Biomedical subjects

Takako Muroi

Publications and source records attributed to Takako Muroi.

8 recordsLinked to original sources

PubMed2005

Ability of the Hershberger assay protocol to detect thyroid function modulators.

In vivo screening methods for detection of thyroid function modulators are now under development in many research laboratories. We assessed the applicability of the Hershberger assay protocol to screen for thyroid function modulators. In experiment 1, castrated male BrlHan WIST@Jcl (GALAS) rats were administered a potent thyroid peroxidase inhibitor, 3-amino-1,2,4-triazole (AT), in doses of 0, 40, 200, and 1,000 mg/kg/day with gravimetric endpoint, and in experiment 2, castrated and intact male rats were administered in doses of 0, 40, and 200 mg/kg/day, with quantification of the extent of hypertrophy of the thyroid epithelium, to assess the effects of castration, by gavage to 8-week-old for 10 consecutive days. At necropsy of both experiments, the thyroid glands and hypophysis were collected and fixed with 10% neutral-buffered formalin. To avoid crushing during weighing because of their fragility, the thyroid glands and hypophysis were weighed approximately 24 h after fixation with 10% neutral-buffered formalin. All animals were sacrificed approximately 24 h after the final dose. In experiment 2, the thyroid glands of all animals were stained with hematoxylin and eosin for histological examination and morphometry of follicular epithelial height. In experiment 1, absolute and relative thyroid weights in all of the AT groups were statistically increased in a dose-dependent manner, regardless of the testosterone propionate (TP)-injection. In experiment 2, the results showed a significant increase in thyroid weight in the 200 mg/kg groups of both castrated and intact rats. Hypophyseal weight was unaltered by AT, but comparison of vehicle-treated groups showed that the hypophyseal weight of the castrated rats was greater than that of the intact rats. Enlarged thyroid glands were observed in the AT-treated rats at necropsy. Histological examination of the thyroid glands of all the AT-treated animals showed hypertrophy and hyperplasia of the follicular epithelial cells, and the height of follicular epithelium of the thyroid glands increased in a dose-dependent manner in both the castrated and intact rats. In experiment 1, assessment of the (anti-) androgenic action of AT in seminal vesicle weight revealed a significant increase in the 200 and 1,000 mg/kg + TP groups in a dose-dependent manner. These results suggest that the effect of AT can be detected by the Hershberger assay 10-day administration protocol and may be useful for screening for thyroid function modulators regardless of whether the animals have been castrated.

Amitrole↗

PubMed2005

Preliminary evaluation of an in utero-lactation assay using 6-n-propyl-2-thiouracil.

In this preliminary study, the potential of an in utero-lactation assay to detect thyroid effectors was evaluated by treating three dams/group with 6-n-propyl-2-thiouracil (PTU), a known thyroid antagonist, by oral gavage at doses of 0, 0.0032, 0.016, 0.08 and 0.4 mg/kg/day during fetal organogenesis and lactation. Hearing disturbances and an elevated relative thyroid weight were observed in offspring of both sexes in the 0.4 mg/kg/day group. The Biel-type water T-maze test showed an increase in the number of errors made by females in the 0.4 mg/kg/day group. Histopathologically, flattening of follicular epithelium, a decrease in resorptive colloid droplets, degeneration of follicular epithelium, and hyperplasia of follicular epithelium were observed in males belonging to the 0.4 mg/kg/day group. Histopathological abnormalities were also observed in some offspring belonging to the 0.08 mg/kg/day group. In the dams, hypertrophy of the follicular epithelium of the thyroid was observed in the 0.4 mg/kg/day group. Although we could not explain the mechanism for the difference in the effects seen in the offspring and the dams, the effect of PTU in utero through lactational exposure is apparently different from that resulting from exposure in homeostatically mature rats. Most reports studying PTU have involved administration in water or in food, and reports on the oral gavage of PTU during the fetal organogenesis and lactation period are very rare. This assumes that dosages >0.4 mg/kg/day would also produce clear anti-thyroid effects by oral gavage and, possibly, emphasizes that dosages <0.4 mg/kg/day did not have a noticeable effect. Based on the present results, a study to determine the reproducibility of the data in a much larger number of dams will be performed to confirm the findings in the present study, and to evaluate other endpoints, such as hormonal evaluation of dams and their offspring, sexual developmental landmarks, and fertility of the offspring.

