Cao, James, Ying, Xiaoyou, Beyer, Bruce K. and Delise, Anthony (2014) The use of optical imaging to assess the potential for embryo-fetal exposure to an exogenous material after intravaginal administration. Reproductive Toxicology, 48. pp. 138-147.

Abstract

The combination of transgenic reporter mice (beta-actin-luc, Taconic) and sensitive optical imaging methodology enables us to quickly measure potential exposure of a developing embryo-fetus after intravaginal exposures to the reporter substrate, D-luciferin. Here we show how the stages of the estrous cycle affect the distribution of imaging agents into the female reproductive tract. Moreover, by crossing transgenic male and wild-type female mice, we produce pregnant female mice with the transgenic imaging reporter gene in a proportion of the offspring only. We clearly demonstrate that the imaging substrate administered intravaginally can rapidly reach the developing embryo-fetus. Transgenic reporter mice provide a unique opportunity to help us better understand the potential mechanism for embryonic/fetal exposure to drugs following intravaginal exposure via seminal fluid or a direct intravaginal delivery system. The drug could cross the cervix and enter the uterine environment, leading to direct embryo-fetal exposure in utero and/or be absorbed into the maternal circulation with subsequent exposure to the embryo-fetus.
After intravaginal administration of the D-luciferin substrate (or D-luciferin mixed with a fluorescent dye), the ability of the substrate to enter the uterus was evaluated during different stages of the estrous cycle. Bioluminescence was observed throughout the reproductive tract during diestrus, but not during estrus. D-luciferin was first detected approximately 2-5 minutes after intravaginal administration to female beta-actin-luc mice. Similar results were obtained when a fluorescent probe was administered intravaginally to wild-type female mice. Intravaginal administration of D-luciferin to wild-type female mice that had been mated with male beta-actin-luc mice indicated that the substrate reached the developing embryo-fetus, with bioluminiescence corresponding to transgene expression in the embryo-fetus. D-luciferin substrate rapidly reached the embryo-fetus (within minutes) regardless of the administration route (intravaginal, intraperitoneal, subcutaneous, or intravenous). Vaginal ligation appeared to block at least some direct exposure to the embryo-fetus, but did not prevent the D-luciferin substrate from eventually reaching the embryo-fetus, perhaps as a result of limited systemic uptake from the vagina. In conclusion, intravaginal administration of a bioluminescent or fluorescent substrate resulted in its rapid distribution (within minutes) to the developing embryo-fetus, which was not prevented by vaginal ligation. Additional work will be necessary to form the basis for a reliable assessment of the human risk for male-mediated teratogenicity.

Item Type:	Article
Keywords:	Imaging, bioluminescence, D-luciferin, fluorescence, intravaginal, estrous cycle, embryo, fetus, exposure, risk assessment
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/21489