Maternal exposure to androstenedione does not induce developmental toxicity in the rat.

Thirty-day old female rats received corn oil or androstenedione (in corn oil) at one of four concentrations (5.0, 10.0, 30.0 or 60.0 mg/kg body weight) by gavage for two weeks prior to mating, during the mating period and until gestation day (GD) 19. Caesarean sections were performed on GD 20. No dose related changes were observed in serum androstenedione, estradiol, LH, FSH, testosterone or progesterone. A statistically significant decrease in estrous cycle length was observed in the 60.0 mg/kg dose group only. Feed and fluid consumption, mean body weight gain, organ weight and fetal parameters were not affected by androstenedione treatment. At the doses given, androstenedione had no specific effect on the development of individual bones or soft tissues.     

Effect of isepamicin (HAPA-B) on reproduction. I. Fertility study in rats (intramuscular administration)

Effect of isepamicin (HAPA-B), a new aminoglycoside antibiotic, on fertility and reproductive performance in Wistar rats was studied. The drug was injected intramuscularly to rats at a daily dose of 25, 100 or 200 mg/kg. Male rats were treated for 63 days before mating and during the mating period, and female rats were treated for 2 weeks and through the mating period to the 7th day after mating. In male rats, an inhibition of body weight gain and a development of a pale color and hypertrophy of the kidney were observed in 100 and 200 mg/kg dose-groups. In female rats, inhibition of body weight gain was observed in 100 and 200 mg/kg dose-groups and a pale color of the kidney was seen in the 200 mg/kg group. No significant differences were observed in mating and fertility performance of male and female rats between the control and treated groups. Numbers of corpora lutea, implantation sites and living fetuses in the 200 mg/kg group decreased significantly. No external, visceral and skeletal anomalies due to the treatment of HAPA-B were observed in the live fetuses. No effect dose levels of HAPA-B found in this study were 25 mg/kg on parent rats and 100 mg/kg on reproduction ability and their fetuses.     

Effects of prenatal exposure to combination of acetaminophen,isopropylantipyrine and caffeine on intrauterine development in rats

The common effects of acetaminophen (paracetamol), isopropylantipyrine (propyphenazone) and caffeine on fetal development were examined in rats. The mixture was given in Tween 80 solution once daily, in a constant proportion of 5:3:1, during days 8-14 of gestation in three different doses. Dose S1 - 3.5 mg/kg acetaminophen, 2.14 mg/kg isopropylantipyrine, 0.7 mg/kg caffeine. Dose S2 was 10 times higher, and S3 100 times higher than dose S1. On day 21 of gestation, the dams were sacrificed and the fetuses were removed. The corpora lutea, resorptions, live and dead fetuses were counted. The pre- and postimplantation mortality were calculated. The weight of fetuses and placentas, and the length of fetuses and their tails were measured. Two-thirds of each litter was processed for Alizarin Red S staining. The remaining third was fixed in Bouin's solution for subsequent visceral examination by using modified Wilson's technique. A significant decrease in body weight in S1 group, and fetal length and placental weight in group S3 were recorded. A significant increase in tail length in group S2 was observed. The number of corpora lutea, fetuses, resorptions, preimplantation and postimplantation mortality did not exhibit any significant difference. Nonsignificant incidence of fetal anomalies was found.     

Sub-chronic exposure of adult male rats to diphenyl ditelluride did not affect the development of their progeny.

The present study was undertaken to evaluate the toxicity of diphenyl ditelluride [(PhTe)(2)] exposure on the progeny of Wistar male rats. Male rats were exposed to (PhTe)(2) subcutaneously for 4 weeks (wk) at the dose of 0.006 mg/kg and 8-wk at the dose of 0.003 mg/kg, prior to mating with unexposed females. The body and sex organ weights of male rats were not affected in both 4- and 8-wk (PhTe)(2)-exposed groups. The gravid uterus weight and the body weight gain (overall or corrected) during the pregnancy were not statistically different to those obtained from females mated with control males. The number of implantation sites, resorptions and live and dead fetuses were not affected by male exposure to (PhTe)(2). Fetal body weight and crown-rump length were not affected, as well. Examination of the fetuses from both exposed groups for external and skeletal changes did not reveal any male-mediated effect of (PhTe)(2). The current study indicated that (PhTe)(2) given sub-chronically (4- or 8-wk) to male rats had no adverse effects on their progeny.     

