A Dose-Response Analysis of Methoxychlor-Induced Alterations of Reproductive Development and Function in the Rat

A Dose-Response Analysis of Methoxychlor-Induced Alterationsof Reproductive Development and Function in the Rat. GRAY, L.E., JR., OSTBY, J., FERRELL, J., REHNBERG, G., LINDER, R., COOPER,R., GOLDMAN, J., SLOTT, V., AND LASKEY, J. (1989). Fundam. Appl.Toxicol12, 92–108. In the present study rats were dosed fromweaning, through puberty and gestation, to Day 15 of lactationwith methoxychlor at 25, 50, 100, or 200 mg/kg/day. Morphologicallandmarks of puberty were measured, including the ages at vaginalopening, first estrus, and first estrous cycle in females andat preputial separation in males. In the female, estrous cyclicity,fertility, litter size, number of implantation sites, organweights, and ovarian and uterine histology were also measured.The viability of the offspring (F1) and their fertility wereevaluated using a continuous breeding protocol. Males were necropsiedafter breeding, the reproductive organs were weighed, and thecauda epididymal sperm counts were determined. One testis wasused for histopathology, while the other was used to quantifyinterstitial fluid (IF) content, IF testosterone concentration,and testicular sperm production. Testosterone and an drogen-bindingprotein were measured in the caput epididymis, and sperm motilityand morphology were evaluated from a caudal sample. The serumand pituitary were saved for hormonal determinations. Methoxychloraccelerated the age at vaginal opening and first estrus, andthe vaginal smears were cornified. Growth was retarded at 100and 200 mg/kg/day and fertility was reduced when the femaleswere bred with untreated or similarly treated males. In thehighest- dose group, the mated females went from constant estrusinto pseudopregnancy following mating, but they had no implants.In males, methoxychlor treatment markedly reduced growth, seminalvesicle weight, cauda epididymal weight, caudal sperm content,and pituitary weight. Puberty was delayed in the two highest-dosagegroups. Testicular sperm measures were much less affected thancaudal measures. Testis weight and histology were slightly affected,and testicular sperm production, sperm morphology, and motilitywere unaffected. Endocrine function of the testes and pituitarywas altered by methoxychlor administration. Leydig cell testosteroneproduction, in response to human chorionic gonadotropin challenge,was reduced and pituitary levels of prolactin, thyroid-stimulatinghormone (TSH), and follicle-stimulating hormone (FSH) were altered.In contrast, serum levels of prolactin, FSH, and luteinizinghormone were unaffected. Serum TSH was reduced by 50% of controlat 100 and 200 mg/kg/day, while pituitary levels were increased.Gonadotropin-releasing hormone concentration in the mediobasalhypothalamus was also elevated. In spite of the many reproductivealterations, the fertility of treated males was not reducedwhen they were mated with untreated females. Growth and viabilityof the offspring (F1) from the 50 mg/kg/day treatment groupwere normal, but in the females, vaginal opening was accelerated,estrous cyclicity was abnormal in the rats during middle age,and fecundity was reduced.