氧氟沙星对小鼠生殖毒性和致畸性的研究

目的研究氧氟沙星对昆明系小鼠胚胎和胎鼠发育的影响,确定其是否存在生殖毒性和致畸性。方法①雄鼠分别灌服各剂量氧氟沙星,连续10d,末次给药24h后与母鼠合笼,在妊娠第三天取胚胎,记录各剂量组胚胎发育率。②孕鼠妊娠零天给药,分别经口灌服高、中、低剂量[36、72和360mg(kg.bw)]氧氟沙星溶液,连续给药3d,在妊娠第三天收集胚胎,记录胚胎发育率。③孕鼠妊娠零天给药,分别经口灌服各剂量氧氟沙星溶液,连续给药10d,在妊娠第16天取出胎鼠,记录胎鼠体重、胎盘重、活胎数、胎鼠外观畸形和内脏畸形等指标。结果给药组与对照组相比,雄鼠服用高剂量组360mg(kg.bw)氧氟沙星对着床前胚胎发育影响显著(P<0.05),而中等剂量和低剂量组对着床前胚胎发育的影响不显著(P>0.05)。雌鼠服用不同剂量氧氟沙星对着床前胚胎发育影响不显著(P>0.05)。氧氟沙星对受孕鼠的活胎数和吸收胎数均无明显影响,给药组的活鼠体重、胎盘重均未见明显差异(P>0.05);药物组和对照组均未出现外观畸形和内脏畸形,也不存在剂量和效应关系。结论孕鼠服用不同剂氧氟沙星对昆明系小鼠胚胎和胎鼠发育无明显的影响,表明氧氟沙星对雌性鼠不具有明显的生殖毒性和致畸性;但雄鼠服用高剂量氧氟沙星对着床前胚胎发育影响显著。     

Amelioration of some metabolic effects produced by hyperthyroidism in late pregnant rats and their fetuses. Effects on lipids and proteins.

We have studied the effect of 40-45 days administration of 1 mg/kg thyroxine on protein and lipid metabolism in liver, heart, lungs, kidneys and adrenal glands of virgin and 21-day pregnant rats and their fetuses and placentae. The chronic administration of thyroid hormone produced significant increases in serum T3 and T4 in both groups as well as in organ weights and protein concentrations in virgin rats, but much smaller modifications in pregnant ones. Hyperthyroidism decreased the weight of fetal livers and increased that of placentae; protein content was increased in all fetal organs. Hyperthyroidism induced increases in phospholipid concentrations in all the organs and in total lipids only in liver and heart of adult rats, which were not counteracted by pregnancy. Pregnant rats had increases in total lipids in liver and kidneys and in adrenal phospholipids. In hyperthyroid fetuses there was an increase in hepatic total lipids and no changes in phospholipids. Hepatic lipogenesis (measured by in vivo incorporation of 3H2O into lipids) was increased by hyperthyroidism in virgin and pregnant rats, but the increase was significantly smaller in the pregnant hyperthyroid rats compared with the virgin ones. Fetal lipogenesis in liver and lung was not changed. In addition, an increase was observed in lipogenic enzyme (fatty acid synthetase and glucose-6-phosphate dehydrogenase) activities in hyperthyroid virgin rats which was prevented by pregnancy. In fetuses only pulmonary glucose-6-phosphate dehydrogenase was increased when expressed in terms of tissue weight. Our results indicate that the metabolic effect of hyperthyroidism is attenuated in pregnant rats and their fetuses, when compared with adult virgin rats, in most of the parameters studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention by tiopronin (2-mercaptopropionyl glycine) of methylmercuric chloride-induced teratogenic and fetotoxic effects in mice

Previous investigations (Fuyuta et al., '76, '79) have shown that a single oral administration of 25 mg/kg methylmercuric chloride (MMC) to pregnant ICR mice on day 10 of pregnancy induced cleft palate in a remarkably high incidence in fetuses. Based on these findings, the present study dealing with the prevention of cleft palate by Tiopronin, (2-mercaptopropionyl glycine, Tp), was initiated. Twenty females in the positive control group were given 25 mg/kg MMC orally on day 10 of pregnancy and then given physiological saline intraperitoneally. Twenty females in the negative control group were given distilled water orally and then given saline intraperitoneally. Cleft palate was found in 98.1% of fetuses in the positive control group and none of them in the negative control group. Twenty females were pretreated with a single oral dose of 25 mg/kg MMC on day 10 of pregnancy and were posttreated with Tp intraperitoneally, immediately and at every 24, 48 and 72 hours after the MMC treatment. The doses of Tp were 320, 160 and 80 mg/kg/day. The incidences of cleft palate in fetuses were reduced to 1.49, 31.3 and 47.8% in the Tp-treated groups with the doses of 320, 160 and 80 mg/kg/day, respectively. Tiopronin could effectively prevent the expected incidence of cleft palate. Other types of abnormalities as well as fetotoxicity represented by reduced fetal body weight were also effectively prevented with the Tp-treatment.     

