Exposure to 17α-ethinyl estradiol during early pregnancy affects fetal growth and survival in mice.

17α-ethinyl estradiol (EE2) is a synthetic compound widely used in the generation of contraceptive pills. EE2 is present in the urine of women taking contraceptives and its presence has been confirmed at increasing concentrations contaminating rivers all over the world. Because of this cycle, it can entry the human food chain when watering plants. A negative influence of EE2 on fertility and reproductive capacity of wildlife was already suggested. The short-term impact of exposure to contaminating EE2 on pregnancy outcome has not been addressed. Pregnant mice were exposed to either 0.005 µg (concentrations found in water) or 5 µg EE2/kg (contraceptive dose) body weight/day from gestation day 1-7 by oral gavage. Control mice received a 0.1% ethanol solution. High frequency ultrasound imaging was used to follow-up fetal and placental growth in vivo. Doppler measurements were utilized to analyze blood flow parameters in uterine and umbilical arteries. Mice were sacrificed at gd5, 10, and 14. We show that most fetuses of mothers exposed to the high EE2 dose die intrauterine at gd10, with implantation sizes beginning to be smaller already at gd8. Mothers exposed to the low EE2 dose show an impaired remodeling of the spiral arteries, a higher placental weight and pups that are large for gestational age. The insulin-like growth factor system that regulates fetal and placental growth and development is affected by the EE2 treatment. Our results show that a short-term exposure to EE2 during early pregnancy has severe consequences for fetal growth and survival depending on the dose. Exposition to synthetic estrogens affects placenta growth and angiogenesis. These findings urge to the study of mechanisms dysregulated upon environmental exposition to estrogens.

Bisphenol A exposure during early pregnancy impairs uterine spiral artery remodeling and provokes intrauterine growth restriction in mice.

Endocrine disrupting chemicals are long suspected to impair reproductive health. Bisphenol A (BPA) has estrogenic activity and therefore the capacity of interfering with endocrine pathways. No studies dissected its short-term effects on pregnancy and possible underlying mechanisms. Here, we studied how BPA exposure around implantation affects pregnancy, particularly concentrating on placentation and uterine remodeling. We exposed pregnant female mice to 50 µg/kg BPA/day or 0.1% ethanol by oral gavage from day 1 to 7 of gestation. High frequency ultrasound was employed to document the presence and size of implantations, placentas and fetuses throughout pregnancy. Blood velocity in the arteria uterina was analyzed by Doppler measurements. The progeny of mothers exposed to BPA was growth-restricted compared to the controls; this was evident in vivo as early as at day 12 as analyzed by ultrasound and confirmed by diminished fetal and placenta weights observed after sacrificing the animals at day 14 of gestation. The remodeling of uterine spiral arteries (SAs) was considerably impaired. We show that short-term exposure to a so-called "safe" BPA dose around implantation has severe consequences. The intrauterine growth restriction observed in more than half of the fetuses from BPA-treated mothers may owe to the direct negative effect of BPA on the remodeling of uterine SAs that limits the blood supply to the fetus. Our work reveals unsuspected short-term effects of BPA on pregnancy and urges to more studies dissecting the mechanisms behind the negative actions of BPA during early pregnancy.