Prenatal exposure to the phytoestrogen daidzein resulted in persistent changes in ovarian surface epithelial cell height, folliculogenesis, and estrus phase length in adult Sprague-Dawley rat offspring.

Daidzein (DZ), an isoflavone with the potential to interfere with estrogen signaling, is found in soy products, which have gained popularity due to purported beneficial effects on the cardiovascular and skeletal systems and potential antineoplastic properties. However, the ingestion of phytoestrogens has been associated with impaired reproductive function in many species. The aim of this study was to determine the long-term effects on the ovaries of rat offspring exposed to DZ or ethinyl estradiol (EE) during prenatal development. Gravid rats were administered either vehicle or 5 or 60 mg DZ/kg body weight/d or 0.002 mg 17-α EE /kg body weight/d on gestational days 6-21. Ovarian-related endpoints were investigated during adulthood in female offspring. The mean cell height of the ovarian surface epithelium was significantly reduced in all treated groups. Alterations in folliculogenesis included increased follicular atresia, a reduction in secondary and tertiary follicle numbers, and cyst formation. An elevated prevalence of a slightly prolonged estrus phase was also observed. The morphological changes to the ovarian surface epithelium are consistent with an antiproliferative effect, while ovarian folliculogenesis was adversely affected. The effects of the high dose DZ were similar to those observed with 17-α EE.

Biological and tumor-promoting effects of dioxin-like and non-dioxin-like polychlorinated biphenyls in mouse liver after single or combined treatment.

To assess the impact of a mixture containing dioxin-like and non-dioxin-like polychlorinated biphenyls (PCBs), male mice were initiated with N-nitroso-diethylamine and subsequently treated with PCB126, an Ah-Receptor agonist, and PCB153, acting via activation of the constitutive androstane receptor. The two congeners were given at two dose levels: the low dose was adjusted to induce ~150-fold increases in cytochrome P450 (Cyp)1a1 (PCB126) and Cyp2b10 mRNAs (PCB153), and the high dose was chosen as twice the low dose. To keep the liver PCB levels constant, mice were given initial loading doses followed by weekly maintenance doses calculated on the basis of the PCBs' half-lives. Mice were treated with the individual congeners (low and high dose) or with a mixture consisting of the low doses of the 2 PCBs. The following results were obtained: (1) the 2 PCBs produced dose-dependent increases in Cyp1a1 and Cyp2b10 mRNA, protein, and activity when given individually; (2) combined treatment caused more than additive effects on Cyp1a1 mRNA expression, protein level, and ethoxyresurofin activity; (3) changes in the levels of several proteins were detected by proteome analysis in livers of PCB-treated mice; (4) besides these biological responses, the individual PCBs caused no significant increase in the number of glucose-6-phospatase (G6Pase)-deficient neoplastic lesions in liver, whereas a moderate significant effect occurred in the combination group. These results suggest weak but significant response-additive effects of the 2 PCBs when given in combination. They also suggest that the Cyp biomarkers tend to overestimate the carcinogenic response produced by the PCBs in mouse liver.

Sex differences in effects on sexual development in rat offspring after pre- and postnatal exposure to triphenyltin chloride.

Consumers are exposed to organotin compounds (OTCs) via contaminated fish and seafood due to the accumulation of these compounds in marine organisms. Certain OTCs are immunotoxic and may also have endocrine disrupting properties resulting in adverse effects on the reproductive tract in mollusks and mammals. Since effects of in utero exposure to endocrine disrupting chemicals on the reproductive system are dependent on the critical window of exposure during its development, we conducted a comprehensive study with the aim to identify the most sensitive window of exposure to TPTCl and to investigate the effects of pre- and postnatal treatment on sexual development in rats. Male and female offspring rats were exposed to 2 or 6 mg TPTCl/kg b.w. and day either in utero and during lactation (gestation day 6 until weaning on PND 21) or from gestation day 6 until termination. As previously reported, offspring in the 6 mg TPTCl dose group exhibited high perinatal mortality and therefore no further evaluation was carried out at this dose level (Grote, K., Hobler, C, Andrade, A.J.M., Wichert Grande, S., Gericke, C., Talsness, C.E., Appel, K.E., Chahoud, I., 2007. Effects of in utero and lactational exposure to triphenyltin chloride on pregnancy outcome and postnatal development in rat offspring. Toxicology 238, 177-185). In the present paper, results on postnatal development obtained from surviving offspring of dams exposed to 2mg TPTCl/kg b.w. are reported. Male offspring were sacrificed on PND 64 or 65 and female offspring at first estrus after PND 58. A clear sex difference in response to treatment was observed. Male postnatal development was severely affected with decreases in body weight gain, reproductive organ weights and testosterone concentration as well as a significant delay in the age at preputial separation. In contrast, females exhibited a precocious completion of vaginal opening while all other endpoints were unaffected. Most of these effects were already present in animals that were only exposed until weaning indicating that these effects may be irreversible and continued treatment until termination had contributed less than expected to the severity of the observed effects. The results of the present study suggest that the sensitive window for the evaluated endpoints seems to be the period of prenatal development and that male offspring rats were more susceptible to treatment.

