ENDOCRINE MECHANISMS UNDERLYING REPRODUCTIVE TOXICITY IN THE DEVELOPING RAT CHRONICALLY EXPOSED TO DIETARY LEAD

A dose-response study was conducted in a rat model to examine the effe cts of lifetime lead exposure on the development of the reproductive s ystem and the endocrine mechanisms underlying these effects. Time-impr egnated female Sprague-Dawley rats (n = 10-15/group) were exposed to l ead acetate in the drinking water at levels of 0.05%, 0.15%, or 0.45% (w/v) initiated on gestational day 5. At birth, litters were culled to four male and four female pups. Exposure of dams to lead was continue d until weaning, following which, the pups continued to be exposed to lead acetate in drinking water until sacrifice. One male and one femal e pup from each litter were sacrificed at age 21, 35, 55, and 85 d. A significant dose-responsive decrease in birth weight and crown-to-rump length was observed in all lead-exposed litters. However, no marked e ffects were observed on anogenital distance/crown-to-rump length ratio s. Lead exposure resulted in a delay in sexual maturity as measured by prostate weight in male pups and time of vaginal opening in female pu ps, which increased with lead dose. These disruptions in reproductive physiology were accompanied by a significant decrease in neonatal sex steroid levels and suppression of the plasma concentrations of testost erone (male) and estradiol (female) during puberty. In male pups, this was accompanied by a significant decrease in plasma luteinizing hormo ne (LH), elevated pituitary LH content, and a decrease in plasma testo sterone/LH ratios at the highest dose. In female pups, although no eff ects were observed on plasma LH concentration, a similar significant e levation in pituitary LH content was observed during early puberty. Po stpuberty, plasma LH and sex steroid concentrations were unaffected at any dose in spite of continued lead exposure. No significant effects were observed on epididymal sperm count in male pups at 85 d of age. I n female pups, estrus cycling was only significantly disrupted at the highest lead dose. These data suggest that the reproductive axis is pa rticularly sensitive to lead during specific developmental periods, re sulting in delayed sexual maturation produced by suppression by sex st eroid biosynthesis. The mechanisms underlying this appear to involve l ead actions on both LH release and gonadal function. At low, environme ntally relevant blood lead concentrations, adaptation to the continuou s presence oi the metal ion occurs and surprisingly little effect is o bserved on adult reproductive endocrinology and physiology.