REPRODUCTIVE TOXICITY AND GROWTH EFFECTS IN RATS EXPOSED TO LEAD AT DIFFERENT PERIODS DURING DEVELOPMENT

The reproductive toxicity and growth effects of developmental lead exp osure were assessed using a rat model in which 0.6% (w/ v) lead acetat e was administered in the drinking water ad libitum. Three series of e xperiments were conducted in which lead exposure was initiated beginni ng in utero, prepubertally, or postpubertally. Lead effects were measu red on reproductive physiology and endocrinology, sexually dimorphic h epatic testosterone hydroxylation, and growth rates in both male and f emale animals. In male animals secondary sex organ weights were signif icantly decreased only in animals exposed prepubertally. In addition, serum testosterone levels were significantly suppressed, most severely in animals exposed from in utero (in the in utero group). Little effe ct was observed in adult female rats. However, in female animals expos ed prepubertally, delayed vaginal opening and disrupted estrus cycling was observed, More severe reproductive disruption was accompanied by suppression of circulating estradiol in the in utero group. Effects on circulating sex steroids were accompanied by variable effects on circ ulating luteinizing hormone (LH) levels, pituitary LH, and pituitary L H beta mRNA, suggesting a dual site of lead action: (a) at the level o f the hypothalamic pituitary unit, and (b) directly at the level of go nadal steroid biosynthesis. Prepubertal growth in both sexes was suppr essed 25% in the in utero group. However, pubertal growth rates were s ignificantly suppressed only in male animals and postpubertal growth w as not significantly different from controls in any of the experiments , despite continued exposure to high lead levels in the drinking water . In addition, at age 85 days, male-specific hepatic hydroxylation of testosterone at positions 2 alpha and 16 alpha, which is catalyzed by a cytochrome P450 isozyme CYP 2C11, itself regulated by sexually dimor phic growth hormone secretion, was unaffected. This suggests that the growth effects of lead are possibly due to a delay in the development of sex-specific pituitary growth hormone secretion patterns rather tha n a persistent developmental defect. Thus, the reproductive and growth effects of lead are complex and sex-dependent, and appear to involve multiple sites on the hypothalamic- pituitary gonadal axis. (C) 1996 a cademic Press, Inc.