Kenneth A. Faber

Dose-response characteristics of neonatal exposure to genistein on pituitary responsiveness to gonadotropin releasing hormone and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in postpubertal castrated female rats

Estrogen exposure during critical periods of development promotes androgenization of the brain, which is reflected in altered morphology, behavior, and cyclic hormone secretion in females. Previous work in our laboratory demonstrated that neonatal female rats injected with pharmaceutical or naturally occurring estrogens had decreased GnRH-induced LH secretion and increased volume of the SDN-POA as 42 day castrates. The current experiment defines the dose-response characteristics of neonatal exposure to the isoflavonoid phytoestrogen genistein (G) on pituitary sensitivity to GnRH and SDN-POA volume. Litters of rat pups received subcutaneous injections of either corn oil, 1, 10, 100, 200, 400, 500, or 1000 micrograms of G on days 1 to 10 of life. The litters were ovariectomized and weaned on day 21. On day 42 blood was drawn from right atrial catheters immediately prior to, 5, 10, 15, and 30 min following a single injection of 50 ng/kg of GnRH. Only the 10 micrograms dose of G was associated with increased pituitary response to GnRH, while progressive increases in exposure levels of G were associated with decreasing LH secretion. The SDN-POA volume was increased in only the 500 micrograms and 1000 micrograms exposure groups compared to controls. The results confirm that low doses of G have nonandrogenizing, pituitary-sensitizing effects, while higher doses of G mimic the more typical effects of estrogens. The use of both morphologic and physiologic end points more completely defines the reproductive consequences of environmental estrogen exposure during critical periods of CNS development.

Evaluation of the Developmental Neuroendocrine and Reproductive Toxicology of Aluminium

Two experiments evaluating functional endpoints pertaining to the developmental neuroendocrine effects of aluminum in the rat are reported. A total of 31 timed mated dams were fed by daily gastric gavage 0, 5, 25, 50, 250, 500 or 1000 mg/kg body weight/day aluminum as a solution of aluminum lactate in distilled water from days 5 to 15 of gestation. The 390 offspring were evaluated for morphological and physiological parameters of reproductive functioning, including birth weight, anogenital distance (AGD), timing of vaginal opening, regularly of oestrous cycles, duration of pseudopregnancy (PSP), number of superovulated oocytes, and gonadal weight. No consistent or reproducible findings suggestive of toxic effect were found in the parameters of birth weight, AGD, timing of vaginal opening, duration of PSP, number of superovulated oocytes, and adult gonadal weight. A temporary increase in the proportion of aberrant oestrous cycles was detected during the first four cycles after vaginal opening, in the 250 mg/body weight/day group, with none by the fifth consecutive oestrous cycle. These results suggest that, apart from a transient disturbance of oestrous cycle regularity, aluminum does not have a developmental reproductive toxic effect.