L-5-Hydroxytryptophan, a metabolite of tryptophan and direct precursor of the biogenic amine, 5-hydroxytryptamine, was evaluated for teratogenicity following maternal exposure. Timed-pregnant CD-1 mice were dosed by gavage (po) on gestational days 6 through 15 with HTP (0.0, 50.0, 150.0, 300.0 or 450.0 mg/kg/da~r) in corn oil. These dose groups are referred to as HTP-O, HTP-50, HTP-150, HTP-300 or HTP-450, respectively. Dams were weighed on gestational days 0, 6 through 15 (prior to daily dosing) and 17 (immediately after sacrifice) and were also observed for clinical signs of toxicity. At sacrifice on gestational day 17, dams were evaluated for body weight, liver weight, gravid uterine weight and status of uterine implantation sites (i.e., sites, resorptions, dead fetuses, live fetuses). Live fetuses were dissected from the uterus and evaluated for live litter size, body weight, sex and gross morphological abnormalities. All live fetuses were examined for visceral malformations employing the Staples' fresh tissue dissection method. Half of the fetuses were decapitated prior to dissection and the heads were fixed in Bouin's solution for free-hand sectioning and examination (Wilson's technique). All fetal carcasses were stained with Alizarin Red S and examined for skeletal malformations.
The maternal mortality rate in the present study was 0.0% for all dose groups. A significant dose-response trend (p<0.05) for reduction in maternal body weight was observed on gestational days 11, 15 and 17, but not on gestational days O or 6 (immediately prior to onset of dosing), with no significant pairwise comparisons. There was also a downward significant trend for maternal weight gain during gestation period and during treatment period but no significant pairwise comparisons. At sacrifice on gestational day 17 a dose-response trend was evident for reduction in maternal liver weight, with the values from HTP-150 and HTP- 450 dams significantly reduced relative to controls. Relative maternal liver weight and absolute and relative kidney weight values did not vary among dose groups. The following clinical signs: maternal weight loss of one gram or more per day (considered to be an indication of toxicity in individual dams), alopecia, piloerection, rough coat, unthriftiness, diarrhea and hyperactivity were all exhibited by dams in a clear dose-dependent manner.
Data concerning the status of uterine implantation sites exhibited a variable response. There were no statistically significant dose- related differences for number of implantation sites per dam, number or percentage of resorptions, fetal deaths, nonlive fetuses (dead plus resorbed) or affected fetuses (non-live plus malformed) per litter, or for the number or proportion of litters with one or more resorptions, fetal deaths, non-live, or affected fetuses. In live litters (i.e. litters with one or more live fetuses) there was no difference in the number of live fetuses per litter or in the proportion of males to females per litter across treatment groups. Body weights of live fetuses in toto, or for male and female fetuses separately, from HTP-treated litters exhibited a significant downward dose-response trend, with values from HTP-300 and HTP- 450 dams significantly reduced relative to controls. There were no significant differences among treated and control litters in the number or percentages of males, females or live fetuses malformed nor in the number or percentages of litters with malformed fetuses. Examination of malformation incidence by category produced no evidence of overall dose-response trends, although exencephaly and trilateral open eye were seen in fetuses only from HTP-150, HTP-300 and HTP-450 dose groups. In conclusion, no evidence for teratogenicity of L-5- hydroxytryptophan was seen in pregnant CD-1 mice when administered in corn oil by gavage during the time of organogenesis at doses which produced marginal evidence of maternal toxicity (clinical signs and trends for reduced body weights and weight gain), and evidence of fetal toxicity as indicated by a highly significant dose-response trend toward decreased fetal weight, with significantly lower values in the HTP-300 and HTP-450 groups relative to controls.