Animals↗

PubMed2005

Effects of in utero and lactational exposure to flutamide in SD rats: comparison of the effects of administration periods.

Pregnant CD(SD) IGS rats were given flutamide (FLUT) orally at doses of 0.4, 2, or 10 mg/kg/day from gestational day 6 to postnatal day (PND) 20, and the effects of FLUT exposure on male offspring were examined 10 weeks after birth, and compared to the effects in offspring treated after weaning and in offspring untreated after weaning. Although the body weight of the dams treated with FLUT remained normal, two dams in the 10 mg/kg/day group were killed because of abnormal parturition periods and loss of all the pups. The number of stillborns and dead newborns at birth was significantly higher in the 10 mg/kg/day group than in the control groups. No abnormalities in the reproductive parameters of the other dams treated with FLUT were detected. The body weights of the male offspring in each group remained normal from birth until the end of the study. The ano-genital distance was significantly shortened in 2 and 10 mg/kg/day groups. Changes in the organ weights and gross findings were detected in the 2 and/or 10 mg/kg/day groups with or without the continuous administration of FLUT after weaning; these changes were more appreciable in groups treated with FLUT after weaning than in groups untreated after weaning. The prolongation of preputial separation was observed in the 0.4 and 2 mg/kg/day groups treated with FLUT after weaning, but this change was not detected in the same dose groups untreated after weaning. The testosterone levels were higher in the 10 mg/kg/day group treated with FLUT after weaning. The present data demonstrated that the endocrine-mediated effects on rats were more appreciable in offspring treated with FLUT after weaning than in offspring untreated after weaning.

Abnormalities, Drug-Induced↗

PubMed2005

Effects of in utero and lactational exposure to tamoxifen in SD rats.

Pregnant CD (SD) IGS rats were given tamoxifen (TMX) orally at doses of 0.12, 0.6, or 3 microg/kg/day from gestational day 6 to postnatal day 21, and the effects of TMX exposure on all offspring were examined 10 weeks after birth; the reproductive performance of the offspring was also evaluated. Although the body weights of the dams treated with TMX remained normal from gestational day 6 until the day of autopsy (postnatal day 21), three dams in the 3 microg/kg/day group died during the pregnancy or partum periods. These deaths were regarded as the toxicological effects of TMX. No changes were detected in the reproductive parameters of all the TMX groups except for a decrease in the number of newborns/live newborns in the 3 microg/kg/day group. No abnormal clinical signs, body weight change, ano-genital distance, vaginal opening, or organ weight changes were detected in any of TMX groups, but the day of preputial separation was prolonged in the male offspring of all TMX groups and cleft phallus was detected in the female offspring of the 0.6 and 3 microg/kg/day groups. No abnormalities were detected in the reproductive performance of the male and female offspring.

Administration, Oral↗

PubMed2004

Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals.

We performed the Hershberger assay of 12 chemicals based on the OECD draft protocol. The chemicals tested by the Hershberger assay were phthalic acid di-n-hexyl ester, phthalic acid di-n-amyl ester, phthalic acid di-n-propyl ester, diethylstilbestrol, 17beta-estradiol, tamoxifen, 5alpha-dihydrotestosterone, dichlorodiphenyldichloroethane, cyproterone acetate, 6alpha-methyl-17alpha-hydroxy-progesterone, atrazine, and spironolactone. Phthalic acid di-n-hexyl ester, phthalic acid di-n-amyl ester, and phthalic acid di-n-propyl ester are phthalates; diethylstilbestrol and 17beta-estradiol are estrogenic chemicals; tamoxifen is partial estrogen receptor antagonist with mainly estrogenic properties; 5alpha-dihydrotestosterone is an androgen derivatives; dichlorodiphenyldichloroethane is a reference androgen antagonistic chemical; cyproterone acetate, 6alpha-methyl-17alpha-hydroxy-progesterone, and spironolactone have an androgenic steroid structure and are known as androgen antagonistic chemicals; and atrazine is a reference endocrine disruptor. We also subjected these chemicals to the receptor binding assay for androgen. A clear androgen agonistic effect was detected in 5alpha-dihydrotestosterone, and an androgen antagonistic effect was observed in five chemicals: cyproterone acetate, spironolactone, 6alpha-methyl-17alpha-hydroxy-progesterone, phthalic acid di-n-amyl ester, and dichlorodiphenyldichloroethane. By contrast, diethylstilbestrol, 17beta-estradiol, tamoxifen, 5alpha-dihydrotestosterone, dichlorodiphenyldichloroethane, cyproterone acetate, 6alpha-methyl-17alpha-hydroxy-progesterone, and spironolactone were positive in the receptor binding assay for androgen. Three estrogenic chemicals, diethylstilbestrol, 17beta-estradiol, and tamoxifen, were negative in the Hershberger assay with receptor binding affinity. On the other hand, the Hershberger assays of three phthalates were performed at the same dosages, and the results showed androgen antagonistic affinity only in the assay of phthalic acid di-n-amyl ester without receptor binding affinity.

