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ABSTRACT: The potential for health effects on humans with exposure to bisphenol A (BPA) has raised concerns, and the adverse effects of low-dose exposure to BPA on reproduction have been controversial. The purpose of the present study was to investigate the effects of low-dose exposure to BPA on reproductive development in F(1) rat offspring. Pregnant female Sprague-Dawley rats (F(0)) were fed a diet containing low doses of BPA (0, 0.33, 3.3, or 33 ppm) from gestational day (GD) 6 through postnatal day (PND) 21. The weanlings (F(1)) from all dose groups were fed a normal diet ad libitum after weaning and then were subjected to necropsy at 5 weeks or 3 months of age. No BPA-related changes were observed in body weight or weight of any of the major reproductive organs in F(1) males and females. Epididymis weight was significantly lower only in 3-month-old F(1) males exposed to 33 ppm BPA. Anogenital distance (AGD), the ratio of AGD to the cube root of body weight, and relative ovary weight were significantly lower in 5-week-old F(1) females exposed to 3.3 and 33 ppm BPA, but significant differences were not observed in 3-month-old females. There were no BPA-related effects on cauda epididymal sperm motility in 3-month-old F(1) males. Plasma reproductive steroid hormone concentrations were not altered among groups in either sex. These outcomes indicate that low-dose exposure to BPA in the diet does not adversely affect reproductive development in F(1) rat offspring.
The Journal of Toxicological Sciences 01/2012; 37(3):565-73. · 1.52 Impact Factor
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ABSTRACT: The present study was conducted to examine the effects of low-dose exposure to bisphenol A on reproduction and development in two generations of mice. Pregnant female C57BL/6J mice (F(0)) were fed a diet containing low doses of bisphenol A (0, 0.33, 3.3, or 33 ppm) from gestational day 6 through postnatal day 22, and the weanlings (F(1) and F(2)) from each F(0) and F(1) dam group, respectively, were also fed these same concentrations of bisphenol A ad libitum until sacrifice. There were no treatment-related changes in body weight, body weight gain, food consumption, gestation length, or the number of live births on postnatal day 1 in F(0) dams between the control group and bisphenol A groups. Sex ratio and viability were similar in all F(1) pups. No treatment-related changes were observed in body weight, food consumption, developmental parameters, anogenital distance, or weight of any of the organs (liver, kidney, heart, spleen, thymus, testis, ovary, or uterus) in F(1) and F(2) adults in either sex. The epididymis weight was slightly higher with 0.33 and 3.3 ppm in F(1) males, but this slight increase was neither dose dependent nor seen across generations. There were no treatment-related effects of bisphenol A on cauda epididymal sperm count or sperm motility in F(1) or F(2) males. These findings indicate that dietary exposure to bisphenol A between 0.33 and 33 ppm does not adversely affect reproduction or development as assessed in two generations of mice.
Congenital Anomalies 09/2010; 50(3):159-70.
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ABSTRACT: The growth-retarded (grt) mouse shows thyroid dysfunction-related hyporesponsiveness to TSH. Thyroid hormone is a critical regulator of metabolism in many cells; thus, derangement of thyroid function affects many organs and systems. Experiments were conducted focusing on the function of the pancreatic islets in grt mice. We showed occurrence of a fasting hyperglycemia and a decreased plasma insulin level response to a glucose load in grt mice, despite normal insulin molecules being stored in secretory granules of pancreatic islets. We also demonstrated a reduction of insulin secretion in response to glucose administration from islets of grt mice in vitro, while the insulin release in response to KCl stimulation was comparable to that in normal mice, indicating that the isolated islets from grt mice have normal ATP-sensitive K(+) channels and postchannel activity. The mRNA expression levels of glucose transporter 2 and glucokinase in the islets of grt mice were similar to those in normal mice. Triiodothyronine administration to grt mice improved insulin secretion very slightly. On the other hand, mRNA for tyrosylprotein sulfotransferase 2 (Tpst2) was found to be expressed in the pancreatic islets of grt mice. Considering that Tpst2 is the responsible gene of grt mice, mutation of which is associated with a poor function of TSH receptor, the findings raise a possibility of involvement of factors including Tpst2 in the insulin hyposecretion in grt mice.
Journal of Endocrinology 08/2010; 206(2):195-204. · 3.55 Impact Factor
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ABSTRACT: Congenitally primary hypothyroid growth-retarded (grt) mice exhibit a characteristic growth pause followed by delayed onset of pubertal growth. We characterized the developmental pattern of somatotropes, lactotropes and thyrotropes in the anterior pituitary, as well as plasma levels of their secretory hormones, in grt mice. Compared with normal mice, the weight of grt pituitary gland was similar at 8 weeks of age but significantly heavier after 12 weeks of age. Compared with normal mice, there were significantly fewer somatotropes in the grt pituitary until 8 weeks of age, but the number gradually increased up to 48 weeks. The number of lactotropes in grt mice was consistently lower than that in normal mice from 2 through 48 weeks, whereas the number of thyrotropes in the grt pituitary was consistently higher than in the normal pituitary. Thyrotropes in the grt pituitary exhibited hypertrophy and hyperplasia with less intensive thyroid-stimulating hormone (TSH) immunoreactivity than normal thyrotropes. In normal mice, the sum of the relative proportions of these cells plateaued at 8 weeks, where it remained up to 48 weeks of age. In grt mice, these proportions almost reached normal levels at 12 weeks of age but gradually declined after 24 weeks. Plasma growth hormone concentrations did not differ between grt and normal mice until 24 weeks of age. Compared with normal mice, grt mice exhibited significantly lower plasma prolactin and thyroxine levels but higher TSH levels. These findings indicate that development of somatotropes, lactotropes and thyrotropes in grt mice is impaired, being followed by altered hormone secretion.
