Effects of in utero exposure to 2,2',4,4',5,5'-hexachlorobiphenyl on postnatal development and thyroid function in rat offspring.

Exposure to polychlorobiphenyls (PCBs) has been reported to affect endocrine glands; however, little is known about the precise toxicological properties of individual PCBs. We determined whether prenatal exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), a di-ortho-substituted non-coplanar congener, affects postnatal development in rat offspring. Pregnant Sprague-Dawley rats were given PCB 153 (0, 1, or 4 mg/kg/d) orally from gestational day (GD) 10 to 16, and somatic parameters and thyroid functions in offspring were examined. We found no dose-dependent changes in body weight, body length, tail length, or weight of liver, kidney, testis, seminal vesicle, prostate, ovary, relative organ weight, anogenital distance (AGD), or AGD index in offspring at 1, 3 or 9 wk of age. We observed no compound-related changes in the plasma concentrations of thyroxine (T(4)), tri-iodothyronine (T(3)) or thyroid-stimulating hormone (TSH), although there was a significant difference in T(3) only in 1-wk-old males. In addition, thyroid glands from PCB 153 groups had normal T(4) responses to exogenous TSH in vivo. These findings suggest that low doses of PCB 153 given prenatally (GD 10-16, 1-4 mg/kg/d) might have little effect on postnatal somatic growth or thyroid development of male and female rat offspring under the experimental conditions of the present study.

Alteration of brain neurotransmitters in female rat offspring induced by prenatal administration of 16 and 64 mg/kg of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153).

PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl), a non-coplanar PCB and the congener most widely distributed in the environment, was orally administered to pregnant Sprague-Dawley (Crj: CD (SD) IGS) rats from gestation day 10 through 16 at doses of 0 (control), 16 and 64 mg/kg body weight. Female pups were sacrificed at 1, 3, 6, and 9 wk, and at 1 yr of age to evaluate the differences in brain neurotransmitters and their metabolites between PCB153-exposed and control groups. Brain levels of norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5HT), 5-hydroxyindoleacetic acid (5HIAA), acetylcholine (ACh), and choline (Ch) in discrete brain regions or in whole brain were measured. At 1 to 3 wk after birth, brain levels of DA, DOPAC, HVA, 5HT and 5HIAA in PCB-exposed groups were higher than those of the control group. At 9 wk after birth, DA turnover was reduced in half of the four brain areas examined (forebrain and hindbrain), and 5HIAA levels were increased in all brain areas in the PCB-treated group compared to those of the control group. At 1 yr after birth, the levels of DA, DOPAC, and HVA in the hippocampus, hypothalamus, and medulla oblongata were lower in the PCB-exposed groups than in the control group. Prenatal exposure to PCB153 stimulated the turnover of 5HT neurons in the brain of female offspring at early stages (1 to 9 wk) of development. On the other hand, the turnover of DA neurons in the PCB-exposed groups was reduced in late stages (9 wk to 1 yr) of development compared with that of the control group. The brain neurotransmitters of dams treated with PCB were assayed at 3 wk after delivery (15 wk old), and decreases in DA, DOPAC, and HVA were observed. PCB153 reduced the activity of DA neurons in the brain of dams. These results are discussed in relation to health effects observed in humans exposed to PCBs.

Effects of in utero exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) on somatic growth and endocrine status in rat offspring.

Exposure to polychlorobiphenyl (PCB) mixtures at an early stage of development has been reported to affect endocrine glands; however, little is known about the precise toxicological properties of individual PCB. The present study was undertaken to determine whether prenatal exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), a di-ortho-substituted non-coplanar congener, affects postnatal development in rat offspring. Pregnant Sprague-Dawley rats (Crj: CD (SD) IGS) were given PCB 153 (0, 16, or 64 mg/kg/day) orally from gestational day (GD) 10 through GD 16, and developmental parameters in the male and female offspring were examined. We found no dose-dependent changes in body weight, body length (nose-anus length), tail length, or the weights of kidneys, testes, ovaries and uterus in offspring at 1 or 3 weeks of age. Liver weights were increased in the PCB 153-treated groups, although we observed a significant difference only in males. Anogenital distance was unaffected in the PCB 153-treated groups. We observed a significant dose-dependent decrease in the plasma concentrations of thyroxine and tri-iodothyronine, whereas those of thyroid-stimulating hormone were not significantly changed. In addition, there were no dose-dependent changes in plasma concentrations of growth hormone and insulin-like growth factor-I in any dose group. These findings suggest that prenatal exposure to PCB 153 (GD 10-16, 16-64 mg/kg/day) may alter the thyroid status in rat offspring to some extent without affecting somatic growth or its related hormonal parameters.

