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

Background: Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, has been extensively demon-strated 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.Objectives: This study is designed to explore the toxicological pathogenesis of chronic inflammation in BPA exposure during obesity. Methods: We 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.Results: Here, 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 beta = 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 attrib-uted up to 30.01% mediating role in the associations between BPA exposure and obesity risk.Discussion: This 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 envi-ronmental endocrine disruptor BPA in metabolic disorders and unveils the potential toxicological mechanisms underpinning such effect.