Developmental Toxicity In Mice Research Articles

Two-Generation Toxicity Study of the Antioxidant Compound Propyl-Propane Thiosulfonate (PTSO).

Propyl-propane thiosulfonate (PTSO), an antioxidant organosulfur compound present in the genus Allium, has become a potential natural additive for food and feed, as well as a possible biopesticide for pest control in plants. A toxicological assessment is necessary to verify its safety for livestock, consumers, and the environment. As part of the risk assessment of PTSO, this study was designed to explore its potential reproductive toxicity in mice following the OECD 416 guideline. The investigation spans two generations to comprehensively evaluate potential reproductive, teratogenic, and hereditary effects. A total of 80 CD1 mice per sex and generation were subjected to PTSO exposure during three phases (premating, gestation, and lactation). This evaluation encompassed three dose levels: 14, 28, and 55 mg PTSO/kg b.w./day, administered through the feed. No clinical changes or mortality attributed to the administration of PTSO were observed in the study. Some changes in the body weight and food consumption were observed, but not related to sex or in a dose-dependent manner. The two parental generations (F0, F1) exhibited normal reproductive performance, and the offspring (F1 and F2) were born without any abnormalities. The serum sexual hormone levels (progesterone -P-, testosterone -T-, estradiol -E2-, follicular stimulating hormone -FSH-, and luteinizing hormone -LH-) were in a normal range. Although significant changes were observed in the sperm analysis in the case of F0 group, no variation was found for F1 group, and no alterations in fertility were recorded either. The absolute organ weights and relative organ weight/body weight and organ weight/brain weight ratios, and the complete histopathological study, showed no significant alterations in males and females for all the generations considered. Considering all the results obtained, PTSO is not considered a reproductive or developmental toxicant in mice under the assayed conditions. These results support the good safety profile of PTSO for its potential application in the agrifood sector.

GR-C/EBPα-IGF1 axis mediated azithromycin-induced liver developmental toxicity in fetal mice

Azithromycin is considered an effective drug to treat the perinatal mycoplasma infection. However, there is a lack of studies on developmental toxicity of azithromycin. In this study, we observed the developmental toxicity of fetal liver induced by prenatal azithromycin exposure (PAE) in mice and explored the potential mechanism. Pregnant Kunming mice were intraperitoneally injected with azithromycin (37.5 and 150 mg/kg·d) from gestational day (GD) 9 to 18. After PAE, the bodyweight gain rates of pregnant mice and the birthweights of the offspring were decreased, and the liver morphology, development indexes and metabolic function were all altered in different degree in the PAE fetuses. Meanwhile, PAE decreased the fetal serum insulin-like growth factor 1 (IGF1) levels and liver IGF1 signal pathway expression, accompanied by glucocorticoid receptor-CCAAT enhancer-binding protein α (GR-C/EBPα) signal enhancement. Furthermore, azithromycin disturbed hepatocyte differentiation, maturation and metabolic function via upregulating GR-C/EBPα signal and reducing the expression and secretion levels of IGF1 in HepG2 cells. These changes could be reversed by GR siRNA or exogenous IGF1. These results indicated that PAE could cause fetal liver developmental toxicity in mice, and one of the main mechanisms was that azithromycin activated the GR-C/EBPα signal, inhibited the IGF1 signal pathway, and then disturbed the hepatic proliferation, apoptosis, differentiation, and glycose and lipid metabolism.

Effects of QDs exposure on the reproductive and embryonic developmental toxicity in mice at various pregnancy stages.

Quantum dots (QDs) have recently attracted considerable attention in the biomedical fields because of their unique and excellent optical properties. However, information on their health effects, particularly in the reproductive system, is limited. The present study focuses on the effects of intravenous injection of CdSe/ZnS QDs on the reproductive system and embryo development at various stages of pregnancy in mice. The CdSe/ZnS QDs intravenously injected in mice during pregnancy accumulated in the maternal liver, uterus and placenta. This accumulation affected the growth and development of the embryo during the early and middle stages of pregnancy. Moreover, genotoxicity to the placenta after exposure to CdSe/ZnS QDs was demonstrated by the increased expression levels of genes related to oxidative stress and apoptosis and the reduced expression levels of genes related to the nutrient and waste transportation. Alterations in the gene expression levels have hindered the transport of metabolites across the placenta, which in turn affected the ability of the fetus to obtain nutrients.