Inhibitory effect of ouabain on epinephrine-induced stimulation of adrenal corticosterone secretion in rats.

Chronic administration of ouabain (3 mg/Kg body weight, subcutaneously, once daily for consecutive 15 days) definitely inhibited epinephrine-induced increase of adrenal corticosterone secretion. The inhibition rate increased along with frequency of ouabain administration. Increase in adrenal corticosterone synthesis and secretion by ACTH (20-50 mU/rat) administration was partially suppressed by pretreatment with chronic ouabain administration. A slight but significant increase of adrenal corticosterone secretion caused by epinephrine administration in hypophysectomized rats was also inhibited by pretreatment with ouabain administration. Chronic administration of neither phentolamine (1 mg/rat, intraperitoneally, once daily for consecutive 15 days) nor propranolol (3 mg/Kg body weight, subcutaneously, once daily for consecutive 15 days) caused significant changes in adrenal corticosterone secretion in response to ACTH as well as to epinephrine. Chronic administration of ouabain in rats causes not only elevated secretion of ACTH from anterior pituitary but also functional change in adrenals leading to suppression of corticosterone secretion in response to ACTH or epinephrine administration.     

Influence of maternal dexamethasone treatment on morphometric characteristics of pituitary GH cells and body weight in near-term rat fetuses

Growth hormone (GH) and glucocorticoids have a powerful influence on controlling fetal growth, differentiation and maturation of numerous tissues. In the present study, the effect of maternal dexamethasone (Dx) treatment on GH cells and body weight in 19- and 21-day-old rat fetuses was investigated using immunocytochemical and morphometric methods. Pregnant female rats received daily injections of 1.0-0.5-0.5 mg Dx/kg b.w. on days 16-18 of pregnancy (experimental group), while the control group received an equal volume of saline. Dx treatment of pregnant rats enhanced immunostaining intensity and significantly increased (p<0.05) GH nuclear and cell volume, as well as volume density and number of GH cells per square millimeter in 19-day-old fetuses compared to the controls. In 21-day-old fetuses after maternal Dx administration, immunoreactivity, volume density and number of GH cells remained significantly increased (p<0.05). Dx treatment of pregnant rats resulted in marked body weight reduction of 21-day-old but not 19 days old fetuses in comparison with the corresponding controls. The presented results demonstrate that maternal Dx application has pronounced effect on morphometric parameters of GH cells of 19- and 21-day-old fetuses. Also, in near-term rat fetuses body weight was largely independent of pituitary GH cell activity.     

Ameltolide. I: Developmental toxicology studies of a novel anticonvulsant

Ameltolide, a novel anticonvulsant agent, has been shown in animal models to be effective in controlling seizures. The developmental toxicity of ameltolide was evaluated in two species. Naturally mated rats and rabbits were dosed once daily by gavage on gestation days (GD) 6-17 and 6-18, respectively. Rats were given doses of 0, 10, 25, or 50 mg/kg; rabbits were given 0, 25, 50, or 100 mg/kg. Laparotomy was performed on rats on GD 20 and on rabbits on GD 28. In rats, maternal toxicity was indicated at the 25- and 50-mg/kg dose levels by depressed body weight gain. Fetal body weight was depressed at the 50-mg/kg dose level. Fetal viability and morphology were not affected. The no-observed effect levels (NOEL) for adult and developmental toxicity in the rat were 10 and 25 mg/kg, respectively. In rabbits, maternal toxicity was indicated by a net loss in body weight at the 50- and 100-mg/kg dose levels. Fetal viability and body weight were depressed at the 100 mg/kg dose level. Shortened digits occurred on the right forepaw of one fetus at the 50-mg/kg dose level (in conjunction with severe maternal toxicity) and on the hindpaws of two fetuses from separate litters at the 100-mg/kg dose level. Incomplete ossification of the phalanges occurred on the forepaws of nine fetuses from four litters at the 100-mg/kg dose level. Ameltolide was weakly teratogenic in the rabbit. The NOEL for adult and developmental toxicity in the rabbit was 25 mg/kg.     

