Neonatal Exposure to Bisphenol A Alters Rat Uterine Implantation-Associated Gene Expression and Reduces the Number of Implantation Sites

Abstract

Endocrine disrupters have been associated with reproductive pathologies such as infertility and gynecological tumors. Using a rat model of early postnatal exposure to bisphenol A (BPA), we evaluated the long-term effects on 1) female reproductive performance, 2) uterine homeobox A10 (Hoxa10) and Hoxa10-target gene expression, and 3) ovarian steroid levels and uterine estrogen receptor α and progesterone (P) receptor expression. Newborn female rats received vehicle, BPA.05 (0.05 mg/kg · d), BPA20 (20 mg/kg · d), diethylstilbestrol.2 (0.2 μg/kg · d), or diethylstilbestrol 20 (20 μg/kg · d) on postnatal d 1, 3, 5, and 7. A significant decrease in the number of implantation sites was assessed in the xenoestrogen-exposed females. To address the molecular effects of postnatal xenoestrogen exposure on the pregnant uterus, we evaluated the expression of implantation-associated genes on d 5 of pregnancy (preimplantation uterus). All xenoestrogen-treated rats showed a lower expression of Hoxa10. In the same animals, two Hoxa10-downstream genes were misregulated in the uterus. β(3) Integrin, which is up-regulated by Hoxa10 in controls, was decreased, whereas empty spiracles homolog 2, which is down-regulated by Hoxa10, was increased. Furthermore a clear down-regulation of estrogen receptor α and P receptor expression was detected without changes in estradiol and P serum levels. The early exposure to BPA produced a lower number of implantation sites in association with a defective uterine environment during the preimplantation period. Alterations in the endocrine-regulated Hoxa10 gene pathways (steroid receptors--Hoxa10--β(3) integrin/empty spiracles homolog 2) could explain, at least in part, the BPA effects on the implantation process.

Effect of prenatal exposure to bisphenol a on the vagina of albino rats: immunohistochemical and ultrastructural study

“…The concentration of phytoestrogens in the diet was not evaluated because food intake was equivalent for control and experimental rats and both groups were exposed to the same levels of phytoestrogens [38]. Two females and one male were housed in a cage.…”

Oviduct: roles in fertilization and early embryo development

“…Bisphenol A (BPA) is known for its action as an endocrine-disrupting compound and a weak estrogen agonist/antagonist. However, BPA is still being used as part of the plastic containers for embryo cultures (Hunt et al 2003, Berger et al 2010, Varayoud et al 2011). Studies indicated a broad range of effects on the embryos upon BPA exposure, such as altered developmental rate and cell death (Ferris et al 2016) and toxicity to the neural progenitor cells (Yin et al 2015).…”

DNA methylation in early mice embryogenesis under the influence of bisphenol A

“…Как показали исследования, изменения гло-бального профиля метилирования генома в тканях матки связаны как с нарушением экспрессии генов эстрогено-вых рецепторов, чувствительных к БФА [65,66], и экс-прессии генов в плаценте [67,68], так и изменениями в метилировании ДНК гена Hoxa. При этом трудно точ-но установить, вовлечена ли в этот механизм сниженная активность ДНК-метилтрансфераз (DNMTs), или про-исходит модификация уровня их экспрессии [63,65,68]. Высокий уровень деметилирования ДНК, сопровожда-ющийся повышением экспрессии ряда импринтирован-ных генов, был выявлен в плаценте и в ткани эмбрионов 9,5-го и 12,5-го дня развития.…”