Embryo-Fetal Developmental Toxicity Studies with Pregabalin in Mice and Rabbits.

Pregabalin was evaluated for potential developmental toxicity in mice and rabbits. Pregabalin was administered once daily by oral gavage to female albino mice (500, 1250, or 2500 mg/kg) and New Zealand White rabbits (250, 500, or 1250 mg/kg) during organogenesis (gestation day 6 through 15 [mice] or 6 through 20 [rabbits]). Fetuses were evaluated for viability, growth, and morphological development. Pregabalin administration to mice did not induce maternal or developmental toxicity at doses up to 2500 mg/kg, which was associated with a maternal plasma exposure (AUC0–24) of 3790 μg•hr/ml, ≥30 times the expected human exposure at the maximum recommended daily dose (MRD; 600 mg/day). In rabbits, treatment‐related clinical signs occurred at all doses (AUC0–24 of 1397, 2023, and 4803 μg•hr/ml at 250, 500, and 1250 mg/kg, respectively). Maternal toxicity was evident at all doses and included ataxia, hypoactivity, and cool to touch. In addition, abortion and females euthanized moribund with total resorption occurred at 1250 mg/kg. There were no treatment‐related malformations at any dose. At 1250 mg/kg, compared with study and historical controls, the percentage of fetuses with retarded ossification was significantly increased and the mean number of ossification sites was decreased, which correlated with decreased fetal and placental weights, consistent with in utero growth retardation. Therefore, the no‐effect dose for developmental toxicity in rabbits was 500 mg/kg, which produced systemic exposure approximately 16‐times human exposure at the MRD. These findings indicate that pregabalin, at the highest dose tested, was not teratogenic in mice or rabbits

The mammary gland is a sensitive pubertal target in CD-1 and C57Bl/6 mice following perinatal perfluorooctanoic acid (PFOA) exposure.

Perfluorooctanoic acid (PFOA) is a developmental toxicant in mice, with varied strain outcomes depending on dose and period of exposure. The impact of PFOA on female mouse pubertal development at low doses (≤1mg/kg) has yet to be determined. Therefore, female offspring from CD-1 and C57Bl/6 dams exposed to PFOA, creating serum concentrations similar to humans, were examined for pubertal onset, including mammary gland development. Pups demonstrated a shorter PFOA elimination half-life than that reported for adult mice. Prenatal exposure to PFOA caused significant mammary developmental delays in female offspring in both strains. Delays started during puberty and persisted into young adulthood; severity was dose-dependent. Also an evaluation of female serum hormone levels and pubertal timing onset revealed no effects of PFOA compared to controls in either strain. These data suggest that the mammary gland is more sensitive to early low level PFOA exposures compared to other pubertal endpoints, regardless of strain.

Health assessment of gasoline and fuel oxygenate vapors: Developmental toxicity in mice

CD-1 mice were exposed to baseline gasoline vapor condensate (BGVC) alone or to vapors of gasoline blended with methyl tertiary butyl ether (G/MTBE). Inhalation exposures were 6h/d on GD 5–17 at levels of 0, 2000, 10,000, and 20,000mg/m3. Dams were evaluated for evidence of maternal toxicity, and fetuses were weighed, sexed, and evaluated for external, visceral, and skeletal anomalies. Exposure to 20,000mg/m3 of BGVC produced slight reductions in maternal body weight/gain and decreased fetal body weight. G/MTBE exposure did not produce statistically significant maternal or developmental effects; however, two uncommon ventral wall closure defects occurred: gastroschisis (1 fetus at 10,000mg/m3) and ectopia cordis (1 fetus at 2000mg/m3; 2 fetuses/1 litter at 10,000mg/m3). A second study (G/MTBE-2) evaluated similar exposure levels on GD 5–16 and an additional group exposed to 30,000mg/m3 from GD 5–10. An increased incidence of cleft palate was observed at 30,000mg/m3 G/MTBE. No ectopia cordis occurred in the replicate study, but a single observation of gastroschisis was observed at 30,000mg/m3. The no observed adverse effect levels for maternal/developmental toxicity in the BGVC study were 10,000/2000mg/m3, 20,000/20,000 for the G/MTBE study, and 10,000/20,000 for the G/MTBE-2 study.

