Effects of environmental estrogen exposure on the heart

描述（由申请方提供）：我们拟定研究的目的是阐明暴露于雌激素外源性物质对心脏系统的毒理学效应，并定义这些药物作用的潜在药理学机制。我们也将探讨性别特异性的敏感性雌激素外源性物质诱导的心脏毒性作用的分子基础。雌激素内分泌干扰物（EDCs）是一类结构多样的化合物，可模拟或拮抗内源性雌激素的作用。内分泌干扰物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生双酚A（BPA）。雌激素性内分泌干扰物能够影响内源性雌激素的作用，即17？人们越来越认识到BPA和其他EDCs可能对生殖、神经和免疫系统产生有害影响。我们目前对EDC暴露的健康风险的认识中的一个显著差距是其对心脏生理学和健康的影响。重要的是，最近的一项流行病学研究表明，在美国成年人群中，较高的尿液BPA浓度与不良健康影响相关，包括心血管疾病（Lang等人，2008）。这一新证据强调了了解暴露于环境相关浓度的雌激素内分泌干扰物对心脏的影响的迫切需要，这是目前未知的。这种对雌激素性外源性物质在心脏中的作用的基本缺乏知识阻碍了对环境心脏危险因素的有效保护，以及预防-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，但不是在男性中的致瘤活性。我们已经表明雌激素药物快速促孕作用的潜在机制可能涉及肌浆网自发性钙泄漏增加，并且对EDCs的性别特异性易感性机制涉及膜雌激素受体（ER）的相反作用。这些研究结果导致我们的中心假设，E2和雌激素样内分泌干扰物，通过激活膜相关的ER机制，改变心脏Ca 2+处理的性别特异性的方式，至少有一些雌激素药物的行动有助于女性心脏的embrymogenesis。我们提出了三个具体的目标来解决这一假设：目标1是确定潜在的细胞机制的EDCs和E_2在大鼠心室肌细胞的促心律失常的作用：目标2是确定敏感性的性别特异性的分子基础快速E_2/EDC效应对心室肌细胞的收缩功能和心律失常的发生;目的3是在全器官水平上研究E2/EDCs对心律失常的影响，特别是在病理应激（包括儿茶酚胺刺激和缺血）时，并探讨潜在的预防/治疗策略。公共卫生相关性：我们的研究探讨了暴露于雌激素外源性物质和其他环境雌激素化合物对心脏系统，特别是女性的毒理学效应和潜在机制。这些研究具有高度的临床相关性，特别是在高危人群中女性心律失常方面。这些结果将为制定针对环境雌激素性心脏危险因素的保护措施以及开发与这些危险因素相关的心脏疾病的新预防或治疗策略提供关键知识。

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. PUBLIC HEALTH RELEVANCE: Our proposed study investigates the toxicological effects and underlying mechanism of exposure to estrogenic xenobiotics and other environmental estrogenic compounds on the cardiac system, particularly in women. These studies have high clinical relevance, particularly with respect to arrhythmias in women in the at risk population. The results will provide critical knowledge for the development of protective measures against environmental estrogenic cardiac risk factors, and the development of novel preventive or therapeutic strategies for cardiac diseases related to these risk factors.