The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
Alpha-Methyldopa, a widely used antihypertensive, was evaluated for toxic and teratogenic effects in timed-pregnant CD-1 mice exposed to MD on gestational days 6 through 17 and sacrificed on gd 17. Prior to the initiation of the teratology study, a preliminary study was conducted in order to establish appropriate doses for use in the teratology study.
MD suspended in corn oil (0, 100, 250, 500, 750 mg/kg/day ) was administered by gavage to timed-pregnant CD-1 mice on gd 6 through 17. Females were weighed and observed during daily treatment for clinical signs of toxicity. At sacrifice on gd 17, the gravid uterus of each dam was weighed. Following uterine dissection, the number and status of uterine implantation sites was recorded. Each live fetus was weighed, sexed, and examined for external, visceral, and skeletal malformations. Fetal heart, whole head, and liver weight were recorded. A total of 21-25 dams (i.e., confirmed-pregnant females) per treatment group were evaluated in the study.
During MD treatment, dams at all dose levels exhibited observable signs of clinical toxicity including rough coat, weight loss, lethargy, vaginal bleeding, and alopecia at various sites on the body. Maternal mortality was 0%, 0%, 0%, 4.3%, and 16% of confirmed-pregnant females in the vehicle through high dose groups. MD at doses of 250 mg/kg/day or more caused significant depression of maternal body weight, weight gain, gravid uterine weight, and absolute maternal liver weight, with 100 mg/kg/day representing a no effect level for these parameters. MD significantly increased embryotoxicity at doses of 500 mg/kg/day and above, as evidenced by a significant increase in the percent resorptions per litter and other indices. Live litter size was significantly reduced at 750 mg/kg/day . and live fetal body weight was depressed in female fetuses at doses of 500 and 730 mg/kg/day MD and in male fetuses at doses of 250 mg/kg/day MD and above. MD significantly increased the percent fetuses malformed per litter and the percent female fetuses malformed per litter at both 500 and 750 mg/kg/day . The percent male fetuses malformed per litter was not significantly affected by treatment. MD caused a trend toward an increase in the incidence of skeletal malformations, but this effect was marginal and not dose-related. MD had no effect on the incidence of external or visceral malformations. Relative fetal heart and whole head weight were not adversely affected by treatment.
In conclusion, exposure of timed-pregnant CD-1 mice to MD (0, 100, 250, 500, or 750 mg/kg/day ) by gavage on gestational days 6-17, produced the following results:
- MD at the 100 mg/kg/day dose level caused mild clinical signs of maternal toxicity in a small number of animals but was a no effect level for other indices of maternal, embryo, and fetal toxicity.
- At 250 mg/kg/day, MD caused significant maternal toxicity, a noticeable but statistically insignificant increase in measures of embryotoxicity, and evidence of marginal fetotoxicity.
- At 500 and 750 mg/kg/day, clear evidence of prenatal mortality and intrauterine growth retardation was observed in the presence of significant maternal toxicity and/or mortality.
- MO caused a small but significant increase in the incidence of malformed fetuses per litter at both 500 and 750 mg/kg/day which appeared to primarily involve female fetuses. The percent fetuses malformed and the number of litters with fetuses with skeletal malformations also exhibited a trend toward an increase. These effects were noted only in the presence of significant maternal, embryo, and fetal toxicity, and therefore may be secondary to generalized effects of MD.
- Evaluation of fetal whole head weight and heart weight indicated that whereas head weight was proportional to body weight for all dose groups, heart weight was not as affected by intrauterine growth retardation.
In addition to the teratology study, a preliminary evaluation of perinatal survival and postnatal growth to postnatal day 21 of mouse pups exposed in utero to MD on gd 6-17 and fostered to untreated mothers was also conducted. In this preliminary perinatal and postnatal evaluation, MD was administered in corn oil by gavage at doses of 0, 100, 250, 500, or 750 mg/kg/day to timed-mated females (6-7 per group) on gestational days (gd) 6 through 17. During treatment, dams exposed to MD exhibited observable signs of toxicity that consisted of weight loss and lethargy, primarily at doses of 250 mg/kg/day or greater; there were no treatment-related maternal deaths. MD had no effect on maternal body weight but caused a trend toward a decrease in maternal weight gain. with 100 mg/kg/day being a no effect level. MD had no significant adverse effect on live litter size, survival and growth of live pups to pnd 4, or pup survival and growth to pnd 21. Evaluation of pup relative liver, heart, and brain weight on pnd 21 indicated that liver and heart weight were unaffected, but suggested that in utero exposure to MD at doses of 250 mg/kg/day and above may result, in the postnatal period, in depressed brain growth relative to body growth.