Exogenous Nucleotides Antagonize the Developmental Toxicity of EthanolIn Vitro

The objective of this study was to assess whether nucleotides supplementation in vitro could suppress ethanol-induced developmental toxicity in mouse. The models of whole embryo culture (WEC) and midbrain (MB) cell micromass culture were used in this study. In WEC system, exposure to 4.0 mg/mL ethanol for 48 h yielded various developmental malformations of the mice embryos. Nucleotides supplementation (0.16, 0.80, 4.00, 20.00, and 100.00 mg/L) improved the growth parameters to some extent, and the protective effects peaked at 4.00 mg/L. In MB cell micromass culture system, exposure to 4.0 mg/mL ethanol for 5 days resulted in suppression of proliferation and differentiation. Supplementation of nucleotides (0.16, 0.80, 4.00, 20.00, and 100.00 mg/L) showed some protective effects, which peaked at 4.00 mg/L, too. The present research indicated that nucleotides supplementation might be of some benefit in the prevention of ethanol-induced birth defects; however, appropriate dosage requires attention.

The Potential Role for Corticosterone in the Induction of Cleft Palate in Mice After Treatment With a Selective NK‐1 Receptor Antagonist, Casopitant (GW679769B)

Casopitant is a potent and selective NK-1 receptor antagonist that has shown clinical efficacy in the prevention of chemotherapy-induced and postoperative-induced nausea and vomiting. In an embryo-fetal development study, pregnant mice were given vehicle (sterile water) or doses of 30, 100, or 300 mg/kg/day casopitant on Gestation Day (GD) 6 to 15. Fetuses were evaluated for external, visceral, and skeletal abnormalities on GD 18. In a follow-on study to investigate casopitant-induced hormonal changes during the developmental period for palate formation, pregnant mice were given vehicle (sterile water) or 300 mg/kg/day casopitant once daily on GD 6 to 13. Blood was collected on GD 13 at various time-points for measurement of plasma adrenocorticotropic hormone and corticosterone (CRT) concentrations. There was no evidence of developmental toxicity in mice at 30 or 100 mg/kg/day but 9% of fetuses at 300 mg/kg/day had cleft palate. Mice are sensitive to glucocorticoid-induced cleft palates, and NK-1 antagonists are known to modulate the hypothalamic-pituitary-adrenal axis leading to increases in corticosterone. On GD 13, mean plasma adrenocorticotropic hormone levels at 300 mg/kg/day were elevated by approximately twofold from vehicle-treated levels at 1 hr post-dose and mean plasma CRT levels were elevated by 3, 5, and 10-fold at 0.5, 1, and 2 hr post-dose, respectively. The increased level of CRT was in the range previously shown in the literature to cause cleft palates in mice and was likely the underlying mechanism behind casopitant-induced cleft palate in mice.

Developmental Toxicity in Mice Following Paternal Exposure to Di-N-Butyl-Phthalate (DBP)

Objective The aim of the present study was to investigate the effects of paternal Di-N-butyl-phthalate (DBP) exposure pre- and postnatally on F1 generation offspring, and prenatally on F2 generation offspring. Methods Male mice were exposed to either 500 mg/kg or 2 000 mg/kg of DBP for 8 weeks, and mated with non-exposed females. Three-quarters of the females were sacrificed a day prior to parturition, and examined for the number of living and dead implantations, and incidence of gross malformations. Pups from the remaining females were assessed for developmental markers, growth parameters, as well as sperm quantity and quality. Results There were no changes in the fertility of parents and in intrauterine development of the offspring. Pups of DBP-exposed males demonstrated growth-retardation. Following paternal exposure to 500 mg/kg bw of DBP, there were almost twice the number of males than females born in the F1 generation. F1 generation females had a 2.5-day delay in vaginal opening. Paternal exposure to 2 000 mg/kg bw of DBP increased the incidence of sperm head malformations in F1 generation males; however, there were no changes in the fertility and viability of foetuses in the F2 generation. Conclusion Paternal DBP exposure may disturb the sex ratio of the offspring, delay female sexual maturation, and deteriorate the sperm quality of F1 generation males.

Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice: Low doses induce elevated serum leptin and insulin, and overweight in mid-life

The synthetic surfactant, perfluorooctanoic acid (PFOA) is a proven developmental toxicant in mice, causing pregnancy loss, increased neonatal mortality, delayed eye opening, and abnormal mammary gland growth in animals exposed during fetal life. PFOA is found in the sera and tissues of wildlife and humans throughout the world, but is especially high in the sera of children compared to adults. These studies in CD-1 mice aim to determine the latent health effects of PFOA following: (1) an in utero exposure, (2) an in utero exposure followed by ovariectomy (ovx), or (3) exposure as an adult. Mice were exposed to 0, 0.01, 0.1, 0.3, 1, 3, or 5 mg PFOA/kg BW for 17 days of pregnancy or as young adults. Body weight was reduced in the highest doses on postnatal day (PND) 1 and at weaning. However, the lowest exposures (0.01–0.3 mg/kg) significantly increased body weight, and serum insulin and leptin (0.01–0.1 mg/kg) in mid-life after developmental exposure. PFOA exposure combined with ovx caused no additional increase in mid-life body weight. At 18 months of age, the effects of in utero PFOA exposure on body weight were no longer detected. White adipose tissue and spleen weights were decreased at high doses of PFOA in intact developmentally exposed mice, and spleen weight was reduced in PFOA-exposed ovx mice. Brown adipose tissue weight was significantly increased in both ovx and intact mice at high PFOA doses. Liver weight was unaffected in late life by these exposure paradigms. Finally, there was no effect of adult exposure to PFOA on body weight. These studies demonstrate an important window of exposure for low-dose effects of PFOA on body weight gain, as well as leptin and insulin concentrations in mid-life, at a lowest observed effect level of 0.01 mg PFOA/kg BW. The mode of action of these effects and its relevance to human health remain to be explored.

Two-Generation Reproductive Toxicity Study of Dietary Bisphenol A in CD-1 (Swiss) Mice

Dietary bisphenol A (BPA) was evaluated in a mouse two-generation study at 0, 0.018, 0.18, 1.8, 30, 300, or 3500 ppm (0, 0.003, 0.03, 0.3, 5, 50, or 600 mg BPA/kg/day, 28 per sex per group). A concurrent positive control group of dietary 17beta-estradiol (0.5 ppm; 28 per sex) confirmed the sensitivity of CD-1 mice to an endogenous estrogen. There were no BPA-related effects on adult mating, fertility or gestational indices, ovarian primordial follicle counts, estrous cyclicity, precoital interval, offspring sex ratios or postnatal survival, sperm parameters or reproductive organ weights or histopathology (including the testes and prostate). Adult systemic effects: at 300 ppm, only centrilobular hepatocyte hypertrophy; at 3500 ppm, reduced body weight, increased kidney and liver weights, centrilobular hepatocyte hypertrophy, and renal nephropathy in males. At 3500 ppm, BPA also reduced F1/F2 weanling body weight, reduced weanling spleen and testes weights (with seminiferous tubule hypoplasia), slightly delayed preputial separation (PPS), and apparently increased the incidence of treatment-related, undescended testes only in weanlings, which did not result in adverse effects on adult reproductive structures or functions; this last finding is considered a developmental delay in the normal process of testes descent. It is likely that these transient effects were secondary to (and caused by) systemic toxicity. Gestational length was increased by 0.3 days in F1/F2 generations; the toxicological significance, if any, of this marginal difference is unknown. At lower doses (0.018-30 ppm), there were no treatment-related effects and no evidence of nonmonotonic dose-response curves for any parameter. The systemic no observable effect level (NOEL) was 30 ppm BPA (approximately 5 mg/kg/day); the reproductive/developmental NOEL was 300 ppm (approximately 50 mg/kg/day). Therefore, BPA is not considered a selective reproductive or developmental toxicant in mice.

