Effects During Puberty

Peripubertal administration of EDCs can alter the onset of pubertal landmarks in male [107,112] and female rats [20,107]. Androgens play a key role in pu-

bertal maturation in young males [113] and antiandrogens like vinclozolin produce predictable alterations in this process. The ease with which a delay in preputial separation (PPS), a landmark of puberty in the rat, can be measured enables us to use this endpoint to evaluate chemicals for this form of endocrine activity. A "pubertal male assay" including an assessment of PPS is being considered by the USEPA and others [114] for screening chemicals for endocrine activity, as mandated by 1996 US legislation (the Food Quality Protection Act and Safe Drinking Water Act).

Peripubertal treatment with the antiandrogen p,p'-DDE [105] or methoxy-chlor [107], which is not only antiandrogenic but also displays estrogenic activity, delays the onset of androgen-dependent PPS. Pubertal delays have also been detected following exposure to weakly antiandrogenic toxicants like linuron and di-M-butyl phthalate [115]. In contrast, reproductive toxicants like carben-dazim that indirectly alter FSH levels without affecting serum testosterone fail to delay PPS even at dosage levels that cause profound alterations of testicular and hypothalamic-pituitary (FSH secretion) function [116].

We conducted a study to examine the effects of peripubertal oral administration of vinclozolin (0,10,30, or 100 mg/kg/day) on morphological landmarks of puberty, hormone levels, and sex accessory gland development in male rats [112]. Since binding of the M1 and M2 to AR alters the subcellular distribution of AR by inhibiting AR-DNA binding, we examined the effects of vinclozolin on AR distribution in the target cells after in vivo treatment, and measured serum levels of vinclozolin, M1, and M2 in the treated males so that these could be related to the effects on the reproductive tract and AR distribution. Vinclozolin treatment delayed pubertal maturation, and retarded sex accessory gland and epididymal growth (at 30 and 100 mg/kg/day). Serum LH (significant at all dosage levels), testosterone and 5a-androstane-3a,17b-diol (at 100 mg/kg/d) levels were increased. Testis size and sperm production, however, were unaffected. It was apparent that these effects were concurrent with subtle alterations in the subcellular distribution of AR. In control animals, most AR was in the high salt cell fraction, apparently bound to the natural ligand and DNA. Vinclozolin treatment reduced the amount of AR in the high salt (bound to DNA) fraction and increased AR levels in the low salt (inactive, not bound to DNA) fraction. M1 and M2 were found in the serum of animals from the two highest dosage groups at levels well below their Ki values. These results suggest that when the vinclozolin metabolites occupy a small percentage of AR, this prevents maximal AR-DNA binding, alters in vivo androgen-dependent gene expression and protein synthesis, which in turn results in obvious alterations of morphological development and serum hormone levels.

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