Low doses of BPA induced abnormal mitochondrial fission and hypertrophy in human embryonic stem cell-derived cardiomyocytes via the calcineurin-DRP1 signaling pathway: A comparison between XX and XY cardiomyocytes
Low doses of BPA induced abnormal mitochondrial fission and hypertrophy in human embryonic stem cell-derived cardiomyocytes via the calcineurin-DRP1 signaling pathway: A comparison between XX and XY cardiomyocytes
复制标题
低剂量 BPA 通过钙调神经磷酸酶-DRP1 信号通路诱导人胚胎干细胞来源的心肌细胞异常线粒体分裂和肥大：XX 和 XY 心肌细胞之间的比较
DOI：
10.1016/j.taap.2019.114850
复制
发表时间：
2020-02-01
影响因子：
3.8
通讯作者：
Wang, Yan
中科院分区：
文献类型：
--
作者：
Cheng, Wei;Yang, Shoufei;Wang, Yan
人类不可避免地通过多种途径接触双酚A（BPA）。因此，应注意与低剂量SPA相关的可能不良反应。流行病学研究已经概述了BPA暴露和心血管疾病（如心脏肥大）风险增加，这已被证实在啮齿动物中具有性别特异性，并且在少数体外研究中存在，尽管分子机制仍不清楚。然而，低剂量BPA是否能通过破坏钙稳态，通过钙调神经磷酸酶-DRP 1信号通路诱导心肌肥大尚不清楚。为了解决这个问题，人胚胎干细胞（H1，XY核型和H9，XX核型）来源的心肌细胞（CM）的纯化和应用研究低剂量BPA对心肌细胞肥大的影响。在我们的研究中，当H1-和H9-CM暴露于非细胞毒性BPA（8 ng/ml）时，肥大相关的mRNA表达水平（如NPPA和NPPB）显著升高，细胞面积增加，ATP补充减少，证明了体外肥大心肌细胞表型。SPA产生的过度分裂由CnA β介导的DRP 1去磷酸化促进。在分子水平上，低剂量BPA引起的胞浆Ca 2+水平的增加可以区分H1-和H9-CM，这可能表明心肌细胞中存在潜在的性别特异性肥大风险，即通过损害CnA β-DRP 1信号传导导致线粒体分裂和ATP产生异常。在CnA β敲低的心肌细胞中，这些变化在XX核型的细胞中高度呈现，而不是在XY核型的细胞中。
Humans are inevitably exposed to bisphenol A (BPA) via multiple exposure ways. Thus, attention should be raised to the possible adverse effects related to low doses of SPA. Epidemiological studies have outlined BPA exposure and the increased risk of cardiovascular diseases (such as cardiac hypertrophy), which has been confirmed to be sex-specific in rodent animals and present in few in vitro studies, although the molecular mechanism is still unclear. However, whether BPA at low doses equivalent to human internal exposure level could induce cardiac hypertrophy via the calcineurin-DRP1 signaling pathway by disrupting calcium homeostasis is unknown. To address this, human embryonic stem cell (H1, XY karyotype and H9, XX karyotype)-derived cardiomyocytes (CM) were purified and applied to study the low-dose effects of BPA on cardiomyocyte hypertrophy. In our study, when H1- and H9-CM were exposed to noncytotoxic BPA (8 ng/ml), markedly elevated hypertrophic-related mRNA expression levels (such as NPPA and NPPB), enhanced cellular area and reduced ATP supplementation, demonstrated the hypertrophic cardiomyocyte phenotype in vitro. The excessive fission produced by SPA was promoted by CnA beta-mediated dephosphorylation of DRP1. At the molecular level, the increase in cytosolic Ca2+ levels by low doses of BPA could discriminate between H1- and H9-CM, which may suggest a potential sex-specific hypertrophic risk in cardiomyocytes in terms of abnormal mitochondrial fission and ATP production by impairing CnA beta-DRP1 signaling. In CnA beta-knockdown cardiomyocytes, these changes were highly presented in XX-karyotyped cells, rather than in XY-karyotyped cells.