Effects of in utero and lactational exposure to di(2-ethylhexyl)phthalate on somatic and physical development in rat offspring.

Di(2-ethylhexyl)phthalate (DEHP) has been reported to act as an antiandrogen and to affect the reproductive organs and accessory genital glands. Thus, to assess the reproductive toxicity of DEHP it is important to examine both its adverse effects on the development of offspring following maternal exposure and its effects on sexual function and fertility. In the present study, we examined whether in utero and lactational exposure to DEHP affects postnatal somatic growth of offspring in the rat. Pregnant females were orally administered various doses of DEHP (0, 25, 100 or 400 mg/kg body weight/day) from gestational day (GD) 6 through postnatal day (PND) 20. There were no significant changes in body weight, body length, tail length, or the weight of individual organs between the control and DEHP-treated groups. Somatic hormonal parameters were the same for all DEHP doses. These findings suggest that in utero and lactational exposure to various concentrations of DEHP has very little effect on postnatal development or endocrine and physical status of male and female rat offspring under the experimental conditions of the present study.

Effects of perinatal exposure to bisphenol A on brain neurotransmitters in female rat offspring.

Pregnant Sprague-Dawley (CD IGS) rats were orally administered doses of bisphenol A (BPA) at 4, 40, and 400 mg/kg, from gestation days 6 to postnatal day 20. Neurotransmitters such as dopamine (DA) and serotonin (5HT) were extracted from the brains of dams and female offspring, and measured using liquid chromatography. BPA at 400 mg/kg was toxic and dosed rats died. At 3 wk after birth, brain levels of 3,4-dihydroxyphenylacetic acid (DOPAC, a DA metabolite), homovanillic acid (HVA, a DA metabolite), 5HT, 5-hydroxyindoleacetic acid (5HIAA, a 5HT metabolite) in female offspring were increased and the HVA/DA ratio was high in some brain areas of BPA-treated groups as compared with controls. At the age of 6 wk, levels of choline (Ch) in BPA-treated groups at 4 and 40 mg/kg were higher than control in all of eight brain areas. No changes were observed in acetylcholine (ACh) contents. In 9-wk-old offspring, changes in monoamines and metabolites were scattered and not great. At 3 wk after delivery, levels of 5HIAA in some brain areas of dams treated with BPA were higher than in control dams. Dose dependent increases in HVA and the HVA/DA ratio of the occipital cortex, and in the HVA/DA ratio of the frontal cortex were observed. The turnover of DA and 5HT was accelerated in 3-wk-old offspring and dams. BPA possesses very weak estrogenic activity. Changes in cerebral neurotransmitters observed in offspring and dams in this study may have been related to the estrogenic activity of BPA. However, further investigation is needed to examine the contribution of hormonal activity to such neurotransmitter changes.

Involvement of thyroxine in ovarian toxicity of di-(2-ethylhexyl) phthalate.

Forced ovulation induced by the administration of exogenous gonadotropin is a useful marker for studying the ovarian toxicity of chemicals in experimental animals. We examined the toxicity of di-(2-ethylhexyl) phthalate (DEHP) in the ovaries of immature F344 female rats. Superovulation was induced by injections of equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG) in rats dosed with 125, 250, 500, 1,000 or 2,000 mg/kg body weight of DEHP for 4 consecutive days. The number of ova shed during superovulation significantly decreased in rats treated with DEHP at 500 mg/kg as compared with control, but no changes were observed in the number of ova in groups given other doses of DEHP. In control rats treated with olive oil, hypophysectomy reduced significantly the number of ovulated ova. When 2,000 mg DEHP was given to hypophysectomized (hypox) rats, the number of ova in the hypox group was significantly smaller than that in the intact group administered with the same doses of DEHP. In contrast, the numbers of ova of the intact and hypox groups did not significantly differ in rats given 500 mg DEHP. The levels of circulating thyroxine (T4) were significantly decreased by 2,000 mg DEHP in intact rats, and a tendency for T4 to decrease in T4 was also observed in hypox rats given 2,000 mg DEHP. These results suggest that daily administration of 500 mg DEHP suppressed superovulation in immature F344 rats by disrupting the hypothalamic-pituitary-ovarian axis in a manner similar to that of hypophysectomy. Decreased circulating T4 levels seemed to negate this disruption as observed in recovered superovulation after treatment with 2,000 mg DEHP.