Reduction of all-trans-retinoic acid-induced teratogenesis in the rat by glycine administration

BACKGROUND: Prenatal rat embryo exposure to retinoids induces severe malformations in various organs; the most active and teratogenic metabolite is all-trans-retinoic acid (atRA). The mechanisms of this embryopathy are only partly known. In the present study, the influence of glycine on the teratogenicity of atRA was investigated. METHODS: Embryos from 5 groups of white rats were studied: Group 1 remained untreated; Group 2 received glycine 2% in drinking water ad libitum from the first gestational day (GD 1); Group 3 was administered vehicle (corn oil); Group 4 was treated with atRA (50 mg/kg of body weight) injected (IP); and Group 5 was treated with atRA (50 mg/kg of body weight IP) plus glycine 2% in drinking water ad libitum from GD 1. atRA was administrated daily from GD 8-10. Dams were killed on the 21st day of pregnancy, and their fetuses were examined to detect external, visceral, and skeletal malformations. RESULTS: The results show that the atRA-administered dose is not toxic for the dams, and that although fetal death was not observed, it produced abnormalities in the fetuses. Glycine reduced atRA-induced teratogenic effects (external and skeletal defects). CONCLUSIONS: The results indicate that glycine effectively reduces the teratogenic effects of atRA. Thus, glycine might be useful for the prevention of vitamin A teratogenicity.     

Preliminary studies on acute and subacute toxicity of an antidiabetic herbal preparation, Dianex

Dianex, a polyherbal formulation intended to use for diabetic patients, has been screened for toxic effects. For acute toxicity studies, Dianex was administered orally in graded doses of 0.75-10 g/kg to the mice. For subacute toxicity studies, different doses of Dianex (1.0, 1.5 and 2.5 g/kg) were administered orally to the rats once daily for 30 days. Animals were observed for physiological and behavioural responses, mortality, food and water intake and body weight changes. Hematological evaluation was performed weekly. All the animals were sacrificed on 31st day and changes in organ weights and histology were examined. Biochemical studies were done in liver and serum. No mortality was observed up to 10 g/kg of Dianex in acute toxicity study. Daily administration of as high as 2.5 g/kg dose of Dianex did not result in any mortality or changes in gross behaviour, body weight, weight and histology of different organs or serum and liver biochemistry. However, significant increase in RBC count and hemoglobin level was observed in the treated animals at all doses. Other peripheral blood constituents were in the normal range. The dose of Dianex to produce significant antidiabetic activity in mouse, 0.25-0.5 g/kg, is much lower than the doses used in the present study. Therefore such doses may be safe for daily administration without causing any serious side effects.     

Abortifacient principle of Achyranthes aspera Linn

Achyranthes apsera is an abundant indigenous herb in India. Extracts of the whole plant had shown an abortifacient effect in mice. Maximal activity was in the benzene extract which was tested. The drug, in olive oil, was given orally to rabbits in doses of 50 mg/kg of body weight on the 8th day postcoitum. Laparotomy was done on the 11th day. No implantation sites were found. However, ovaries contained prominent corpus luteum, indicating that the drug had prevented pregnancy. In rats, the drug was given orally as a single dose of 50 mg/kg of body weight on the 6th or 7th day after mating. No effect was observed. In mice the drug was given at a single dose of either 10, 15, 25, or 50 mg/kg of body weight. For toxicity tests in mice, a single dose of 1000 mg/kg of body weight was given. After 1 month animals were autopsied and the organs examined. The drug was nontoxic. For a chronic toxicity test 75 mg/kg of body weight was given every 21 days. After 6 months of drug treatment, blood and tissue samples were examined. No toxic effects were observed. For a teratogenic study, 15 mated female mice were fed 10 or 25 mg/kg of body weight on Day 6 of gestation. 3 generations of offspring showed no malformations. In mice, abortifacient effects were noted with a maximum activity at 50 mg/kg of body weight. The drug showed no estrogenic, antiestrogenic, or androgenic effects in mice. Progesterone or pituitary extract given along with the drug did not prevent abortions in mice. The drug was species-specific in that no abortifacient effect was found in rats.     

