Effect of sex hormones on the fate of methylmercury and on glutathione metabolism in mice

Abstract

To investigate the mechanisms for the sex-related difference in the in vivo fate of methyl-mercury (MeHg), the effects of hormonal manipulation on the distribution and urinary excretion of the mercurial moiety (Hg) of injected MeHg and on hepato-renal metabolism of glutathione were studied in C57BL/6N mice. Twenty-four hours after oral administration of MeHg, urinary Hg levels were significantly higher in males than in females. Tissue Hg levels of males were higher in the kidney, but lower in the brain, liver and plasma than those of females. The fate of injected MeHg in castrated males was similar to that in normal females except for its brain levels. This feminization of the mercurial behavior in the castrated males was restored by treating with testosterone propionate (TP). When control mice were treated with TP, urinary excretion of Hg increased in both sexes, whereas renal Hg level increased only in females. Administration of estradiol benzoate (EB) to males decreased the renal accumulation and urinary excretion of Hg, whereas its hepatic levels increased. However, no significant change in the fate of MeHg was found in females pretreated with EB. Castration of females slightly decreased the urinary excretion of Hg. Thus, tissue distribution and urinary excretion of the administered MeHg seem to be subject to sex hormone control. Since MeHg has a high affinity for GSH, effects of hormonal manipulation on the metabolism of hepato-renal glutathione were also investigated. A significant sex-related difference in glutathione levels was found in plasma but not in the kidney, liver and erythrocytes. The half-lives of glutathione in the liver and kidney were significantly shorter in males than in females as determined by treatment with buthionine sulfoximine, a specific inhibitor of GSH synthesis. This difference was also modulated by the hormonal treatment. Since half-lives of GSH in the liver and kidney predominantly reflect the rate of its efflux from these tissues, the results suggest that GSH metabolism and/or secretory transport may be regulated by sex hormones. These and other observations suggest that the fate of MeHg may be modulated by way of regulating the inter-organ metabolism and transport of glutathione and its derivatives.