IN-UTERO 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) ALTERS REPRODUCTIVE MORPHOLOGY AND FUNCTION IN FEMALE RAT OFFSPRING

Exposure to pesticides or toxic substances that disrupt the endocrine system during sex differentiation can permanently alter reproductive f unction and produce morphological pseudohermaphrodism. While some deve lopmental toxicants affect either the male or the female, in utero exp osure to 0.5 mu g TCDD/kg/day from Gestational Day (GD) 6 to GD 15 ind uces infertility in both sexes (K. S. Khera and J. A. Ruddick, Chlorod ioxins-Origin and Fate, pp. 70-84, Am. Chem. Sec., Washington, DC, 197 3), Although a number studies have focused on the effects of a single dose of TCDD on sex differentiation of the male rat and hamster, the r eproductive alterations that account for female-mediated infertility a fter in utero exposure to TCDD have not been described. Hence, it was our objective to describe the anatomical and functional reproductive a lterations in female progeny after gestational administration of TCDD. In the first experiment, LE Hooded rats were given a single dose of 1 mu g TCDD/kg by gavage on GD 8 (i.e., a period that includes major or ganogenesis) or GD 15 (i.e., a period prior to sex differentiation and a dosing regime that alters sex differentiation of the male LE rat). In a second experiment, Holtzman rats were dosed with TCDD at 1 mu g/k g on GD 15, to determine if the progeny of this strain displayed malfo rmations of the external genitalia and vaginal orifice as did LE rats. TCDD-treated female LE offspring displayed a number of unusual reprod uctive alterations. In the GD 15 group, puberty was delayed, more than 65% of the female offspring displayed complete to partial clefting of the phallus, and 80% displayed a permanent ''thread'' of tissue acros s the opening of the vagina. In the GD 8 treatment group, 25% displaye d partially cleft phallus and 14% had a vaginal thread. GD 15 TCDD adm inistration also induced a high incidence of malformations in Holtzman female progeny (100% clefting and 83% with a vaginal thread). At necr opsy ( > 550 days old), ovarian weight was significantly reduced by 23 % in both rat strains. In the LE rat, vaginal and behavioral estrous c yclicity, estrous cycle-mediated running wheel activity, and female se xual behaviors at proestrus (darting and lordosis to mount ratios) wer e not affected by gestational GD 15 TCDD treatment. However, untreated stud males had difficulty attaining intromission and took longer to e jaculate and vaginal bleeding was displayed during mating by GD 15 TCD D-exposed female offspring. GD 8 TCDD-treated female offspring display ed enhanced incidences of constant estrus (CE) (47% CE in GD 8 versus 16% CE in the control and GD 15 groups at middle age) acid cystic endo metrial hyperplasia. In addition, in the GD 8 group the fertility rate declined significantly faster than in controls (p < 0.02) and fecundi ty was reduced by 38% (p < 0.07). In condusion, administration of a si ngle dose of 1 mu g TCDD/kg on GD 15 results in malformations of the e xternal genitalia in female LE and Holtzman rats. While GD 15 treatmen t is generally more toxic than GD 8 to the offspring with respect to g rowth, viability, male reproductive effects (L. E. Gray, W. R. Kelce, E. Monosson, J. S. Ostby, and L. S. Birnbaum, Toxicol. Appl. Pharmacol . 131, 108-118, 1995) and malformations of the external genitalia in t he female progeny, treatment on GD 8 is more effective in inducing fun ctional reproductive alterations in female progeny. (C) 1995 Academic Press, Inc.