Evaluating mechanisms of sex differences in environmentally-induced metabolic diseases

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Mechanistic studies pertaining to sex-based differences in metabolic syndrome (MetS) are currently insufficient to explain and prevent the higher prevalence of certain MetS symptoms in women versus men and higher prevalence of other symptoms such as hyperlipidemia in men versus women. MetS describes a constellation of risk factors, such as abdominal adiposity, hypertension, glucose intolerance/hyperglycemia, and dyslipidemia, leading to diabetes and cardiovascular morbidity. High-caloric intake and sedentary lifestyle habits are among key players shown to induce symptoms of MetS. However, exposures to environmental chemicals such as persistent organic pollutants (POPs), often dictated by socio-economic status and education levels, have been increasingly identified as additional key players leading to MetS consequences. Previous studies showed that exposures to POPs, such as organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), in in-vivo models and human studies were associated with diabetes, obesity and non-alcoholic fatty liver disease, which are hallmarks for MetS development. Furthermore, using in- vitro models and diet-induced obesity mouse models, we had previously demonstrated that the liver was the predominant target organ of toxicity to POPs, including PCBs, and mechanism(s) of toxicity were primarily through activation of hepatic receptors leading to metabolic disruption. The liver has long been established as a sexually dimorphic organ and it is therefore important to address POPs toxicity in term of biological differences or sex. Additionally, POPs such as OCPs are endocrine disrupting chemicals, having the ability to interact with androgen or estrogen receptors, and potentially promoting variable effects in men and women. However, most epidemiologic studies demonstrating associations between POPs exposure with liver toxicity/metabolic diseases including diabetes either focused on agricultural workers who were mostly men or adjusted for sex; but POPs exposures occur in both men and women and thus their health risks may vary. POPs exposures today is primarily through ingestion of contaminated food and water, and serum levels can vary depending on sex and gender. Hence, it is relevant to examine exposures to POPs such as OCPs based on ‘environment-sex-gene’ interactions to better address such discrepancies.