Potential endocrine-disrupting effects of metals via interference with glucocorticoid and mineralocorticoid receptors

As a result of human activities, the pollution of metals is becoming ubiquitous in the environment. Among various toxicological mechanisms of action, metals have been considered as endocrine-disrupting chemicals (EDCs) through interference with steroid receptors. However, information regarding the potential endocrine disruption of metals on glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) is especially scarce. In this study, a total of 16 metals were assessed for their GR/MR activities using luciferase reporter gene assay. None of the tested metals exhibited GR or MR agonistic activity, but a total of 7 and 5 candidate metals showed obvious GR and MR antagonistic properties, respectively. All 7 GR antagonistic metals [ BaCl₂, CoCl₂, CuCl₂, Pb(NO₃)₂, LiCl, SnCl₂ and ZnCl₂] inhibited glucocorticoid-responsive gene GILZ expression in J774A.1 cells. Further investigations indicated that the 5 MR antagonistic metals [ CdCl₂, Pb(NO₃)₂, LiCl, MnCl₂ and SnCl₂] antagonized aldosterone-inhibited hepatocellular carcinoma cell proliferation. Among these metals, Pb(NO₃)₂, LiCl, and SnCl₂ showed both anti-glucocorticoid and anti-mineralocorticoid activities. Comprehensive screening and evaluation of GR and MR antagonists and agonists among metals should be considered to better understand the ecological and health risks of metals.