Evaluation of Embryotoxic Potential of Olaquindox and Vitamin A in Micromass Culture and in Rats

Abstract

Limb bud (LB) and central nerve system (CNS) cells were prepared from 12.5 day old pregnant female Crj:CD (SD) rats and treated with olaquindox and vitamin A. Cytotoxicity and inhibition on differentiation were measured in each cell. Three doses of olaquindox (4, 21 and 100 mgkg) , and 0.2 and 75 mg/kg of vitamin A were administered to pregnant rat for 11 days from 6th to 16th of pregnancy. IC50 values of olaquindox for proliferation and differentiation in CNS cell were 22.74 and 28.32 μg/ml and 79.34 and 23.29 μg/ml in LB cell and those values of vitamin A were 8.13 and 5.94 μg/ml in CNS cell and 0.81 and 0.05 μg/ml in LB cell, respectively. Mean body weights of pregnant rats were decreased at high dose of olaquindox (110 mg/kg) but relative ovary weight, number of corpus lutea, and number of implantation were not changed. Resorption and dead fetus were increased at high dose of olaquindox, and relative ovary weight, the number of corpus lutea and implantation, and sex ratio of male to female were not significantly changed in all dose of olaquindox. Mean fetal and placenta weights were significantly (p < 0.01) decreased in rats of high group. Seven fetuses out of 103 showed external anomaly like bent tail, and 10 out of 114 fetuses showed visceral anomalies at high group. The ossification of sternebrae and metacarpals were significantly (p < 0.01) increased by low and middle dose of olaquindox but it was significantly (p < 0.01) prohibited by high dose of olaquindox. In rats treated with vitamin A, the resorption and dead fetus were increased by high dose. Mean fetal weights were significantly (p < 0.01) increased by low dose but significantly (p < 0.01) decreased by high dose. Thirty four fetuses out of 52 showed external anomaly; bent tail (1) , cranioarchschisis (14) , exencephaly (14) , dome shaped head (22) , anophthalmia (15) , brcahynathia (10) and others (19) . Forty five fetuses out of 52 showed soft tissue anomaly; cleft palate (42/52) and anophthalmia (22/52) by high dose of vitamin A. Sixty one fetuses out of 61 (85.2%) showed skull anomaly; defect of frontal, partial and occipital bone (21/61) , defect of palatine bone (52/61) and others (50/61) . In summary, we support that vitamin A is strong teratogen based on our micromass and in vivo data, and olaquindox has a weak teratogenic potential in LB cell but not in CNS cell. We provide the in vivo evidence that a high dose of olaquindox could have weak embryotoxic potential in rats.

Pregnancy and Lactation Alter Vitamin A Metabolism and Kinetics in Rats under Vitamin A-Adequate Dietary Conditions

“…Numerous studies have revealed that VA is involved in multiple fetal organogenesis processes, and that either a deficiency or an excessive intake of VA is detrimental to fetal development [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Previous studies have investigated the VA content of the maternal liver, certain peripheral tissues, placenta, and embryo [ 12 , 13 , 14 ], while pharmacokinetic studies have focused on maternal VA kinetics and the exposure of the embryo to VA after dosing at selected gestational stages [ 15 , 16 ]. However, to date, no studies have investigated the dynamic changes in maternal VA metabolism that may occur across the period from pregnancy and lactation, from the viewpoint of whole-body retinol kinetics and compartmental analysis.…”