Lady Davis Institute for Medical Research, Montréal, Québec H3T 1E2, Canada.
Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
Toxicol Sci. 2017 Sep 1;159(1):189-202. doi: 10.1093/toxsci/kfx133.
Bisphenol A (BPA) leaches from plastics to contaminate foodstuffs. Analogs, such as bisphenol S (BPS), are now used increasingly in manufacturing. Greater BPA exposure has been correlated with exacerbation of cardiovascular disease, including myocardial infarction (MI). To test the hypothesis that bisphenol exposure impairs cardiac healing, we exposed C57bl/6n mice to water containing 25ng/ml BPA or BPS from conception and surgically induced an MI in adult male progeny. Increased early death and cardiac dilation, and reduced cardiac function were found post-MI in BPA- and BPS-exposed mice. Flow cytometry revealed increased monocyte and macrophage infiltration that correlated with increased chemokine C-C motif ligand-2 expression in the infarct. In vitro BPA and BPS addition increased matrix metalloproteinase-9 (MMP) protein and secreted activity in RAW264.7 macrophage cells suggesting that invivo increases in MMP2 and MMP9 in exposed infarcts were myeloid-derived. Bone marrow-derived monocytes isolated from exposed mice had greater expression of pro-inflammatory polarization markers when chemokine stimulated indicating an enhanced susceptibility to develop a pro-inflammatory monocyte population. Chronic BPA exposure of estrogen receptor beta (ERβ) deficient mice did not worsen early death, cardiac structure/function, or expression of myeloid markers after an MI. In contrast, BPS exposure of ERβ-deficient mice resulted in greater death and expression of myeloid markers. We conclude that lifelong exposure to BPA or BPS augmented the monocyte/macrophage inflammatory response and adverse remodeling from an MI thereby reducing the ability to survive and successfully recover, and that the adverse effect of BPA, but not BPS, is downstream of ERβ signaling.
双酚 A（BPA）会从塑料中渗出，污染食物。现在，类似物双酚 S（BPS）越来越多地用于制造。更多的 BPA 暴露与心血管疾病的恶化有关，包括心肌梗死（MI）。为了测试双酚暴露会损害心脏愈合的假设，我们从受孕开始就让 C57bl/6n 小鼠暴露于含有 25ng/ml BPA 或 BPS 的水中，并在成年雄性后代中进行了手术诱导的 MI。在 BPA 和 BPS 暴露的小鼠中，MI 后发现早期死亡率增加和心脏扩张，以及心脏功能降低。流式细胞术显示单核细胞和巨噬细胞浸润增加，与梗死部位趋化因子 C-C 基序配体-2 表达增加相关。体外 BPA 和 BPS 添加增加了 RAW264.7 巨噬细胞中的基质金属蛋白酶-9（MMP）蛋白和分泌活性，表明暴露的梗死灶中 MMP2 和 MMP9 的增加是骨髓源性的。从暴露的小鼠中分离出的骨髓源性单核细胞在趋化因子刺激时具有更高的促炎极化标志物表达水平，表明它们对发展促炎单核细胞群体的易感性增强。慢性 BPA 暴露于雌激素受体β（ERβ）缺陷小鼠不会加重 MI 后的早期死亡、心脏结构/功能或髓样标志物的表达。相比之下，BPS 暴露于 ERβ 缺陷小鼠会导致更多的死亡和髓样标志物的表达。我们得出结论，终生暴露于 BPA 或 BPS 会增强 MI 后的单核细胞/巨噬细胞炎症反应和不良重塑，从而降低生存和成功恢复的能力，而 BPA 的不良影响，而不是 BPS，是 ERβ 信号下游的。
