Effects of environmental estrogen exposure on the heart

描述(申请人提供)：我们提议的研究的目标是阐明暴露于雌激素类外源物质对心脏系统的毒理学影响，并确定这些物质作用的潜在药理学机制。我们还将研究雌激素性异源生物诱导的心脏毒性效应的性别易感性的分子基础。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。内分泌细胞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源双酚A(BPA)。雌激素样的内分泌细胞能够影响内源性雌激素的作用，即17β-雌二醇(E_2)，人们越来越认识到BPA和其他内源性内分泌细胞对生殖、神经和免疫系统有不良影响。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，在美国成年人群中，较高的尿双酚A浓度与包括心血管疾病在内的不良健康影响相关(Lang等人，2008年)。这一新证据突显了了解暴露于环境相关浓度的雌激素内分泌细胞对心脏的影响的迫切需要，这些影响目前尚不清楚。对雌激素类外源物质在心脏中的影响缺乏基本的了解，这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上相关的低剂量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，但对男性没有。我们已经证明雌激素快速致心律失常作用的潜在机制可能是增加肌浆网的自发性钙泄漏，而性别特异性易感性的机制涉及膜雌激素受体(ER)S的相反作用。这些发现导致我们的中心假设，E2和雌激素样的EDCs通过激活膜相关的ER机制，以性别特异性的方式改变心脏的钙处理，至少一些雌激素药物的作用有助于女性心脏的心律失常。我们针对这一假说提出了三个具体的目标：目的1是确定EDCs和E_2对大鼠心室肌细胞促心律失常作用的细胞机制(S)；目的2是确定对快速的E_2/E_2作用的易感性对心室肌细胞收缩功能和心律失常易感性的分子基础；以及目的3是确定E_2/E_DC在整个器官水平上对心律失常的影响，特别是在病理性应激期间，包括儿茶酚胺刺激和缺血，并探索潜在的预防/治疗策略来保护此类心律失常。公共卫生相关性：我们拟议的研究调查了雌激素异源化合物和其他环境雌激素化合物对心脏系统的毒理学影响和潜在机制，特别是在女性。这些研究具有很高的临床相关性，特别是关于高危人群中女性的心律失常。这一结果将为制定针对环境雌激素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.