Effect of TCDD on Maternal Toxicity and Chorionic Gonadotropin──Bioactivity in the Immediate Post-implantation Period of Macaque

The purpose of this experiment was to observe the alterations in bioactivity of chorionic gonadotropin (CG) associated with early fetal loss (EFL), induced by the environmental toxin TCDD (2,3,7,8\|tetrachlorodibenzo\| p \|dioxin) in the cynomolgus macaque. Ten of twelve females administered single doses of 1, 2 or 4 μg/kg TCDD on gestational day (GD) 12 had EFL from ten to twenty days later. Seven control animals treated only with the vehicle had normal pregnancies. Blood samples were repeatedly collected for hormone evaluation, from two days before treatment to thirty\|one days following treatment. Immunoreactive monkey chorionic gonadotropin (mCG) was measured in serum using ELISA, and bioactive mCG was measured using a luminescence LH/CG bioassay. No change in immunoreactive mCG levels was detected as a result of TCDD, treatment, but bioactive mCG levels were significantly lower in TCDD\|treated animals compared to controls. This change in bioactivity of mCG was also reflected in the ratio of mCG bioactivity to mCG immunoreactivity (B/I ratio) which began to rise in normal pregnancies by GD 20, but did not rise in TCDD treated animals. These results demonstrate that normal pregnancy in the monkey, as in humans, is characterized by a post\|implantation change in the B/I ratio of CG. These findings therefore suggest that changes in the production of bioactive CG may be used as a biomarker of environmental toxicant exposures which lead to EFL.

Reproductive toxicity study with a novel deoxyguanosine analogue （Metacavir） in pregnant SD rats

Our preliminary studies demonstrated that Metacavir has potential to become a new anti-HBV agent. The main targets of the toxic effects of Metacavir, in rhesus monkeys, were gastrointestinal tracts, liver, blood, and kidneys, which were not related to mitochondrial effects. In this study, the maternal toxicity, embryo-fetal developmental toxicity and teratogenicity were studied in pregnant Sprague-Dawley rats after intragastric administration of Metacavir （200, 100, 50, 0 mg/kg body weight） during the first 6-15 days of pregnancy. Slower weight gain was observed in 5 out of 21 rats subjected to a 200 mg/kg dose, as well as 2 out of 20 subjected to a 100 mg/kg dose. Compared with the solvent control group, the calibration weight gain in the 200 mg/kg and 100 mg/kg dosage groups respectively, during first 6-20 pregnant days were significantly different （P 〈 0.01, P 〈 0.05）. Significant dose related adverse effects to other reproductive parameters were not seen in F0 and F1, but the number of stillbirths in high dose group showed notably difference compared with the control group （P 〈 0.05）, while the litter incidence showed no difference. No Metacavir-associated pathological changes were observed. The present research indicated that at a dose of 200 mg/（kg·d） （i.e., 40 times the effective dose in rats）, Metacavir shows some maternal toxicity to SD rats. The embryotoxicity in the 200 mg/kg group encompass decreased fetal body weight, and higher fetal mortality rates, compared with the control group. However, the litter incidence showed no statistical difference. All the treated rats displayed normal bone development, no teratogenicity and without adverse effects on fetal development, thus indicating that below a dose of 200 mg/（kg· d） there is no teratogenic side effects.