Influence of ACTH secreting tumor (MtTF4) on fetal rat adrenal gland steroidogenesis in vitro in prolonged pregnancy

Pregnant female rats with ACTH secreting tumor (MtTF4) have prolonged pregnancy and cannot deliver. The fetuses of tumor bearing females have in prolonged pregnancy on days 24 and 25 of pregnancy greater body weight and smaller adrenal weight as compared to intact fetuses of the 22nd day of pregnancy. The fetal adrenal glands converted to vitro 4-14C progesterone to radioactive 11-deoxycorticosterone (DOC), corticosterone (B), 18-hydroxy-11-deoxycorticosterone (18-OH-DOC), 18-hydroxy-corticosterone (18-OH-B) and aldosterone. Fetal adrenal glands in prolonged pregnancy synthetized in vitro less amount of radioactive DOC, B and 18-OH-DOC. A negative relationship exists between the maternal corticosterone which passes the placenta to fetuses and corticosteroidogenesis of fetal adrenal glands. These results indicate the possibility that fetal rat adrenal glands with their corticosteroids participate in pregnancy and influence normal delivery.     

Effect of polychlorocamphene on the organs and their neural apparatus in pregnant animals]

Experiments conducted on pregnant albino rats showed that in daily oral administration of polychlorokamphene--a chlorine organic compound widely used in agriculature--in a dose of 12 mg/kg (1/20 LD50) there was interrelation between the structural and the enzymatic changes in the nerve elements of the organs under study. They consisted in the focality of the affection of the nervous structures of the brain cortex, and in increase in the destructive processes involving the nervous structures of the heart, uterus, spinal cord at the end of pregnancy. A peculiar enzymatic reconstruction with the preservation of the activity of the cholinesterase (CE)-positive pericellular structures (whose number was markedly decreased in comparison with control) was noted against the background of reduction of the CE activity. The prevalence of destructive processes by the end of pregnancy was conditioned by a considerable accumulation of the preparation in the heart, uterus, and the brain (as shown by thin-layer chromatography). The presence of polychlorkamphene in the organs of fetuses pointed to disturbances in the permeability of the transplacental barrier and to a possible influence of the preparation on the development of the fetal nervous system.     

Effects of AET and MEA treatment of mice on the first day of pregnancy

Porton female mice were injected intraperitoneally with 2-aminoethylisothiouronium bromide hydrobromide (AET) or cysteamine hydrochloride (MEA) in a dose of 40 mg/kg of body weight on the first day of pregnancy. On the last, nineteenth, day of gestation, taking into consideration females in whose uterus live fetuses were observed, the increase in their body weight throughout pregnancy, the number of fetuses in the uterus, the body weight of fetuses, and placental weight were found smaller in mice treated with AET or MEA, than in control ones. Among the injected compounds, AET appeared to be less toxic than MEA.     

Effects of (D-ala2, met5)-enkephalinamide and naloxone on ACTH and corticosterone secretion

An intravenous administration of (D-ala2, met5)-enkephalinamide (DALA) caused a significant elevation of plasma ACTH and corticosterone at 10 to 20 min after injection in unanesthetized freely moving rats. An intraperitoneal administration of cyproheptadine tended to reduce plasma ACTH and corticosterone levels at 60 min after injection, but it did not attenuate the DALA-induced ACTH and corticosterone elevation. A large dose of naloxone (1-10 mg/kg body weight) caused a significant elevation in plasma corticosterone, but naloxone at 10 mg/kg body weight reduced the basal ACTH level and DALA-induced ACTH elevation. When both DALA and naloxone were injected, the steroidogenic effect was attenuated. Neither DALA nor naloxone affected the basal ACTH release and CRF-induced ACTH stimulation in rat anterior pituitary cell cultures. These results suggest that DALA acts at the extra-hypophyseal level to stimulate ACTH and corticosterone and that the naloxone stimulatory effect on steroidogenesis acts on the adrenal gland or is mediated by stimulating corticosterone stimulating factors other than ACTH.     

