Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) severely alters reproductive function of female hamster offspring

Abstract

Low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), administered as a single dose to the dam during gestation, alter development of the fetal rodent reproductive system. In male rat and hamster offspring, dosing with TCDD during gestation reduces epididymal and ejaculated sperm counts and delays puberty. In female rats, in utero TCDD-exposure results in reduced ovarian weight and fecundity, and induces cleft phallus and a persistent thread of tissue across the vaginal orifice. Here, we demonstrate that 2-μg TCDD/kg, administered as a single oral dose prior to sexual differentiation, alters reproductive function in female hamster offspring, a species relatively resistant to the lethal effects of TCDD. In the current study, pregnant hamsters (P0 generation) were dosed orally with vehicle (corn oil) or 2 μg TCDD/kg on gestational day (GD) 11.5. P0 maternal viability, body weight, fertility, and F1 litter size did not differ between control and treated groups. In the F1 generation, body weights were permanently reduced by about 30%, vaginal opening was delayed (p < 0.0001), and vaginal estrous cycles were altered by TCDD treatment. In contrast, most treated female offspring displayed regular 4-day behavioral estrous cycles, indicating that in utero TCDD treatment did not markedly disrupt hypothalamic-pituitary- gonadal hormonal cyclicity. Although both control and TCDD-treated F1 females mated successfully with a control male (estrous cyclicity was abolished by mating), 20% of the F1 treated females did not become not pregnant (no implants). In addition, 38% of pregnant F1 females from the TCDD group died near-term, and the numbers of implants in pregnant animals (treated 5.1 versus 11.3) and pups born live (2.7 treated vs. 8.7 control) were reduced by TCDD-treatment. In the F2, survival through weaning was drastically reduced (15% treated vs. 78% for control) by TCDD treatment of P0 dams. F1 female hamster offspring exposed in utero to TCDD displayed external urogenital malformations, with most females having complete clefting of the phallus, an effect previously reported in the rat. Unlike rats exposed to TCDD (0.2-1.0 μg/kg) on GD 15 or GD 8, hamster offspring did not display vaginal threads. These results demonstrate that in utero administration of TCDD adversely affects growth, reproductive function, and anatomy in female hamster offspring given a dosage level nearly four orders of magnitude below the dosage level toxic to the adult animal. Adverse effects of TCDD persisted through two generations (F1 and F2), even though the F1 was only indirectly exposed during gestation and lactation.