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

Abstract

Dimethoate is a widely used organophosphate insecticide that has been shown to disrupt reproductive function in animals. Although the pathogenesis of Dimethoateinduced reproductive toxicity remains to be determined, a reduction in serum testosterone levels is thought to play an important role in the development of Dimethoate-induced infertility. Since Leydig cells play a crucial role in male reproductive function by producing testosterone, the mouse MA-10 Leydig tumor cell line was used to determine if Dimethoate can directly block steroid hormone biosynthesis and to identify the site of steroidogenic inhibition. Dimethoate inhibited steroidogenesis in both a dose-and time-dependent manner without affecting total protein synthesis or protein kinase A activity. While it decreased the activity of the P450 side chain cleavage (P450 scc) enzyme, a reduction in the activity of this enzyme alone could not account for the level of Bu 2 cAMP-inhibited progesterone production. Instead, our results suggest that Dimethoate inhibited steroidogenesis primarily by blocking transcription of the steroidogenic acute regulatory (StAR) gene. This finding is significant since StAR protein mediates the rate-limiting and acutely-regulated step in steroidogenesis, the transfer of cholesterol from the outer to the inner mitochondrial membrane. This study indicates that StAR may be an important target for environmental pollutants which disrupt steroidogenesis and impair reproductive function.

Circulating estradiol in men is inversely related to urinary metabolites of nonpersistent insecticides

“…Our results are consistent with a recent study of Mexican agricultural workers, where Recio et al (36) measured dialkylphosphate metabolite concentrations in urine and sex hormone levels in serum from 64 men. They found an inverse association between diethylphosphate (DEP), a non-specific metabolite of chlorpyrifos, and estradiol (p-value = 0.04).…”

Effects of daidzein on testosterone secretion in cultured immature mouse testis

“…It is well known that testosterone is synthesized from cholesterol. The conversion of cholesterol to testosterone involves series of key steroidogenic proteins, such as StAR protein, cytochrome P450scc, and 3β-HSD [11][12][13]. The ratelimiting step in the synthesis of testosterone is the transfer of cholesterol to pregnenolone via P450scc; StAR mediates this rate-limiting step in steroidogenesis [35].…”

“…In addition, testosterone biosynthesis is involved in a series of biochemical processes and is mediated by several key proteins, such as steroidogenic acute regulatory protein (StAR) [11][12][13], cholesterol side-chain cleavage enzyme (p450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD) [11]. However, it is whether daidzein influences testosterone biosynthesis by influencing the expression of these proteins has hitherto remained unknown.…”

Influence of pesticides on male fertility

“…Several pesticides are able to decrease steroidogenesis, for example, by inhibiting specific enzymatic steps in the biosynthesis pathway of these hormones (30). Examples of pesticides with this mechanism are dimethoate, roundup, and lindane, which all reduce steroidogenic acute regulatory (StAR) protein expression (26,31,32). This particular protein mediates the transfer of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting and acutely regulating step in steroidogenesis.…”

“…By blocking the expression of this protein, Leydig cells produce less testosterone in vitro. Another mechanism of action is the reduction of P450 cholesterol side-chain cleavage enzyme (P450 scc ) activity by, for example, dimethoate, roundup, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane, a metabolite of methoxychlor, and ketoconazole (26,31,33,34). P450 scc is an enzyme that catalyzes the first reaction in the testosterone biosynthesis pathway: the conversion of cholesterol to pregnenolone.…”