Journal of Toxicologic Pathology 09/2009; 22(3):187-94. · 0.48 Impact Factor
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ABSTRACT: The growth-retarded (grt) mouse, originally isolated from a closed colony of Snell's dwarf mouse (DW/J strain), shows growth retardation that is inherited in a recessive manner. We have already reported that this strain exhibits severe primary hypothyroidism with significantly reduced plasma levels of thyroxine (T4), dramatically elevated plasma titers of thyroid-stimulating hormone (TSH) and an increase in the number of immunoreactive TSH cells in the pituitary gland. The thyroid gland of the grt mouse exhibits characteristically numerous smaller follicles with poor colloid accumulation. In order to elucidate the possible site of the defect in the grt mouse, and in particular to clarify the discrepancy between elevated plasma TSH titers and reduced T4 levels, we examined the bioactivity of TSH recovered from the plasma sample of the grt animal and the responses of the grt thyroid gland to exogenous TSH and other thyroid hormone secretagogues. Plasma samples from the grt mice invariably exhibited significant levels of TSH bioactivity following injection into normal test mice. Thus, the reduced responsiveness to TSH exhibited by the grt mice is not due to the reduced bioactivity of TSH. Administration of exogenous TSH to the grt mice failed to elevate the plasma T4 and triiodothyronine (T3) levels in vivo or to stimulate free T4 and free T3 releases from the grt thyroid gland in vitro. The thyroid gland of the grt mouse exhibited a markedly diminished response of adenylate cyclase to exogenous TSH as compared to the gland of euthyroid littermates. Production of cAMP in the grt mouse was significantly increased following stimulation of the thyroid glands with forskolin, cholera toxin, prostaglandin (PG) E1 and isoproterenol. These results strongly suggest a defect in TSH responsiveness, particularly in TSH-TSH receptor-Gs protein-adenylate cyclase signalling system including the expression and the function of TSH receptor and the TSH receptor-Gs protein coupling, in the thyroid gland of the grt mice.
ZOOLOGICAL SCIENCE 08/2009; · 0.95 Impact Factor
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ABSTRACT: 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.
Industrial Health 05/2009; 47(2):189-97. · 0.94 Impact Factor
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ABSTRACT: 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.
Industrial Health 02/2009; 47(1):11-21. · 0.94 Impact Factor
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ABSTRACT: 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.
Congenital Anomalies 01/2009; 48(4):151-7.
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ABSTRACT: To assess delayed fertility in male growth-retarded (grt) mice with congenital primary hypothyroidism, their testes were chronologically examined. The testicular weight in grt mice was significantly lower than age-matched normal mice until 8 weeks but was comparable at 13 and 26 weeks. While normal mice had mature sperm cells in both testes and epididymides at 5 weeks, age-matched grt mice did not. The size of the seminiferous tubules in testes of grt mice was smaller than that of normal mice before 13 weeks but was comparable at 26 weeks. These findings suggest that male grt mice might need more than 13 weeks to develop mature testes.
Experimental Animals 11/2007; 56(5):393-7. · 0.92 Impact Factor
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ABSTRACT: 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.
Industrial Health 11/2006; 44(4):652-60. · 0.94 Impact Factor
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ABSTRACT: 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.
Industrial Health 08/2006; 44(3):510-24. · 0.94 Impact Factor
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ABSTRACT: 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.
Industrial Health 11/2005; 43(4):685-90. · 0.94 Impact Factor
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ABSTRACT: Growth-retarded (grt/grt) mice are congenitally primary hypothyroid. Our previous study indicated that thyroid-stimulating hormone (TSH) responsiveness was defective in the grt/grt thyroid gland. We now report additional studies of impaired grt/grt thyroid function. Semiquantitative RT-PCR confirmed that TSH receptor (TSHR) mRNA expression in the grt/grt thyroid was significantly decreased compared with +/+ thyroids. Scatchard analysis revealed that grt/grt and +/+ mice have only one type of TSH binding site. grt/grt thyroids had fewer TSH binding sites, although this did not apparently affect the affinity of TSH for its receptor. The present data suggest that reduced TSHR levels or defects in TSHR signaling could be one of the possible defective sites in the grt/grt thyroid gland.
Congenital Anomalies 10/2005; 45(3):89-92.
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ABSTRACT: 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.
Industrial Health 11/2003; 41(4):338-41. · 0.94 Impact Factor
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ABSTRACT: 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.
Industrial Health 11/2002; 40(4):375-81. · 0.94 Impact Factor