Administration, Oral↗

PubMed2003

In utero through lactational exposure to ethinyl estradiol induces cleft phallus and delayed ovarian dysfunction in the offspring.

Most of the attention currently focused on endocrine-active chemicals is directed to their effects on the development of offspring exposed to them in utero or during the neonatal period. Pregnant Crj:CD(SD)IGS rats were given ethinyl estradiol (EE) orally in doses of 0.5-50 microg/kg/day from gestational day 7 to postnatal day 18, and their offspring were examined for its effects. Our previous study according to a similar protocol demonstrated the occurrence of cleft phallus in the female offspring exposed to 50 microg/kg of EE in utero and during the lactation period. The present study was designed to assess (1) the reproducibility of the induction of cleft phallus, (2) the fertility of female rats with cleft phallus, and (3) whether any delayed effects, possibly delayed anovulation, were induced. At 50 microg/kg cleft phallus was observed in almost all of the female offspring, and slight retardation of body weight gain was detected in both sexes. At 15-17 weeks of age the animals with cleft phallus could copulate and had fertility comparable to the control group. At 6 months of age, on the other hand, 6/8 of the female offspring at 50 microg/kg exhibited abnormal cyclicity, including persistent estrus, and histological examination revealed follicular cysts and absence of corpora lutea in the ovaries of the rats with persistent estrus. These findings are consistent with delayed anovulation syndrome. The results suggest that observation of cyclicity at 6 months old is able to detect possible delayed ovarian dysfunction induced by perinatal exposure to chemicals.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Effect of gonadotropin-releasing hormone antagonist on ovarian and uterine weights in immature female rats.

The immature rat uterotrophic assay has been proposed as a screening test method for detecting estrogenic and antiestrogenic chemicals. Although the immature rat uterotrophic assay is advantageous because the test animals are not traumatized by the ovariectomizing process, the effect of endogenous estrogen on ovarian and uterine weight in the immature animals that are used in immature rat uterotrophic assay has not received much attention. In this study, 19-day-old rats were treated with antide, a gonadotropin-releasing hormone antagonist, antide, to block gonadal production of endogenous estrogen. Uterine and ovarian weights of the antide-treated animals were markedly lower than those of control animals. This finding suggests that endogenous gonadal estrogen may already be acting on the uterus and ovaries in immature rats. Blocking endogenous estrogen with a gonadotropin-releasing hormone antagonist may enhance the sensitivity of the immature rat uterotrophic assay; however, the possibility that this protocol may interfere with the ability of the immature rat uterotrophic assay to detect centrally-mediated effects can not be discounted.

Animals↗

PubMedDate not supplied

Evaluation of an in utero through lactational exposure protocol for detection of estrogenic effects of ethinyl estradiol on the offspring of rats: preliminary trial.

As a preliminary trial of an in utero through lactational exposure protocol, ethinyl estradiol, 0, 0.5, 5, or 50 micro g/kg/day, was administered by gavage to pregnant Crj: CD (SD) IGS BR rats from gestational day (GD) 7 to day 18 after delivery to evaluate the efficacy of this protocol and to estimate optimal endpoints. The dams showed no abnormalities. Cleft phallus was observed in female offspring at 50 micro g/kg. Other than a retardation of body weight gain in both sexes at 50 micro g/kg/day, no other abnormal findings were detected. The fact that cleft phallus was the only change induced suggests that the protocol is applicable to the detection of effects of estrogenic chemicals given to pregnant rats on offspring development and that the morphology of the female external genitalia may be a useful endpoint.

Abnormalities, Drug-Induced↗