from NHANES suggest associations between BPA levels and “consumption of soda, school lunches and meals prepared outside the home.”Factors that are associated with both the dependent (obesity) and independent variable (BPA) are called confounders. Confounding can be corrected for with statistical analyses but only if that information is collected at the time of the study.
So does BPA cause obesity? There is data supporting in utero BPA exposure and obesity in rodents. However, obesity develops over time and the current epidemiological data, obtained from cross-sectional studies, provides only a snapshot of recent exposure. Combined with the short half life of urinary BPA (estimated to be between <2 to 43 hours for urinary excretion), which does not provide an estimate of the biological dose, all that these cross-sectional analyses tell you is that individuals with higher urinary BPA are more likely to be obese. Nothing more.
Finally, as Paracelsus, the father or toxicology, is credited for saying: “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.”
Kirsten received her PhD in clinical biochemistry from Cambridge University, where she studied the developmental origins of health and disease, an area of research she continued when she joined Dr. Maureen Charron’s lab as a postdoc. In 2010 she joined Dr. Irwin Kurland’s lab in the Diabetes Research Center, and used metabolomics and stable isotopes to study metabolic flexibility. In 2012 she decided it was time for a career change and was accepted into the MPH program at Einstein. She hopes to transition into a career working to prevent obesity in people rather than study obesity in mice. She contends, “as scientists we have a responsibility to communicate research in a way that is both understandable and accurate. Being interesting and fun is a bonus. Some people are better at this than others. Contributing to the EJBM blog is my way of sharing stories that I think are important while improving my own writing skills.”
Follow Kirsten on twitter @khartil
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