Effects of folinic acid and Vitamin B 12 on ethanol-induced developmental toxicity in mouse

The objective of this study was to assess whether combined supplementation of folinic acid (FA) and Vitamin B 12 (VB 12) could suppress ethanol-induced developmental toxicity better than FA alone in mouse embryos cultured in vitro. In this study, exposure to 4.0 mg/ml ethanol for 48 h yielded growth retardation and various malformations of the embryos. FA (10 −5, 10 −4 mol/l) or VB 12 (10 −6, 10 −5 mol/l) alone supplementation improved the growth parameters moderately, however combined supplementation of the two vitamins (10 −5 mol/l FA plus 10 −6 mol/l VB 12, 10 −5 mol/l FA plus 10 −5 mol/l VB 12, 10 −4 mol/l FA plus 10 −6 mol/l VB 12 and 10 −4 mol/l FA plus 10 −5 mol/l VB 12) showed better protective effects, including both the growth and development parameters of the embryos, than either vitamin alone at the same dosage. The present investigation indicated that combined supplementation of folic acid and VB 12 might be a better choice than folic acid alone in the prevention of ethanol-induced birth defects.

Embryotoxicity of oral administered chlorothalonil in mice

Chlorothalonil (2,4,5,6-tetrachloroisophthalonitril), the nephrotoxic fungicide, was examined for its potential to produce developmental toxicity in mice after oral administration. Pregnant ICR (CD-1) mice were given sublethal doses of 0 (corn oil), 100, 400, and 600 mg/kg/day chlorothalonil by gavage on gestation days (GD) 6-15. Maternal effects in 400 and 600 mg/kg/day dose groups included signs of toxicity such as weakness and depression in the maternal activity, and reduction in body weight and weight gain. No maternal toxicity was apparent in the 100 mg/kg/day dose group. Maternal exposure to chlorothalonil during organogenesis significantly affected the number of live fetuses, early resorption, and mean fetal weight in the 400 and 600 mg/kg/day dose groups. No external, visceral, and skeletal abnormalities were observed among any of the treated groups compared to the control. On the basis of the present results chlorothalonil can produce clinical signs of toxicity and fetotoxicity without teratogenic effects at 400 and 600 mg/kg/day dose groups.

The maternal combined supplementation of folic acid and Vitamin B 12 suppresses ethanol-induced developmental toxicity in mouse fetuses

Maternal ethanol consumption during pregnancy can induce developmental defects in the fetus. The objective of this study was to assess whether combined supplementation of folic acid (FA) and Vitamin B 12 (VB 12) in dams would suppress ethanol-induced developmental toxicity in CD-1 mice. Ethanol (5.0 g/kg) was given intragastrically from gestational day (GD) 6 to GD15. Vitamin supplementation groups were additionally given 60.0 mg/kg FA, 1.0 mg/kg VB 12, or 60.0 mg/kg FA + 1.0 mg/kg VB 12 during GD1-16. The control group received distilled water only. Results of litter evaluation on GD18 showed that combined supplementation of FA and VB 12 ameliorated many of the adverse effects of ethanol. In contrast, the single vitamin supplementation groups showed little or no amelioration. These results suggest that combined supplementation of FA and VB 12 was more effective than each vitamin toward suppressing ethanol-induced developmental toxicity in CD-1 mice.

Teratogenicity and developmental toxicity of chlorpyrifos: Maternal exposure during organogenesis in mice

Chlorpyrifos, an organophosphate pesticide, was evaluated for potential teratogenicity and developmental toxicity in mice. Pregnant females were given a single intraperitoneal injection (40 or 80 mg/kg) on day 10 of gestation and fetuses were evaluated on gestation day 17. At 80 mg/kg, chlorpyrifos treatment resulted in a significant reduction in numbers of live fetuses, and increase in resorptions, versus control litters. There was no indication of maternal toxicity. External and skeletal malformations were observed at 80 mg/kg, but not 40 mg/kg. Rates of fetuses with cleft palate increased significantly ( p < 0.05) following 80 mg/kg chlorpyrifos (5.97%) versus control litters (0.97%). Similarly, the absence of thoracic vertebrae was increased and the number of caudal vertebrae was significantly decreased. It is suggested that chlorpyrifos is teratogenic and embryotoxic in mice at doses below those that cause significant maternal toxicity.