二月桂酸二丁基锡对大鼠妊娠及对子代毒性作用

目的通过染毒观察二月桂酸二丁基锡（Dibulytin Dilaurate,简称DBTD）对子代胎鼠形态、体重、性别及骨骼发育状的影响。方法按随机分组的原则,将大鼠分为对照组和染毒组,对照组用玉米油,染毒组用DBTD玉米油溶液,浓度分别是2.5 mg/kg体重（1/72 LD50）、10 mg/kg体重（1/18 LD50）和20 mg/kg体重（1/9 LD50）,采用灌胃的方式进行染毒,6 d/周,每天同一时间进行染毒,共计染毒48 d。染毒第五周后,各组大鼠与正常雄性大鼠以1：1的比例合笼,合笼期间不染毒,每只雌鼠查到阴栓为妊娠第0天,继续染毒,于妊娠第18天处死取胎鼠。结果1/18 LD50及1/9LD50剂量组中活胎及胎儿的体重明显下降,1/18 LD50剂量组胎儿的性别开始发生明显的变化（P〈0.05）。结论DBTD染毒对大鼠每胎存活数、胎重、胎儿的形态及性别有影响,有一定的生殖毒性。     

Immunomodulatory effect of Moringa oleifera Lam. extract on cyclophosphamide induced toxicity in mice

Immunomodulatory effect of ethanolic extract (50%) of M. oleifera leaves (MOE) has been studied in normal and immunosuppressed mice models. Different doses of MOE i.e. 125, 250 and 500 mg/kg body weight of mice were administered orally for 15 days. Cyclophosphamide at a dose of 30 mg/kg body weight was administered orally for the next 3 days. On day 16 and 19, hematological parameters like white blood cell (WBC) count, red blood cell (RBC) count, haemoglobin level (Hb), percent neutrophils and organ weight were recorded. Effect of MOE on phagocytic activity of mice macrophages was determined by carbon clearance test. MOE showed significant dose dependent increase in WBC, percent neutrophils, weight of thymus and spleen along with phagocytic index in normal and immunosuppressed mice. The results indicate that MOE significantly reduced cyclophosphamide induced immunosuppression by stimulating both cellular and humoral immunity.     

Hormone mediated changes in monoamine stores and regulation of enzymes of biosynthesis and metabolism in the rat adrenal gland. Influence of progesterone, estradiol, ACTH and testosterone administration

The influence of daily injections, for 7 days, of 17-hydroxyprogesterone caproate (8 mg/100 g body weight pro die), of estradiol-17 beta 17-undecylate (1.2 mg/100 g body weight pro die) of testosterone enanthate (2 mg/100 g body weight pro die) and of ACTH (4 IU/100 g body weight pro die) to male Wistar rats, weighing 200 g, were investigated. Monamine storage and regulation of enzymes phenylethanolamine N-methyl transferase (PNMT), monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) were studied in the adrenal glands. Results from testosterone treated rats were especially significant : the hormone administration decreased the stores of dopamine and norepinephrine (epinephrine precursors), stimulated PNMT and decreased metabolism of epinephrine by MAO and COMT. However, the adrenal content of epinephrine remained in the normal range. These findings suggest that uptake of epinephrine is accelerated in peripheral tissues by testosterone.     

Hypervitaminosis A resulting in DNA aberration in fetal transgenic mice (Muta Mouse)

Treatment with excessive amounts of Vitamin A during maternity induces fetal malformations. However, it is unclear whether these malformations are due to gene mutations or not. Using transgenic mice (containing lacZ gene showing beta-galactosidase enzymatic activity), we planned to observe whether gene mutations occur in the fetal tissues after treatment during maternity with Vitamin A (retinol palmitate). On the 11th day of pregnancy, mothers were given 30 mg (group 2), 150 mg (group 3) and 300 mg (group 4) of Vitamin A/kg body weight orally. Fetuses obtained on the 18th day of gestation showed malformations, such as cleft palate, origodactyly, brachydactyly and ectromeria. Most notably, cleft palate occurred dose dependently. The incidental rates were 100% in group 4, 58% in group 3 and 6% in group 2. The number of dead and absorbed fetuses also increased dose dependently with the treatments. DNA (integrated vectors containing lacZ genes) extracted from each fetus showed Vitamin A-induced lacZ mutations, especially in the malformed fetuses. The mutation frequencies were 4.99x10(-5) in group 4, 5.28x10(-5) in group 3 and 4.26x10(-5) in group 2. The frequencies of group 3 were significantly higher (p<0.05) than that of the controls (group 1), 2.79x10(-5). Maternal treatment with Vitamin A (150 mg/kg of body weight) was carried out on the 11th day of pregnancy. Fetuses obtained on the 14th day of gestation showed a much higher incidence of mutation, approximately 8.91x10(-5) (group 6) that was significantly higher (p<0.0001) than those from the controls (group 5), 2.94x10(-5). The present study indicates a possibility that hypervitaminosis A-induced fetal malformation and death might be caused by gene mutations.     

