Inorganic Arsenic Exposure Induces Sex Disparate Effects and Exacerbates Ischemia-Reperfusion Injury in the Female Heart

Arsenic is a common contaminant in drinking water throughout the world, and recent studies support a link between inorganic arsenic (iAS) exposure and ischemic heart disease in men and women. Female hearts exhibit an estrogen-dependent reduction in susceptibility to myocardial ischemic injury compared to males, and as such, female hearts may be more susceptible to the endocrine disrupting effects of iAS exposure. However, iAS exposure and susceptibility to ischemic heart injury have not been examined in mechanistic studies. Male and female mice (eight weeks) were exposed to environmentally relevant concentrations of sodium arsenite (0 parts per billion (ppb), 10 ppb, 100 ppb, and 1000 ppb) via drinking water for four weeks. Pre- and post-exposure echocardiography was performed, and post-exposure plasma was collected for 17β-estradiol measurement. Hearts were excised and subjected to ischemia-reperfusion (I/R) injury via Langendorff perfusion. Exposure to 1000 ppb iAS led to sex-disparate effects, such that I/R injury was exacerbated in female hearts, but unexpectedly attenuated in males. Assessment of echocardiographic parameters revealed statistically significant structural remodeling in iAS-treated female hearts with no change in function; males showed no change. Plasma 17β-estradiol levels were not significantly altered by iAS in male or female mice vs. non-treated controls. Although total eNOS protein levels did not change in whole heart homogenates from iAS-treated male or female mice, eNOS phosphorylation (Ser1177) was significantly elevated in iAS-treated male hearts. These results suggest that iAS exposure can induce sex disparate effects and modulate susceptibility to ischemic heart injury by targeting distinct sex-dependent pathways.