Environmental endocrine disruptor Bisphenol A induces metabolic derailment and obesity via upregulating IL-17A in adipocytes

Abstract

BackgroundBisphenol A (BPA), a ubiquitous environmental endocrine disruptor, has been extensively demonstrated to be associated with metabolic disorders, including obesity and type 2 diabetes mellitus. However, the underlying mechanism underpinning the environmental etiology of chronic metabolic disorders has not been sufficiently elucidated. ObjectivesThis study is designed to explore the toxicological pathogenesis of chronic inflammation in BPA exposure during obesity. MethodsWe investigated the role of IL-17A in the association of BPA exposure and obesity from human cross-sectional study to animal models, including genetically modified IL-17A-/- mice. ResultsHere, our work started from case-control observation that BPA exposure was significantly associated with risk of obesity (odds ratio = 4.72, 95%CI: 3.18 – 11.18, P < 0.01), metabolic disorder and levels of interleukin-17A (IL-17A) in human adipose (estimated changes β = 0.46, 95%CI: 0.15 – 1.01, P < 0.01) with bariatric surgery. Animal model fed with high-fat diet (HFD) confirmed that BPA exposure aggravated body weight gain and insulin resistance, concurrent with much heightened inflammatory responses in the adipose tissue including increase in IL-17A and macrophage polarization towards M1 stage. Genetically modified IL-17A ablated mice (IL-17A-/-) showed reversed adipose tissue inflammation response, improved macrophage polarization homeostasis, along with insulin sensitivity in both HFD group alone or much more significantly the HFD + BPA group. Moreover, mediation analysis in human epidemiological investigation demonstrated that plasma IL-17A attributed up to 30.01% mediating role in the associations between BPA exposure and obesity risk. DiscussionThis research paradigm from human to animal provides strong evidence for the elucidation of IL-17A moderating inflammation and insulin resistance in obesity. Such findings reiterate the obesogenic role of environmental endocrine disruptor BPA in metabolic disorders and unveils the potential toxicological mechanisms underpinning such effect.