Male-mediated developmental toxicity in mice after 8 weeks'exposure to low doses of X-rays

Purpose: The aim of the study was to investigate the effects of subchronic irradiation of male mice on reproduction ability and induction of male-mediated teratogenesis.Materials and methods: Male mice were irradiated to 0.05 Gy, 0.10 Gy and 0.20 Gy daily for 8 weeks, 5 days per week. The total doses were 2.00 Gy, 4.00 Gy and 8.00 Gy, respectively. After the end of exposure each male was caged with two untreated females. The females were sacrificed on day 17 based on the finding of a vaginal plug. Females were examined for the number of live and dead implantations and the incidence of congenital malformations of survival foetuses.Results: The fertilization ability of males was not diminished. The exposure to 0.20 Gy daily significantly decreased the percent of pregnant females and the number of total implantations. Exposure to 0.10 Gy and 0.20 Gy daily caused decreases in the number of live foetuses and induced dominant lethal mutations (over 50% at the highest dose). Exposure to each dose significantly enhanced the number of deaths (especially early) implants. The incidence of gross and skeletal malformations was not statistically significant, except for skeletal malformations at the highest dose.Conclusions: Results confirmed that irradiation of male germ cells cause genetic effects which could be transmitted to the offspring. After subchronic exposure to low doses the majority of mutations caused premature death. Subchronic exposure to low doses of X-rays did not induce external and skeletal malformations of surviving foetuses.

The effects of gestational arsenic exposure and dietary selenium deficiency on selenium and selenoenzymes in maternal and fetal tissues in mice

Although toxicological and metabolic interactions of arsenic (As) and selenium (Se) have been suggested by epidemiolgical literatures, the past experimental studies mostly focused on acute, high-dose interaction, leaving the long-term, low-dose interaction unexplored. In the present study pregnant mice, fed either Se-deficient or adequate (0 or 5 μmol Se/kg diet, respectively) diet, were given oral gavage of sodium arsenite (0 or 58 μmol/kg per day; chosen as less than half of the fetotoxic dose in this protocol) from gestational day (GD) 7–16. The levels of As and Se as well as five selenoenzymes (glutathione peroxidase (GPx), thioredoxin reductase (TRxR), and type-I, -II and -III iodothyronine deiodinases (DI-I, -II and -III) were examined on GD17 in the tissues of dams and of fetus. The Se-deficient mice showed significantly enhanced accumulation of As compared to the Se-adequate mice in maternal liver (increased by 48%) and fetal brain (by 31%). Although no direct evidence of the enhanced toxicity in the Se-deficient group was obtained, the As exposure affected the levels of Se and selenoenzymes, an effect which was more discernible in Se-deficient group. Although most of theses changes were mild or moderate, the DI-II activity in Se-deficient fetal brain showed a drastic four-fold increase by As exposure, suggesting a possible disturbance of thyroid hormone environment in the fetus. These data suggested that apparently non-toxic, in utero dose of As, showed enhanced accumulation when combined with Se-deficiency and could affect the metabolism/kinetics of Se in fetal brain, which might result in developmental toxicity in mice.

Preclinical Overview of WHI-07, A Novel Nucleoside Analog-based Dual- Function Microbicide