Reproductive and developmental toxicity screening test of basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats

Twelve male and female rats per group were exposed to the rubber accelerator 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 8, 20 or 50 mg/kg bw/day. Males were dosed for a total of 49 days beginning 14 days before mating. Females were dosed for a total of 40-49 days beginning 14 days before mating to day 3 of lactation throughout the mating and gestation period. At 50 mg/kg bw/day, deaths were observed in two males and three females. Lowered body weight gain and food consumption were noted in males at 50 mg/kg bw/day and females at 20 and 50 mg/kg bw/day. Mydriasis, decreased locomotor activity, bradypnea, prone position, tremor and/or salivation were observed in males and females at 20 and 50 mg/kg bw/day. No effects of DTG were found on the estrous cyclicity, precoital interval, copulation, fertility and gestational indices, numbers of corpora lutea and implantations, or gestation length. A significant decrease in the number, body weight and viability of offspring and increase in the incidence of fetuses with external malformations were found at 50 mg/kg bw/day. Oligodactyly, anal atresia and tail anomalies were observed. These data suggest that DTG may be teratogenic. The NOAELs of DTG for general and developmental toxicity in rats are 8 and 20 mg/kg bw/day, respectively.     

A study of the effect of (2"R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic, on reproduction. II. Its teratogenicity in rats and rabbits

This paper describes the embryotoxicity and teratogenic effects of (2"R)-4'-O-Tetrahydropyranyladriamycin (THP). The drug was administered intravenously to female rats at 0.01, 0.03, 0.1 or 0.3 mg/kg daily from day 7 to day 17 of pregnancy and to female rabbits at 0.01, 0.05 or 0.1 mg/kg daily from day 6 to day 18 of pregnancy. Results were summarized as follows. Rats THP, at the highest dose of 0.3 mg/kg, decreased body weight gains of pregnant females. This dose caused a decrease in body weights of fetuses, tendencies to increase the rate of death of fetuses or of resorption, an increase in the number of lumbar vertebrae and a delayed ossification of forelimbs of fetuses. Other parameters were not affected by THP at any dose levels. At any dose levels, THP did not produce external, visceral or skeletal malformations in the offspring (F1), nor did it affect the development, physiological functions, behavior, mating, fertility or pregnancy of the offspring. However, at the highest dose level, THP decreased the weight of testes of the offspring. The results suggest that the maximum "no effect" dose level of THP to pregnant females and offspring is 0.1 mg/kg/day intravenously. Rabbits The highest dose of THP, 0.1 mg/kg, decreased the consumption of food and water by pregnant females, but at any dose levels, it did not affect their body weight gain. THP did not cause teratological effects such as external malformation or visceral and skeletal anomalies in the fetuses at any dose levels tested. The results suggest that the maximum "no effect" dose of THP is 0.05 mg/kg/day intravenously to pregnant females and above 0.1 mg/kg/day intravenously to fetuses.     

Fertility and General Reproduction Studies in Rats with the HMG-CoA Reductase Inhibitor, Atorvastatin

Fertility and reproduction studies were conducted in rats withthe 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductaseinhibitor, atorvastatin. Male rats received vehicle (0.5% methylcellulose)or atorvastatin at 20, 100, or 175 mg/kg by oral gavage for11 weeks prior to mating with untreated females; treatment continuedthroughout mating and until necropsy on Day 115. An untreatedcontrol group of males was also included in the same procedures.Dose-related body weight gain suppressions of 17 and 25%, andfood consumption suppressions of 7 and 16%, occurred duringthe 11-week premating treatment period at 100 and 175 mg/kg,respectively, compared with vehicle controls. There were notreatment-related effects on testes, epididymides, or accessoryorgans weights, testicular or epididymal sperm counts, spermmotility, or sperm morphology during Week 15 of treatment. Plasmadrug concentrations during Week 15 Increased with dose to aCmax of 1820 ± 1020 ng eq/ml at 175 mg/kg. There wereno effects on copulation or fertility indices, number of daysto mating, or female reproductive parameters (number of implants,live fetuses, or pre- and postimplantation loss). In the femalefertility study, female rats received vehicle (0.5% methylcellulose)or atorvastatin at 20, 100, or 225 mg/kg by oral gavage for2 weeks prior to mating with untreated males; treatment continuedthroughout mating and until Gestation Day 7. Sperm-positivefemales were sacrificed on presumed Gestation Day 13 to 15 forevaluation of reproductive parameters. Body weight gain in atorvastatingroups was comparable to controls during the premating period,but was suppressed by 35% at 225 mg/kg during the treatmentperiod of gestation (Days 0–8), and was significantlyincreased at 225 mg/kg during the posttreatment period of gestation(Days 8–13). Plasma drug concentrations on premating treatmentDay 14 increased with dose to a Cmax of 7030 ± 3680 ngeq/ml at 225 mg/kg. The mean number of estrous cycles, copulationand fertility indices, number of days to mating, and numberof viable litters were comparable between groups. In addition,term sacrifice parameters (number of corpora lutea, implants,live fetuses, pre- and postimplantation loss) were not significantlydifferent between groups. Thus, these studies demonstrate noadverse effects of atorvastatin on fertility and reproductionin rats at doses up to 175 and 225 mg/kg in males and females,respectively, and 20 mg/kg was a no-effect dose.     

