Rapid Estrogen Receptor-Mediated Mechanisms Determine the Sexually Dimorphic Sensitivity of Ventricular Myocytes to 17β-Estradiol and the Environmental Endocrine Disruptor Bisphenol A

Abstract

Previously we showed that 17β-estradiol (E(2)) and/or the xenoestrogen bisphenol A (BPA) alter ventricular myocyte Ca(2+) handing, resulting in increased cardiac arrhythmias in a female-specific manner. In the present study, the roles of estrogen receptors (ER) in mediating the rapid contractile and arrhythmogenic effects of estrogens were examined. Contractility was used as an index to assess the impact of E(2) or BPA on Ca(2+) handling in rodent ventricular myocytes. The concentration-response curve for the stimulatory effects of BPA and E(2) on female myocyte was inverted-U shaped. Detectable effects for each compound were observed at 10(-12) M, and the most efficacious concentrations for each were at 10(-9) M. Sensitivity to E(2) and BPA was not observed in male myocytes and was abolished in myocytes from ovariectomized females. Analysis using protein-conjugated E(2) suggests that these rapid actions are induced by membrane-associated receptors. Analysis using selective ER agonists and antagonists and a genetic ERβ knockout mouse model showed that ERα and ERβ have opposing actions in myocytes and that the balance between ERβ and ERα signaling is the prime regulator of the sex-specific sensitivity toward estrogens. The response of female myocytes to E(2) and BPA is dominated by the stimulatory ERβ-mediated signaling, and the absence of BPA and E(2) responsiveness in males is due to a counterbalancing-suppressive action of ERα. We conclude that the sex-specific sensitivity of myocytes to estrogens and the rapid arrhythmogenic effects of BPA and estradiol in the female heart are regulated by the balance between ERα and ERβ signaling.

The regulation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor promotion by estradiol in female A/J mice

“…These results are consistent with previous studies showed that estrogen not only promotes the malignant development of breast cancer, but also acts on non-target organs, including lung cancer through various molecular mechanisms [21,22]. In addition to the solitary effect of estrogen, females exposed to other environmental chemicals such as benzo [a]pyrene that may interfere with the physiological functions of estrogen leading to increasing susceptibility of cancers [23][24][25]. However, our present study indicated that NNK combined with E2 and TCDD did not show an addictive effect in lung tumor formation, instead, the tumor multiplicity of NNK+TCDD+E2 groups was lower than NNK+E2 groups (Table 2).…”

The Adverse Cardiac Effects of Di(2-ethylhexyl)phthalate and Bisphenol A

“…Similar to previous reports, Patel et al identified sex-specific differences following BPA exposure, including concentric remodeling (male), increased systolic and diastolic blood pressure (female) and modified calcium handling protein expression (male & female). Interestingly, the authors reported a reduced ability to remove and store calcium in female rats – a result that contradicts data from previously published in vitro studies 119,120 . These conflicting results may be due to a compensatory effect resulting from long-term BPA exposure, and highlight the importance of assessing toxicity using multiple models and time points.…”

Low dose effects of bisphenol A

“…[60][61][62] Overall, these in vitro studies have examined a large number of cell types and biological endpoints that may be relevant to cellular function in vivo. The low dose cut-off of 1 × 10 -7 M has been debated and it may be reasonable to shift the low dose cut-off for in vitro studies to 10 One final study deserves attention due to its use of Organization for Economic Cooperation and Development (OECD) guidelines to test the effects of BPA on histopathological changes in the ovary.…”