The effects of environmental pollutants on steroidogenesis and steroidogenic acute regulatory protein expression

Many environmental pollutants disrupt male reproductive function, inhibit steroid hormone biosynthesis, reduce serum testosterone levels, and decrease sperm counts. Although a disruption in steroidogenesis may underlie toxicant-induced reproductive toxicity, the mechanism by which these compounds inhibit steroid production remains unclear. The steroidogenic acute regulatory (StAR) protein mediates the rate-limiting and acutely-regulated step in steroidogenesis, the transfer of cholesterol from the outer to the inner mitochondrial membrane where die cytochrome P450 side chain cleavage (P450scc) enzyme initiates the synthesis of all steroid hormones. We hypothesized that environmental toxicants block steroidogenesis by disrupting StAR protein expression for several reasons: first, in contrast to the steroidogenic enzymes which have long half-lives and are chronically regulated, StAR protein is not an enzyme, is acutely regulated, its active form is highly labile and it must be continuously synthesized for steroid production to persist. Second, because StAR protein mediates the rate-limiting step in steroidogenesis, steroid production is very sensitive to disruptions in its expression. Finally, recent studies suggest that some environmental pollutants inhibit steroidogenesis by reducing cholesterol availability, implicating StAR protein as a potential target for these compounds.

Using mouse MA-10 Leydig tumor cells, we studied the effects of acute exposure (<4 h) to the organochlorine insecticide lindane (y-hexachlorocyclohexane; HCH), the organophosphate insecticide Dimethoate, the herbicide Roundup, and the imidazole antifungal drugs econazole and miconazole on: (1) steroid production, (2) total cellular protein synthesis, (3) StAR and steroidogenic enzyme activity and expression, and (4) protein kinase A (PKA) activity. Our studies demonstrate that these toxicants reversibly inhibited steroidogenesis without causing cell toxicity or affecting PKA activity. While lindane and Dimethoate reduced StAR protein expression by reducing StAR mRNA levels. Roundup, econazole and miconazole reduced StAR protein levels post-transcriptionally. Although Roundup and Dimethoate inhibited P450scc activity, a reduction in StAR protein expression alone could account for the effects of these compounds on steroidogenesis, suggesting that the inhibition of P450scc activity in these instances has little physiological significance, its activity being distal to StAR function. Our studies strongly suggest that several different classes of environmental pollutants inhibit steroidogenesis by reducing StAR protein expression, thus supporting our hypothesis.