Novel Pathways of Endocrine Disruption Through Pesticides Interference With Human Mineralocorticoid Receptors

Mineralocorticoid receptor (MR) is one member of the steroid receptor family. In addition to its important role in Na+/K+ homeostasis, MR is reported as a tumor-suppressor in carcinogenesis. So far, little was known about the ability of pesticides to interfere with MR. In this study, a total of 43 pesticides and/or metabolites were investigated for their potential effects on human MR. None of the tested pesticides exhibited MR agonistic potency, whereas 16 compounds showed antagonistic activities. Further investigations indicated that these 16 chemicals individually antagonized aldosterone-induced alkaline phosphatase expression in vascular smooth muscle cells and aldosterone-inhibited hepatocellular carcinoma cell proliferation at higher concentrations, and the mixture of these 16 pesticides at environmentally relevant concentrations significantly disrupted MR activity. The additional quantitative mixture experiments indicated a good agreement between the combined anti-mineralocorticoidic activities of 16 pesticides and the responses predicted by concentration addition model instead of independent action model. The interruption of nuclear translocation of MR was clarified as a main mechanism for the anti-mineralocorticoidic activities by these pesticides. These data suggest that the health risk may increase when multiple MR antagonists cooperate following concentration addition model and exhibit a combined effect. Our findings emphasize that comprehensive risk assessment of adverse effects of environmental MR ligands on human health should be considered.