Toxicological studies on a new cephamycin, MT-141. VIII. Its fertility test in rats

A fertility study of MT-141 was performed in SD rats with the intramuscular (i.m.) injections at the dose levels of 400, 800 and 1,600 mg/kg/day. The male rats were injected with MT-141 for 63 days before mating and during the mating period, while the female rats were injected with MT-141 from the 14th day before mating up to the day 7 of gestation. All pregnant rats were sacrificed on day 20 of gestation followed by external, visceral and skeletal observations of their fetuses. The results are summarized as follows. The suppression of body weight gain was observed in males given above 800 mg/kg/day i.m. and in females of all treated groups during early period of gestation. However, no significant differences were found between treated groups and the control with regard to copulation rate and conception rate. Though no defects were observed for visceral and skeletal specimens in the fetuses of treated groups, MT-141 produced a delayed ossification of forelimbs in the fetuses at the doses above 800 mg/kg/day and of sternebrae at the dose of 1,600 mg/kg/day. It is concluded from the above-mentioned results that the maximal "no 'effective" dose of MT-141 on the fertility is above 1,600 mg/kg/day i.m. in parental rats and less than 800 mg/kg/day i.m. for the fetuses.     

Reproductive toxicology of acephate in male mice

The reproductive toxicity of the insecticide acephate was studied in male mice. Adult male mice were treated by gavage with acephate at doses of 0, 7, 14, and 28 mg/kg/day for 4 weeks before mating with untreated females. Signs of cholinergic effects were observed in the 28 mg/kg/day group. Brain and skeletal muscle acetylcholinesterase activity was inhibited only in this group. Acephate treatment was associated with a decreased number of implantations and live fetuses, and an increased number of early resorptions at 28 mg/kg/day. The percent morphologically normal spermatozoa was unaffected in all dose groups; however, sperm motility and count were decreased in the 14 and 28 mg/kg/day groups compared to the control. Histologic examination of brain did not reveal any abnormalities. Dose related histologic changes, including degeneration of muscle fibers, were observed in the muscles of male mice treated with any of the doses of acephate. The current study demonstrated adverse effects of male acephate exposure on pregnancy outcome with effects on sperm parameters at 14 and 28 mg/kg/day.     

Characterization of the effect of deoxynivalenol on selected male reproductive endpoints.

The effect of deoxynivalenol (DON) exposure on male reproductive function was assessed in the rat. Male rats were divided into a control group (n=15 rats) and four treatment groups (0.5 mg/kg, n=15; 1.0 mg/kg, n=15; 2.5 mg/kg, n=15; and 5.0 mg/kg DON, n=16) and exposed to DON daily for 28 days via gastric intubation. Both body weight gain and the final body weight of animals in the 5.0 mg/kg dose group and feed consumption in animals in the 2.5 mg/kg and 5.0 mg/kg dose groups were significantly reduced compared to controls. Fluid consumption was not affected in any of the treated groups. Epididymal and seminal vesicle weights expressed per gram of body weight and brain weight were significantly reduced, compared to control weights, in animals from the 2.5 and 5.0 mg/kg dose groups while prostate weight expressed per gram of brain weight and body weight was significantly lower than controls only in the 5.0 mg/kg dose group. A statistically significant, dose-related decrease in homogenization resistant testicular spermatid counts, spermatid numbers, absolute cauda epididymal sperm numbers and cauda epididymal sperm numbers per gram of cauda epididymis was observed in the 5.0 mg/kg DON treatment group. Sperm tail abnormalities (broken tails) in the 5.0 mg/kg dose group were significantly higher than in the control group. Sperm swimming speed (VSL and VCL) was significantly increased only in the 2.5 mg/kg dose group. Serum FSH and LH concentrations were increased in a dose dependent manner across all treated groups while serum testosterone concentrations were decreased in a dose-related manner across all dose groups. An increase in germ cell degeneration, sperm retention and abnormal nuclear morphology was observed in the 2.5 mg/kg and 5.0 mg/kg dose groups. Treatment related effects included lesions in the non-glandular stomach, thymic lymphoid depletion and splenic hematopoiesis in the 5.0 mg/kg treatment group.     

Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats

Perfluorooctanesulfonate (PFOS) is a persistent acid found widely distributed in wildlife and humans. To understand the potential reproductive and developmental effects of PFOS, a two-generation reproduction study was conducted in rats. Male and female rats were dosed via oral gavage at dose levels of 0, 0.1, 0.4, 1.6, and 3.2 mg/(kg day) for 6 weeks prior to mating, during mating, and, for females, through gestation and lactation, across two generations. Due to substantial F1 neonatal toxicity observed in the 1.6 and 3.2 mg/(kg day) groups, continuation into the second generation was limited to F1 pups from the 0, 0.1, and 0.4 mg/(kg day) groups. No adverse effects were observed in F0 females or their fetuses upon caesarean sectioning at gestation day 10. Statistically significant reductions in body-weight gain and feed consumption were observed in F0 generation males and females at dose levels of 0.4 mg/(kg day) and higher, but not in F1 adults. PFOS did not affect reproductive performance (mating, estrous cycling, and fertility); however, reproductive outcome, as demonstrated by decreased length of gestation, number of implantation sites, and increased numbers of dams with stillborn pups or with all pups dying on lactation days 1-4, was affected at 3.2 mg/(kg day) in F0 dams. These effects were not observed in F1 dams at the highest dose tested, 0.4 mg/(kg day). Neonatal toxicity in F1 pups, as demonstrated by reduced survival and body-weight gain through the end of lactation, occurred at a maternal dose of 1.6 mg/(kg day) and higher while not at dose levels of 0.1 or 0.4 mg/(kg day) or in F2 pups at the 0.1 or 0.4 mg/(kg day) dose levels tested. In addition to these adverse effects, slight yet statistically significant developmental delays occurred at 0.4 (eye opening) and 1.6 mg/(kg day) (eye opening, air righting, surface righting, and pinna unfolding) in F1 pups. Based on these data, the NOAELs were as follows: reproductive function: F0> or =3.2 and F1> or =0.4 mg/(kg day); reproductive outcome: F0=1.6 and F1> or =0.4 mg/(kg day); overall parental effects: F0=0.1 and F1> or =0.4 mg/(kg day); offspring effects: F0=0.4 and F1> or =0.4 mg/(kg day). To distinguish between maternal and pup influences contributing to the perinatal mortality observed in the two-generation study, a follow-up cross-foster study was performed. Results of this study indicated that in utero exposure to PFOS causally contributed to post-natal pup mortality, and that pre-natal and post-natal exposure to PFOS was additive with respect to the toxic effects observed in pups.     