Fertile estrus induced in bitches by bromocryptine, a dopamine agonist: a clinical trial

The dopamine agonist bromocryptine, probably through amplifying gonadotroph (mainly FSH) secretion, was found to be suitable for provoking fertile estrus during the anestrous phase in bitches without functional cycles and/or ovarian activity. We studied estrus induction in 48 bitches after treatment with semisynthetic ergot alkaloid bromocryptine. For habituation a fractional dose of 0.3 mg/bitch was administered for three days followed by larger doses within the range of 0.6 to 2.5 mg/bitch by selecting dose rates on the basis of individual responsiveness and body weight. The long-term daily bromocryptine dose did not exceed 0.6 mg/bitch and 2.5 mg/bitch in small and large sized bitches, respectively. Gradual habituation and individual dose rates have almost completely eliminated the unwanted side effect of emesis. The period between treatment and onset of estrus varied but the average was 19 days. After the onset of estrus bromocryptine administration was usually continued for another 3 to 6 days. Occurrences of estrus, ovulation and pregnancy were monitored by cytological evaluation of vaginal epithelium, rapid ELISA for plasma progesterone and ultrasonography, respectively. Samples for progesterone were taken on Days 7, 9, 12 and 15 and sonograms of ovarian follicles and of fetuses were taken on Days 0, 22 and 35. The bitches involved in the study either regular or irregular cycles. Bromocryptine treatment induced estrus in all of the bitches including 40 of 48 (83%) with ovulation within a regular estrus and 6 of 48 (12.5%) that showed estrus but did not ovulate. Mating or artificial insemination of bitches in their fertile periods twice at two day intervals resulted in an 83% pregnancy rate (40 cases) and 39 (97.5%) of them gave birth to puppies. However, the average litter size was small with 4.8 +/- 1.6 pups.     

Antifertility effect of tamoxifen as tested in the female bonnet monkey (Macaca radiata)

The administration of a potent antiestrogen, tamoxifen at a dose of 3 mg/kg body weight/day orally post-coitally to cycling mated bonnet monkeys(Macaca radiata) from days 18–30 of cycle resulted in inhibition of establishment of pregnancy in 9 out of 10 monkeys. Tamoxifen effect was not due to interference with luteal function. The effect was specific to tamoxifen as exogenously administered progesterone could not reverse it. In addition to suggesting a role for estrogen in maintenance of early pregnancy in the primate the present study could be a prelude to the development of an effective post-ovulatory approach for regulation of fertility in the human female     

Evaluation of developmental toxicity in rats exposed to the environmental estrogen bisphenol A during pregnancy.

Bisphenol A (BPA) is an essential component of epoxy resins used in the lacquer lining of metal food cans, as a component of polycarbonates, and in dental sealants. The present study was conducted in an attempt to evaluate the adverse effects of the environmental estrogen BPA on initiation and maintenance of pregnancy and embryofetal development after maternal exposure during the entire period of pregnancy in Sprague-Dawley rats. The test chemical was administered by gavage to mated females from days 1 to 20 of gestation (sperm in varginal lavage = day 0) at dose levels of 0, 100, 300, and 1000 mg/kg. All females were subjected to caesarean section on day 21 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, significant toxic effects including abnormal clinical signs, decreased maternal body weight and body weight gain, and reduced food consumption were observed in pregnant rats. An increase in pregnancy failure was also found in the successfully mated females. In addition, increased number of embryonal deaths, increased postimplantation loss, reduced litter size and fetal body weight, and decreased number of fetal ossification centers of several skeletal districts were seen. On the contrary, no significant changes induced by BPA were detected in the number of corpora lutea and implantation sites and by fetal morphological examinations. In the 300 mg/kg group, suppressed maternal body weight and body weight gain, decreased food intake and reduced body weight of male fetuses were seen. There were no adverse signs of either maternal toxicity or developmental toxicity in the 100 mg/kg group. It was concluded that BPA administration during the entire period of pregnancy in rats produced pregnancy failure, pre- and postimplantation loss, fetal developmental delay and severe maternal toxicity, but no embryo-fetal dysmorphogenesis at an oral exposure level of 1000 mg/kg.