Dimethoate inhibits steroidogenesis by disrupting transcription of the steroidogenic acute regulatory (StAR) gene

Dimethoate is a widely used organophosphate insecticide that has been shown to disrupt reproductive function in animals. Although the pathogenesis of Dimethoate-induced reproductive toxicity remains to be determined, a reduct ion in serum testosterone levels is thought to play an important role in th e development of Dimethoate-induced infertility. Since Leydig cells play a crucial role in male reproductive function by producing testosterone, the m ouse MA-10 Leydig tumor cell line was used to determine if Dimethoate can d irectly block steroid hormone biosynthesis and to identify the site of ster oidogenic inhibition. Dimethoate inhibited steroidogenesis in both a dose- and time-dependent manner without affecting total protein synthesis or prot ein kinase A activity. While it decreased the activity of the P450 side cha in cleavage (P450 sec) enzyme, a reduction in the activity of this enzyme a lone could not account for the level of Bu(2)cAMP-inhibited progesterone pr oduction. Instead, our results suggest that Dimethoate inhibited steroidoge nesis primarily by blocking transcription of the steroidogenic acute regula tory (StAR) gene. This finding is significant since StAR protein mediates t he rate-limiting and acutely-regulated step in steroidogenesis, the transfe r of cholesterol from the outer to the inner mitochondrial membrane. This s tudy indicates that StAR may be an important target for environmental pollu tants which disrupt steroidogenesis and impair reproductive function.