Teratogenic Evaluation of Tributyltin Chloride in Rats Following Oral Exposure

ABSTRACT

The teratogenicity of tri-n-butyltin chloride (TBTC1) was examined in Wistar rats. The pregnant rats were administered orally 25, 15, 9, 5 and 0(Control) mg of TBTCl/kg of body weight/day from day 7 to 15 of pregnancy. Maternal toxicity, as evidenced by both of decreased body weight gain and food consumption was observed at 25, 15 and 9 mg/kg/day dose group. However, only in the 25 mg/kg/day dose group some clinical signs of toxicity (sedation, diarrhoea and salivation) were observed and 70 percent of the dams were dead. In the 25 mg/kg/day dose group, all fetuses were dead. Statistically significant reductions in the female fetal body weight were observed in 9 and 5 mg/kg/day dose groups. In all groups treated with TBTC1 except the 25 mg/kg/day dose group, no significant differences in the numbers of live fetuses and intrauterine death (dead fetuses and resorptions) or sex ratios of fetuses were found between the TBTC1-treated and control groups. Fetal external, skeletal and internal malformations were not observed at any of the dose levels. However, several types of skeletal and internal variations including delayed ossifications were observed in some groups treated with TBTC1, but the incidences were not significantly different from controls. Also, two fetuses with dilatation of the renal pelvis were found in 9 and 5 mg/kg/day dose group. Statistically significant increases of placental weight in all TBTC1-treated groups were observed when compared to that of control group. In conclusion, TBTC1 administered orally to Wistar rats during days 7–15 of pregnancy produced related signs of fetal toxicity but no evidence of teratogenicity and induced a marked increase in placental weight.     

Teratogenic evaluation of tributyltin chloride in rats following oral exposure

The teratogenicity of tri-n-butyltin chloride (TBTC1) was examined in Wistar rats. The pregnant rats were administered orally 25, 15, 9, 5 and 0(Control) mg of TBTC1/kg of body weight/day from day 7 to 15 of pregnancy. Maternal toxicity, as evidenced by both of decreased body weight gain and food consumption was observed at 25, 15 and 9 mg/kg/day dose group. However, only in the 25 mg/kg/day dose group some clinical signs of toxicity (sedation, diarrhoea and salivation) were observed and 70 percent of the dams were dead. In the 25 mg/kg/day dose group, all fetuses were dead. Statistically significant reductions in the female fetal body weight were observed in 9 and 5 mg/kg/day dose groups. In all groups treated with TBTC1 except the 25 mg/kg/day dose group, no significant differences in the numbers of live fetuses and intrauterine death (dead fetuses and resorptions) or sex ratios of fetuses were found between the TBTC1-treated and control groups. Fetal external, skeletal and internal malformations were not observed at any of the dose levels. However, several types of skeletal and internal variations including delayed ossifications were observed in some groups treated with TBTC1, but the incidences were not significantly different from controls. Also, two fetuses with dilatation of the renal pelvis were found in 9 and 5 mg/kg/day dose group. Statistically significant increases of placental weight in all TBTC1-treated groups were observed when compared to that of control group. In conclusion, TBTC1 administered orally to Wistar rats during days 7-15 of pregnancy produced related signs of fetal toxicity but no evidence of teratogenicity and induced a marked increase in placental weight.     

Neonatal mortality from in utero exposure to perfluorooctanesulfonate (PFOS) in Sprague-Dawley rats: dose-response, and biochemical and pharamacokinetic parameters

Perfluorooctanesulfonate (PFOS) is a widely distributed, environmentally persistent acid found at low levels in human, wildlife, and environmental media samples. Neonatal mortality has been observed following PFOS exposure in a two-generation reproduction study in rats and after dosing pregnant rats and mice during gestation. Objectives of the current study were to better define the dose-response curve for neonatal mortality in rat pups born to PFOS-exposed dams and to investigate biochemical and pharmacokinetic parameters potentially related to the etiology of effects observed in neonatal rat pups. In the current study, additional doses of 0.8, 1.0, 1.2, and 2.0 mg/kg/day were included with original doses used in the two-generation study of 0.4 and 1.6 mg/kg/day in order to obtain data in the critical range of the dose-response curve. Biochemical parameters investigated in dams and litters included: (1) serum lipids, glucose, mevalonic acid, and thyroid hormones; (2) milk cholesterol; and (3) liver lipids. Pharmacokinetic parameters investigated included the interrelationship of administered oral dose of PFOS to maternal body burden of PFOS and the transfer of maternal body burden to the fetus in utero and pup during lactation, as these factors may affect neonatal toxicity. Dosing of dams occurred for 6 weeks prior to mating with untreated breeder males, through confirmed mating, gestation, and day four of lactation. Dose levels for the dose-response and etiological investigation were 0.0, 0.4, 0.8, 1.0, 1.2, 1.6, and 2.0 mg/kg/day PFOS. Statistically significant decreases in gestation length were observed in the 0.8 mg/kg and higher dose groups. Decreases in viability through lactation day 5 were observed in the 0.8 mg/kg and higher dose groups, becoming statistically significant in the 1.6 and 2.0 mg/kg dose groups. Reduced neonatal survival did not appear to be the result of reductions in lipids, glucose utilization, or thyroid hormones. The endpoints of gestation length and decreased viability were positively correlated, suggesting that late-stage fetal development may be affected in pups exposed to PFOS in utero and may contribute to the observed mortality. Benchmark dose (BMD) estimates for decreased gestation length, birth weight, pup weight on lactation day 5, pup weight gain through lactation day 5, and viability resulted in values ranging from 0.27 to 0.89mg/kg/day for the lower 95% confidence limit of the BMD5 (BMDL5). Results of analyses for PFOS in biological matrices indicate a linear proportionality of mean serum PFOS concentration to maternal administered dose prior to mating and through the first two trimesters of gestation. However, at 21 days of gestation, mean serum PFOS concentrations were notably reduced from values measured earlier in gestation. Urinary and fecal elimination was low as expected from prior observations in adult rats. Significant transfer of PFOS from dam to fetus in utero was confirmed, and results suggest that dam and corresponding fetal body burdens, as indicated by serum and liver PFOS levels, correlate with neonatal survival.     