In utero and lactational exposures to low doses of polybrominated diphenyl ether-47 alter the reproductive system and thyroid gland of female rat offspring.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are capable of disrupting thyroid hormone homeostasis. PBDE-47 (2,2',4,4'-tetrabromodiphenyl ether) is one of the most abundant congeners found in human breast adipose tissue and maternal milk samples. OBJECTIVES: We evaluated the effects of developmental exposure to low doses of PBDE-47 on the female reproductive system. METHODS: Pregnant Wistar rats were administered vehicle (peanut oil) or PBDE-47 [140 or 700 microg/kg body weight (bw)] on gestation day (GD) 6, or 5 mg 6-n-propyl-2-thiouracil (PTU)/L in the drinking water from GD7 through postnatal day (PND) 21. RESULTS: In female offspring sacrificed on PND38, there was a significant decrease in ovarian weight after exposure to PTU or 140 microg/kg PBDE-47. Alterations in folliculogenesis were apparent: we observed a decrease in tertiary follicles and serum estradiol concentrations in the offspring exposed to either PTU or 700 microg/kg PBDE-47. PTU exposure also resulted in a decrease in primordial follicles. On PND100, persistent effects on the thyroid glands included histologic and morphometric changes after exposure to either PTU or PBDE-47. No relevant changes in reproductive indices were observed after mating the exposed F1 females with nontreated males. CONCLUSIONS: Administration of PBDE-47 at doses relevant to human exposure led to changes in the rat female reproductive system and thyroid gland.

Effects of peripubertal exposure to triphenyltin on female sexual development of the rat.

Triphenyltin (TPT) belongs to the group of organotin compounds which have been shown to affect reproduction in mammals. It is used as a fungicide and antifouling agent and the main source of human exposure is via food. We studied the effects of 2 or 6 mg TPT/kg bw on female sexual development using a modification of the Rodent 20-Day Thyroid/Pubertal Female Assay. Moreover, the effect of TPT before the onset of puberty was investigated. Beginning at postnatal day (PND) 23 female Wistar rats were treated per gavage until either PND 33 or the first estrus after PND 53. A delay in the completion of vaginal opening (VO) was observed in the 6 mg TPT group, while the 2mg TPT group showed advanced VO. Significantly increased ovarian weights were observed in both treatment groups. Steroid hormone levels and ovarian aromatase activity were affected after exposure to 6 mg TPT/kg bw, while treatment with 2mg TPT/kg bw resulted in minor changes of these endpoints. We conclude that peripubertal exposure to 6 mg TPT/kg bw, and to a lesser extent to 2mg TPT/kg bw, affects female sexual development.

Effects of organotin compounds on pubertal male rats.

Tributyltin (TBT) and triphenyltin (TPT) induce effects in male and female reproductive organs of rodents. They also cause tumors in these organs and it is theorized that they result from endocrine disruption. We studied the effects of 40 mg methyltestosterone (MTT), 0.5 or 15 mg TBT and 2, 6 or 12 mg TPT/kg bw on the male sexual development using a modification of the Rodent 20-Day Thyroid/Pubertal Male Assay. Male Wistar rats were treated per gavage for 30 days beginning at 23 days of age. A delay in the completion of preputial separation was observed after administration of MTT and 15 mg/kg TBT. Changes in weights of one or more reproductive organs were observed in all treatment groups. Testosterone concentration was decreased in the MTT, the 15 mg TBT as well as in the 6 and 12 mg TPT groups. A decrease in luteinizing hormone (LH) concentration was observed in the MTT and 15 mg TBT groups while an increase was seen after exposure to 6 mg TPT/kg bw. We conclude that peripubertal exposure to 15 mg TBT and 6 mg TPT/kg bw clearly affected male sexual development.