Abstract
Procymidone is a fungicide with anti-androgenic properties, widely used to protect fruits from fungal infection. Thereby it contaminates fruit products prepared for human consumption. Genistein-containing soy products are increasingly used as food additives with health-promoting properties. Therefore we examined the effects of long-term dietary administration (3 months) of the anti-androgen procymidone (26.4 mg/animal per day) or the phytoestrogen genistein (21.1 mg/animal per day) to rats on the pituitary-gonadal axis in vivo, as well as on Leydig cell steroidogenesis and on spermatogenesis ex vivo. The procymidone-containing diet elevated serum levels of LH and testosterone and, furthermore, Leydig cells isolated from procymidone-treated animals displayed an enhanced capacity for producing testosterone in response to stimulation by hCG or dibutyryl cAMP, as well as elevated expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450 scc) and cytochrome P450 17alpha (P450c17). In contrast, the rate of DNA synthesis during stages VIII and IX of spermatogenesis in segments of seminiferous tubules isolated from genistein-treated rats was decreased without accompanying changes in the serum level of either LH or testosterone. Nonetheless, genistein did suppress the ex vivo steroidogenic response of Leydig cells to hCG or dibutyryl cAMP by down-regulating their expression of P450 scc. Considered together, our present findings demonstrate that long-term dietary administration of procymidone or genistein to rats exerts different effects on the pituitary-gonadal axis in vivo and on Leydig cell steroidogenesis ex vivo. Possibly as a result of disruption of hormonal feedback control due to its anti-androgenic action, procymidone activates this endocrine axis, thereby causing hyper-gonadotropic activation of testicular steroidogenesis. In contrast, genistein influences spermatogenesis and significantly inhibits Leydig cell steroidogenesis ex vivo without altering the serum level of either LH or testosterone.
Highlights
It is increasingly clear that certain industrial chemicals, pharmaceuticals, phytosterols and food supplements can mimic or antagonize the actions of endogenous hormones and in this manner adversely affect the endocrine and reproductive systems (Gray et al 2001)
Dietary administration of procymidone to rats for 12 weeks resulted in 3- and 6-fold increases in their serum concentrations of luteinizing hormone (LH) and testosterone, respectively; whereas similar treatment with genistein was without significant effect on these parameters (Fig. 1)
To determine whether the significant alterations in Leydig cell steroidogenesis ex vivo observed in rats administered either genistein or procymidone, as well as the increase in the plasma concentration of testosterone observed in procymidone-treated animals, were correlated with changes in the expression of the key steroidogenic enzymes, the levels of these proteins were measured by Western blotting
Summary
It is increasingly clear that certain industrial chemicals, pharmaceuticals, phytosterols and food supplements can mimic or antagonize the actions of endogenous hormones and in this manner adversely affect the endocrine and reproductive systems (Gray et al 2001). Environmental chemicals suspected of acting as endocrine disrupters can be divided into two major classes: anti-androgens, primarily pesticides, that are antagonists of the androgen receptor; and compounds with estrogen-like structures that act as agonists for estrogen receptors. The pesticide procymidone is used as a fungicide and was shown to be present in fruit products prepared for human consumption (Ostby et al 1999, Ohno et al 2003). It is a typical anti-androgen, competitively inhibiting the binding of androgens to the human androgen receptor and thereby preventing androgen-induced gene expression (Ostby et al 1999). This substance reduces anogenital distance and the size of accessory sex glands in male pups
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