The current pandemic of sexually transmitted HIV / AIDS has created an urgent need for a new type of microbicide, one that is both a spermicide and a virucide. WHI-07 is a novel 5-bromo 6-methoxy aryl phosphoramidate derivative of 3-azido-3-deoxythymidine (zidovudine, ZDV / AZT) with potent anti-HIV and spermicidal activities. WHI-07 was rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions. WHI-07 was formulated via a nontoxic gel-microemulsion for intravaginal use as a potential candidate anti-HIV spermicide. The in vivo efficacy as well as safety studies of WHI-07 included: (i) vaginal as well as rectal microbicide efficacy studies in the feline immunodeficiency virus (FIV) / domestic cat model for AIDS; (ii) in vivo retention of anti-HIV activity in the nonhuman primate; (iii) vaginal contraceptive efficacy studies in rabbits; (iv) single- and/ or multiple-dose toxicity studies in mice, rabbits, cats as well as monkeys; (v) mucosal, reproductive, and developmental toxicity studies in mice and rabbits; (vi) cytotoxicity, mutagenicity, and genotoxicy tests using human and yeast cells; and (vii) long-term carcinogenicity studies in mice. WHI-07 which exhibited nanomolar in vitro anti-HIV IC50 and low micromolar spermicidal EC50 values was significantly less active against genital epithelial cells and did not induce primary DNA damage in human and yeast cells. WHI-07 retained full activity in TK-deficient cells, the main carriers of HIV in semen. Both vaginal as well as rectal instillation of WHI-07 gel-microemulsion, either alone or in combination with a vanadocene dithiocarbamate, effectively protected domestic cats from a subsequent vaginal or rectal exposure to feline T cells chronically infected with a mucosally transmissible FIV strain. WHI-07 gel-microemulsion was a potent vaginal contraceptive in the rabbit model. Both short-term (up to 90 days) and long-term (2-yr) repetitive intravaginal administrations of WHI-07 at concentrations as high as 5.7 ´ 106 times its in vitro anti-HIV IC50 and 5700-times its spermicidal EC50 were not associated with mucosal, systemic, reproductive or developmental toxicity in mice and rabbits and did not produce increased carcinogenicity in mice. WHI-07 has clinical potential as a safe prophylactic contraceptive anti-HIV microbicide for sexually active women. Keywords: contraceptive, microbicide, toxicity, zidovudine

Induction of developmental toxicity in mice treated with Alstonia scholaris (Sapthaparna) In utero

The teratogenic effect of hydroalcoholic extract of Alstonia scholaris (ASE) was studied in the pregnant Swiss albino mice administered with 0, 60, 120, 240, 360, and 480 mg/kg ASE on Day 11 of gestation. Females were allowed to complete the term and parturiate. The litters were monitored regularly for mortality, growth retardation, congenital malformations, and appearance of physiological markers up to 7 weeks post-parturition (p.p.). The administration of 60, 120, 180, and 240 mg/kg ASE to the pregnant mice on Day 11 did not induce mortality, congenital malformations, or alter the normal growth patterns. A further increase in the herbal extract dose up to 360 or 480 mg/kg resulted in a dose dependent increase in the mortality, growth retardation, and congenital malformations, characterized mainly by bent tails and syndactyly. The administration of higher doses (360 or 480 mg) of ASE also caused a significant delay in the morphological parameters such as fur development, eye opening, pinna detachment, and vaginal opening. The incisor eruption and testes decent were found to be delayed in litters born to the mothers treated with 240-480 mg/kg ASE. Our study indicates clearly that ASE treatment caused teratogenic effect only at doses above 240 mg/kg (>20% of LD(50)). Lower doses had no developmental toxicity.

Developmental toxicity of a commercial herbicide mixture in mice: I. Effects on embryo implantation and litter size.

We investigated the developmental toxicity in mice of a common commercial formulation of herbicide containing a mixture of 2,4-dichlorophenoxyacetic acid (2,4-D), mecoprop, dicamba, and inactive ingredients. Pregnant mice were exposed to one of four different doses of the herbicide mixture diluted in their drinking water, either during preimplantation and organogenesis or only during organogenesis. Litter size, birth weight, and crown-rump length were determined at birth, and pups were allowed to lactate and grow without additional herbicide exposure so that they could be subjected to additional immune, endocrine, and behavioral studies, the results of which will be reported in a separate article. At weaning, dams were sacrificed, and the number of implantation sites was determined. The data, although apparently influenced by season, showed an inverted or U-shaped dose-response pattern for reduced litter size, with the low end of the dose range producing the greatest decrease in the number of live pups born. The decrease in litter size was associated with a decrease in the number of implantation sites, but only at very low and low environmentally relevant doses. Fetotoxicity, as evidenced by a decrease in weight and crown-rump length of the newborn pups or embryo resorption, was not significantly different in the herbicide-treated litters.