The pro-atherogenic effects and the underlying mechanisms of chronic bisphenol S (BPS) exposure in apolipoprotein E-deficient mice

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Atherosclerosis (AS) and its related cardiovascular diseases (CVDs) remain the most frequent cause of morbidity and mortality worldwide. Researches showed that bisphenol A (BPA) exposure might exacerbate AS progression. However, as an analogue of BPA, little is known about the cardiovascular toxicity of bisphenol S (BPS), especially whether BPS exposure has the pro-atherogenic effects in mammals is still unknown. Here, we firstly constructed an apolipoprotein E knockout (ApoE -/- ) mouse model and cultured cells to investigate the risk of BPS on AS and explore the underlying mechanisms. Results showed that prolonged exposure to 50 μg/kg body weight (bw)/day BPS indeed aggravated AS lesions both in the en face aortas and aortic sinuses of ApoE -/- mice. Moreover, BPS were found to be implicated in the AS pathological process: 1) stimulates adhesion molecule expression to promote monocyte-endothelial cells (ECs) adhesion with 3.6 times more than the control group in vivo ; 2) increases the distribution of vascular smooth muscle cells (VSMCs) with 9.3 times more than the control group in vivo , possibly through the migration of VSMCs; and 3) induces an inflammatory response by increasing the number of macrophages (MACs), with 3.7 times more than the control group in vivo , and the release of inflammatory mediators. Furthermore, we have identified eight significant AS-related genes induced by BPS, including angiopoietin-like protein 7 (Angptl17) and lipocalin-2 (Lcn2) in ECs; matrix metalloproteinase 9 (Mmp13), secreted phosphoprotein 1 (Spp1), and collagen type II alpha 1 (Col2a1) in VSMCs; and kininogen 1 (Kng1), integrin alpha X (Itgax), and MAC-expressed gene 1 (Mpeg1) in MACs. Overall, this study firstly found BPS exposure could exacerbate mammalian AS and might also provide a theoretical basis for elucidating BPS and its analogues induced AS and related CVDs. • Bisphenol S (BPS) exacerbated atherosclerosis (AS) development in mice. • BPS induced-AS might be caused by impairing vascular cell function. • Several BPS-induced AS-related genes were identified at the molecular level. • This might give inspiration for the pro-atherogenic effect of BPS analogues.

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