Developmental toxicity of cobalt in the rat

To determine the potential developmental toxicity of cobalt, pregnant Sprague-Dawley rats were given by gavage a daily dose of 0, 25, 50; and 100 mg/kg cobalt(II) chloride on d 6-15 of gestation. Females were sacrificed on d 20. Maternal effects included significant reductions in weight gain and food consumption, particularly at 100 mk/kg.d. Hematocrit, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and reticulocytes were increased significantly in the 100-mg/kg.d group. No treatment-related changes were recorded in the number of corpora lutea, total implants, resorptions, the number of live and dead fetuses, fetal size parameters, or fetal sex distribution data. Increased incidence of stunted fetuses per litter was the only adverse finding at 50 and 100 mg/kg.d group. However, this increase was not statistically significant. Examination of fetuses for gross external abnormalities, skeletal malformations, or ossification variations revealed that cobalt did not produce teratogenicity or significant fetotoxicity in the rat at doses as high as 100 mg/kg.d.     

Teratological assessment of the oxidative dye 4-methyl-N-ethylamino phenol sulfate

The oxidative dye 4-methyl-N-ethylamino phenol sulfate was evaluated for teratogenic potential. The dye was administered by gavage to pregnant Sprague-Dawley rats at dose levels of 300, 600, and 1200 mg/kg on gestation days six through fifteen. No signs of toxicity were observed during the treatment period. A significant reduction in mean maternal weight gain was noted during treatment at the high dose level of 1200 mg/kg. The test material did not produce embryotoxic nor fetal toxic effects at dose levels utilized. Evaluation of fetal external, visceral, and skeletal anomalies revealed no statistically significant differences between dye treated and control groups. Oral exposure of dams to the positive control, Vitamin A, resulted in a significant increase in the number of litters with abnormal fetuses.     

紫杉醇对大鼠的一般生殖毒性作用

紫杉醇是一种抗肿瘤新药，对大鼠的一般生殖毒性实验结果表明，给药剂量在１．０ｍｇ／ｋｇ时雄鼠和雌鼠摄食量减少，体重增长下降，雌鼠肾上腺及卵巢重量减轻，雄鼠的生育率和雌鼠受孕率下降，但对交配率无明显影响；母鼠剖检时发现黄体数、着床数及活胎数减少，着床痕数增加。未见致畸胎作用。对活胎体重、身长和尾长无明显影响。     