Effects of in utero and lactational exposure to bisphenol A on thyroid status in F1 rat offspring.

Bisphenol A (BPA), a xenoestrogen, has been reported to mimic the actions of estrogen or to affect the endocrine glands in vivo and in vitro. In this study, we examined whether in utero and lactational exposure to BPA alters thyroid status in rat F1 offspring. Dams were orally administered various doses of BPA (0, 4 or 40 mg/kg body weight per day) from gestation day (GD) 6 through postnatal day (PND) 20. The BPA and control groups did not differ significantly with respect to plasma thyroxine (T4) concentration. The thyroid glands from the BPA groups had normal T4 responses to exogenous thyroid-stimulating hormone in vivo. These results suggest that in utero and lactational exposure (indirect exposure) to BPA (4-40 mg/kg/day, GD 6 - PND 20) does not affect thyroid functions in the F1 generation of male and female rats.

Imbalance of testosterone level in male offspring of rats perinatally exposed to bisphenol A.

The purpose of this study was to investigate whether exposure to bisphenol A (BPA) through the placenta and milk has any effect on the reproductive system in male offspring. Pregnant rats were treated with BPA at 0, 4, 40 and 400 mg/kg body weight, from gestation day 6 through lactation day 20 by gavage. Plasma testosterone concentrations in offspring at 9 weeks old were significantly high in BPA groups as compared with those of the control. At the age of 36 weeks the hormone concentrations showed an increase in a dose-dependent manner, although without statistical significance. Testosterone content in testes showed a similar tendency to that in plasma, though statistically insignificant. Little alteration in testes weight was seen in BPA-exposed offspring. There was no remarkable change in plasma concentrations of luteinizing hormone and follicle-stimulating hormone at 9 weeks old. The pathway of E2 (17beta-estradiol) formation from testosterone seemed not to be affected by BPA. The results indicate that exposure to BPA during the perinatal period has a significant effect on testosterone homeostasis in male offspring of rats.

Experimental model to study reproductive toxicity of chemicals using induced ovulation in immature F344 rats.

We investigated a simple method using induced ovulation in immature rats to detect ovarian injury due to chemicals. We investigated the influence of di-(2-ethylhexyl) phthalate (DEHP) on ovulation induced by equine chorionic gonadotropin (eCG) in immature F344 rats. Single injections of 15 and 30 iu eCG induced ovulation in 4 of 6 rats and in all of 4 rats, respectively. The mean number of ovulated ova was 12.7 in the 15 iu eCG group and 8.0 in the 30 iu group. When rats received 4 daily doses of DEHP at 500 mg/kg, ovulation occurred in 4 of 6 rats in the 15 iu eCG group and in 1 of 3 rats in the 30 iu group. Mean numbers of ovulated ova were 2.50 and 0.33 ova in the 15 and 30 iu groups, respectively. Changes in ovarian and uterine weights were not found. Inhibition of ovulation by the injection of DEHP indicated the utility of induced ovulation in immature rats to detect reproductive toxicity in females.

Effects of in utero and lactational exposure to bisphenol A on somatic growth and anogenital distance in F1 rat offspring.

Bisphenol A (BPA), a xenoestrogen, has been reported to mimic the actions of estrogen or to affect the endocrine glands in vivo and in vitro. In this study, we examined whether in utero and lactational exposure to BPA altered the somatic growth and anogenital distance (AGD) of F1 offspring (1, 3, and 9 weeks of age) in vivo in rats. Dams were orally administered with various doses of BPA (0, 4, or 40 mg/kg body weight (BW)/day) from gestation day (GD) 6 through postnatal day (PND) 20. There were no significant changes in body weight, liver weight, kidneys weight, testes weight, AGD, the ratio of AGD to BW, or the ratio of AGD to the cube root of BW in BPA exposed pups compared to the vehicle-exposed control. This suggests that prenatal and postnatal exposure (indirect exposure) to BPA (4-40 mg/kg/day, GD 6-PND 20) does not affect on somatic growth or AGD of F1 generation of male and female rats.