Effects of environmental estrogen exposure on the heart

描述（由申请人提供）：我们提出的研究目的是阐明暴露于雌激素异种药物对心脏系统的毒理学影响，并确定这些药物作用的潜在药理学机制。我们还将研究雌激素外源性药物诱导的心脏毒性效应的性别特异性易感性的分子基础。雌激素内分泌干扰化学物质（EDCs）是一种结构多样的化合物，可以模仿或拮抗内源性雌激素的作用。EDCs对人类健康的一个特别重要的例子是几乎无处不在的雌激素异种双酚A （BPA）。雌激素性EDCs有能力影响内源性雌激素的作用，即17？越来越多的人认识到BPA和其他EDCs对生殖系统、神经系统和免疫系统都有有害的影响。在我们目前对EDC暴露的健康风险的认识中，一个显著的差距是它对心脏生理和健康的影响。重要的是，最近的一项流行病学研究表明，在美国成年人中，较高的尿液BPA浓度与不利的健康影响有关，包括心血管疾病（Lang et al, 2008）。这一新证据强调了迫切需要了解暴露于环境相关浓度的雌激素EDCs对心脏的影响，这一点目前尚不清楚。对雌激素异种抗生素在心脏中的作用缺乏基本的认识，阻碍了对环境心脏危险因素的有效保护，也阻碍了预防治疗策略的发展。我们提出了令人信服的初步结果，表明暴露于环境或生理相关的低剂量BPA和E2迅速促进女性心室肌细胞和女性心脏的心律失常活动，但在男性中没有。我们已经表明，雌激素药物快速促心律失常作用的潜在机制可能与肌浆网自发钙泄漏增加有关，而EDCs的性别特异性易感性机制与膜雌激素受体（ER）的相反作用有关。这些发现导致我们的中心假设，E2和雌激素EDCs，通过激活膜相关的内质网机制，以性别特异性的方式改变心脏Ca2+处理，至少一些雌激素药物的作用有助于女性心脏心律失常的发生。我们提出了三个具体目标来解决这一假设：目标1是确定EDCs和E2在大鼠心室肌细胞中的促心律失常作用的细胞机制；目的2：明确E2/EDC快速影响心室肌细胞收缩功能和心律失常的易感性性别特异性的分子基础；目的3是在全器官水平上确定E2/EDCs对心律失常的影响，特别是在病理性应激下，包括儿茶酚胺刺激和缺血，并探索潜在的预防/治疗策略，以保护心律失常。

DESCRIPTION (provided by applicant): The goal of our proposed study is to elucidate the toxicological effects of exposure to estrogenic xenobiotics on the cardiac system, and to define the underlying pharmacological mechanisms of actions of these agents. We will also investigate the molecular basis for the sex-specific susceptibility to estrogenic xenobiotics-induced cardio-toxic effect. Estrogenic endocrine-disrupting chemicals (EDCs) are structurally diverse compounds that mimic, or antagonize the actions of endogenous estrogens. A particularly significant example of EDCs to human health is the nearly ubiquitous estrogenic xenobiotic bisphenol A (BPA). Estrogenic EDCs have the ability to impact the actions of endogenous estrogen, i.e. 17?-estradiol (E2), and it is increasingly recognized that BPA and other EDCs can have harmful effects on the reproductive, nervous and immune systems. A notable gap in our current knowledge on health risks of EDC exposure is its impact on cardiac physiology and health. Importantly, a recent epidemiologic study has shown that in the US adult population, higher urine BPA concentrations are associated with adverse health effects, including cardiovascular disease (Lang et al, 2008). This new evidence highlights the critical need to understand the effects of exposure to environmentally relevant concentrations of estrogenic EDCs on the heart, which are currently unknown. This fundamental lack of knowledge regarding the effects of estrogenic xenobiotics in the heart hinders effective protection against environmental cardiac risk factors, and the development of preventive-therapeutic strategies. We present compelling preliminary results showing that exposure to environmentally or physiologically relevant low-dose of BPA and E2 rapidly promotes arrhythmogenic activity in female ventricular myocytes and female hearts, but not in male. We have shown that the underlying mechanism of the rapid pro-arrhythmic effects of estrogenic agents likely involve increased spontaneous Ca leak from the sarcoplasmic reticulum, and that the mechanism of the sex-specific susceptibility to EDCs involves the opposing effects of membrane estrogen receptors (ER)s. These findings lead to our central hypothesis that E2 and estrogenic EDCs, via activation of membrane associated ER mechanisms, alter cardiac Ca2+ handling in a sex-specific manner, and that the actions of at least some estrogenic agents contribute to arrhythmogenesis in female hearts. We propose three Specific Aims to address this hypothesis: Aim 1 is to determine the cellular mechanism(s) underlying the pro- arrythmogenic effects of EDCs and E2 in rat ventricular myocytes; Aim 2 is to define the molecular basis for the sex-specificity of susceptibility to rapid E2/EDC effects on contractile function and arrhythmogenesis of ventricular myocytes; and Aim 3 is to determine the effects of E2/EDCs on cardiac arrhythmias at the whole organ level, especially during pathologic stress, including catecholamine stimulation and ischemia, and explore potential preventive/therapeutic strategies for protection against such arrhythmias.