The Developmental Toxicity of Boric Acid in Rabbits

Boric acid (BA), an ingredient of many pharmaceutical, cosmetic,and pesticide products, was previously shown to induce reproductiveand developmental toxicity in laboratory rodents. In this study,BA (0, 62.5, 125, or 250 mg/kg/day, po) was administered onGestational Days (GD) 6–19 to New Zealand White rabbits(18–23 pregnant/group). Maternal body weight, food consumption,and clinical condition were monitored at regular intervals throughoutgestation. At termination (GD 30), the numbers of uterine implantations,resorptions, dead fetuses, and live fetuses were determined.Fetuses were weighed, and live fetuses examined for external,visceral, and skeletal defects. Maternal food intake decreasedduring treatment at 250 mg/kg/day and increased at 125 mg/kg/dayafter treatment. Maternal body weight (GD 9–30), weightgain during treatment, gravid uterine weight, and number ofovarian corpora lutea decreased at 250 mg/kg/day. In contrast,maternal corrected gestational weight gain increased at 125mg/kg/day. Maternal liver weight was not affected. Relative(but not absolute) maternal kidney weight increased at 250 mg/kg/day,and microscopic evaluation revealed no treatment-related renalpathology. At 250 mg/kg/day, prenatal mortality was increased(90% resorptions/litter vs 6% for controls), the proportionof pregnant females with no live fetuses was increased (73%vs 0%), and live litter size was reduced (2.3 fetuses/littervs 8.8). As a result, there were only 14 live fetuses (6 livelitters) available for evaluation in the high-dose group, comparedto 153–175 live fetuses (18–23 live litters) inthe other groups. The percentage malformed fetuses/litter wasincreased at 250 mg/kg/day, primarily due to cardiovasculardefects in 72% of high-dose fetuses vs 3% of controls. The mostprevalent cardiovascular malformation (in terventricular septaldefect) was observed in 57% of high-dose fetuses compared to0.6% among controls. At 250 mg/kg/day, average fetal body weight/litterwas 92% of the average control weight (not statistically significant).In summary, no definitive maternal or developmental toxicitywas observed at 62.5 or 125 mg/kg/day BA. Mild maternal effectsand severe developmental toxicity were observed at 250 mg/kg/day.     

Toxic effects of butyltin trichloride during early pregnancy in rats.

The objective of this study was to determine the toxic effects of butyltin trichloride (BTCl) during early pregnancy. Following successful mating, female rats were given BTCl by gastric intubation at 0,56,226, or 903 mg/kg on days 0-3 or 4-7 of pregnancy. Female rats were sacrificed on day 20 of pregnancy and fetuses were examined for number, abnormality, mortality, and weight. The maternal body weight gain and food consumption during the administration period was significantly decreased after administration of BTCl at 903 mg/kg on days 0-3 or 4-7 of pregnancy. The pregnancy rate in the BTCl-treated groups was comparable to the control value, regardless of the days on which BTCl was given. The incidence of pre-implantation embryonic loss was not significantly affected after administration of BTCl on days 0-3 or 4-7. In females having implantations, the numbers of corpora lutea, implantations, and live fetuses and the incidences of pre- and postimplantation loss in the groups given BTCl on days 0-3 were comparable to the controls. Although a significant increase in the incidence of postimplantation loss was observed after administration of BTCl on days 4-7 at 56 mg/kg, this change was small and inconsistent across doses and seems unlikely to be toxicologically significant. A significant decrease in weight of female fetuses was found after administration of BTCl at 903 mg/kg on days 0-3 or 4-7. It could be concluded that BTCl treatment during early pregnancy is maternal and developmental toxic at 903 mg/kg.     

Sodium 2-mercaptoethane sulfonate protection against cyclophosphamide-induced teratogenicity in rats

Certain deleterious effects of cyclophosphamide, for example urotoxicity, can be prevented by the administration of thiol compounds such as 2-mercaptoethane sulfonate (MESNA) without altering the therapeutic efficacy of cyclophosphamide. To evaluate the effect of MESNA on the teratogenicity of cyclophosphamide, pregnant Sprague-Dawley rats were divided into nine treatment groups. Individual groups were administered 0.9% NaCl or cyclophosphamide (10 or 15 mg/kg) alone or in combination with MESNA at one of two doses (5 or 30 mg/kg) on Day 13 of gestation. The fetuses were examined for malformations on Day 20 of gestation. Cyclophosphamide alone produced malformations in 50% (10 mg/kg) or 100% (15 mg/kg) of the fetuses. The abnormalities observed were hydrocephaly, hind- and forelimb defects, open eyes, cleft palate, edema, micrognathia, omphalocele, and various skeletal defects. MESNA alone did not induce a significant number of fetal malformations compared to control. The low dose of MESNA had no significant effect on the total incidence of external malformations produced by either dose of cyclophosphamide. The high dose of MESNA significantly reduced the total number of externally abnormal fetuses and fetuses with skeletal defects produced by both 10 and 15 mg/kg of cyclophosphamide. This protection, although statistically significant (p less than or equal to 0.05), is probably not extensive enough for MESNA to be considered effective in protecting pregnant women from the teratogenic effects of cyclophosphamide chemotherapy.