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The possibility of altering neuroendocrine differentiationby administering homologs of the pesticide DDT to neonatal male and female rats was investigated. The estrogenic isomer o, p’-DDT pro-duced precocious puberty with an inverse relationship between age at vaginal opening and dose of DDT. 0.1 mg o, p’-DDT on the 2nd, 3rd, and 4th days of life was the minimum effective dose for inducing per-sistent vaginal estrus and anovulation. In addition, as the dosage was increased, the syndrome appeared earlier in life. Uterine histology in adult rats treated as neonates with high doses of o, p’-DDT was markedly altered, i.e., patches of stratified squamous epithelium were evident. The feedback rise in serum gonadotropin concentration in response to ovariectomy was reduced in rats treated with high doses of o, p’-DDT neonatally when compared to vehicle-treated controls. Male rats treated as neonates with high doses of the DDT homologs, o, p’-DDT, DDA, methoxychlor, p, p’-DDE and p, p’-DDT, had normal reproductive organ weights and motile sperm as adults in spite of the known estrogenic activity of the first three compounds. It is concluded that o, p’-DDT given to newborn female rats may, in a dose-dependent fashion, permanently alter neuroendocrine differentiation, but that male rats are unaffected by such treatment.

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SUMMARY1. In a study of the site of action of a steroid in current use for contraceptive purposes (6-chloro-A6-dehydro-17az-acetoxyprogesterone; 'chlormadinone acetate'), the ovarian responses [secretion rate of 20a-hydroxypregn-4-en-3-one (20 x-OH), and the occurrence of ovulation] were observed in control oestrous rabbits and in rabbits following mating, injection of luteinizing hormone, and after electrical stimulation of the median eminence.2. Chlormadinone acetate pretreatment (0 5 mg i.v.) did not lower significantly the secretion of 20 ax-OH in otherwise untreated oestrous rabbits.3. Chlormadinone acetate, given 24 hr before mating, prevented the rise in 20ac-OH that would otherwise have occurred, and also blocked the ovulation response following mating.4. Chlormadinone acetate pretreatment did not prevent the ovarian responses to administration of luteinizing hormone.5. Chlormadinone acetate pretreatment did not prevent the ovarian responses to electrical stimulation of the median eminence of the tuber cinereum of the hypothalamus.6. The conclusion is drawn that the chlormadinone acetate block of the ovarian responses following mating is at a site in the central nervous system located above the median eminence.

We tested the hypothesis that neonatal treatment of rats with testosterone propionate (TP) or estradiol benzoate (EB) reduces the uterine responsiveness to estradiol and reduces the concentration of estrogen "receptor" before puberty, and that both of these events precede the onset of the persistent estrus syndrome. Thre-day-old female rats were injected with 100 mug EB, TP or sesame oil (controls) and at 23 and 31 days of age (before the onset of puberty) the uterine cytoplasmic content of specific 8S estradiol-binding protein was measured by sucrose density gradients. Binding by the nuclear fraction was also measured utilizing an exchange assay. In a subgroup of rats also treated neonatally, 2 mug/kg body weight estradiol-17beta was injected at 22 and 30 days of age and uterine wiights were measured as a test for uterine responsiveness. At 23 and 31 days of age the uterine cytoplasmic 8S estrogen "receptor" was significantly reduced in the EB-treated rats, but the uterotropic response to estradiol was blocked only in the 23 day old rats; the uterine response at 31 days was slightly, but not significantly, reduced. In contrast, neonatally administered TP had no effect on either the concentration of cytoplasmic estradiol-binding sites or uterine responsiveness. Nuclear binding of estradiol was unaffected by either TP or EB treatment in both age groups. In a futher experiment in rats ovariectomized at 9 days of age, those treated neonatally with EB had significantly smaller uteri than their untreated ovariectomized controls, thus providing indirect evidence for an extravarian factor affected by neonatal treatment. These data support the hypothesis that neonatal EB treatment may directly inhibit the synthesis or replenishment of the 8S estradiol "receptor" prior to the development of the persistent estrus syndrome (persistent vaginal estrus, anovulation and polycystic ovaries). A neonatally-induced neuroendocrine disorder affecting steroid secretion by the ovary or adrenal may also exist prepubertally to account for the uterine defects.

Eight female rats with electrolytic lesions involving the arcuate nucleus in the posterior tuberal region of the hypothalamus matured significantly earlier than unoperated controls. Lesions placed in the anterior hypothalamus, mammillary body, hippocampus, cortex and thalamus of immature female rats had no effect on the age at which vaginal opening and first oestrus occurred.

The o,p'-isomer of the insecticide DDT when injected into neonatal female rats significantly advanced puberty, induced persistent vaginal estrus after a period of normal estrous cycles, and caused the ovaries to develop follicular cysts and a reduced number of corpora lutea. The uterotropic response to administered estradiol was reduced, and the female pattern of mating behavior was slightly disturbed. Residues of DDT in ovarian, brain, and adipose tissues of the adult animals were the same in both treated and control groups.