title: Reproductive toxicity and growth effects in rats exposed to lead at different periods during development.
abstract: The reproductive toxicity and growth effects of developmental lead exposure were assessed using a rat model in which 0.6% (w/v) lead acetate was administered in the drinking water ad libitum. Three series of experiments were conducted in which lead exposure was initiated beginning in utero, prepubertally, or postpubertally. Lead effects were measured on reproductive physiology and endocrinology, sexually dimorphic hepatic testosterone hydroxylation, and growth rates in both male and female animals. In male animals secondary sex organ weights were significantly 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 effect was observed in adult female rats. However, in female animals exposed 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 circulating luteinizing hormone (LH) levels, pituitary LH, and pituitary LH beta mRNA, suggesting a dual site of lead action: (a) at the level of the hypothalamic pituitary unit, and (b) directly at the level of gonadal steroid biosynthesis. Prepubertal growth in both sexes was suppressed 25% in the in utero group. However, pubertal growth rates were significantly suppressed only in male animals and postpubertal growth was 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 dimorphic 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 than 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.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ronis
authors.forename: T M
authors.initials: TM
authors.lastname: Badger
authors.forename: S J
authors.initials: SJ
authors.lastname: Shema
authors.forename: P K
authors.initials: PK
authors.lastname: Roberson
authors.forename: F
authors.initials: F
authors.lastname: Shaikh
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005314:Embryonic and Fetal Development / Q000187:drug effects; D004958:Estradiol / Q000097:blood; D005260:Female; D005837:Genitalia, Male / Q000187:drug effects; D007854:Lead / Q000097:blood / Q000633:toxicity*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D018811:Maternal Exposure; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000378:metabolism; D014621:Vagina / Q000187:drug effects
chemical_list: D007854:Lead; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase