[OBJECTIVE] Teratogenicity represents the risk of irreversible functional and morphological disorders in the fetal organs caused by the pharmaceuticals or food ingredients ingested by the mother. In general, the teratogenicity of a pharmaceutical is evaluated by observing the shape of the fetus associated with the administration of the test compound to the pregnant rats. Retinoid X receptor agonist bexarotene (1), which is a pharmaceutical for cutaneous T cell lymphoma, has been reported to be teratogenic in zebrafish (Excotoxicology, 2012, 21, 1465–75.), in addition to the description of teratogenicity. However, there have been no detailed reports on the teratogenicity and fetal transfer of 1 using pregnant rats. In this study, we evaluated the teratogenicity and fetal transferability of 1 in rats. [RESULTS and DISCUSSIONS] Four pregnant rats were orally treated with 1 at 30 mg/kg/day from day 1 to day 19 of pregnancy. On day 20 of pregnancy, the fetuses were removed from the mother and skeletal specimen was prepared. Compared to the control group, the 1-administered one showed a decrease in the number of implantations, fetuses, and the weight of fetuses, as well as significant skeletal abnormalities. Since the fetal transferability of the compound refers to one of the causes of teratogenicity, we focused on the fetal transferability of 1. To measure this, we paid our attention to positron emission tomography (PET), which enables to detect dynamic pharmacokinetics. Based on the previous method we reported (J. Med. Chem., 2017, 60, 7139–45), [11C]1 was obtained from the trialkyltin precursor with a radiochemical yield of 0.11% and radiochemical purity of 99.8%, and we conducted dynamic fetal transfer imaging of [11C]1. However, the dynamic imaging has not been achieved because only a very small amount is transferred compared to the whole body. Thus, fetal transfer of [11C]1 was compared with the radioactivity of maternal blood by γ-counter. As a result, a radioactivity per weight in fetus was confirmed similar to that of blood. Since fetal blood vessels are not directly connected to the mother, this implies a fetal transferability of 1. Interestingly, the radioactivity per weight of placenta was twice more than those of fetuses.

Teratogenicity and fetal transfer assessment of retinoid X receptor agonist bexarotene

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.