title: Chronic Exposure to Bisphenol A Affects Uterine Function During Early Pregnancy in Mice.
abstract: Environmental and occupational exposure to bisphenol A (BPA), a chemical widely used in polycarbonate plastics and epoxy resins, has received much attention in female reproductive health due to its widespread toxic effects. Although BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In this study, we addressed the effect of prolonged exposure to an environmental relevant dose of BPA on embryo implantation and establishment of pregnancy. Our studies revealed that treatment of mice with BPA led to improper endometrial epithelial and stromal functions thus affecting embryo implantation and establishment of pregnancy. Upon further analyses, we found that the expression of progesterone receptor (PGR) and its downstream target gene, HAND2 (heart and neural crest derivatives expressed 2), was markedly suppressed in BPA-exposed uterine tissues. Previous studies have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor and the MAPK signaling pathways and inhibiting epithelial proliferation. Interestingly, we observed that down-regulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with enhanced activation of fibroblast growth factor and MAPK signaling in the epithelium, thus contributing to aberrant proliferation and lack of uterine receptivity. Further, the differentiation of endometrial stromal cells to decidual cells, an event critical for the establishment and maintenance of pregnancy, was severely compromised in response to BPA. In summary, our studies revealed that chronic exposure to BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy.
authors.affiliation: Department of Comparative Biosciences (Q.L., J.D., A.K., J.A.F., I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802.
authors.forename: Quanxi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Comparative Biosciences (Q.L., J.D., A.K., J.A.F., I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802.
authors.forename: Juanmahel
authors.initials: J
authors.lastname: Davila
authors.affiliation: Department of Comparative Biosciences (Q.L., J.D., A.K., J.A.F., I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802.
authors.forename: Athilakshmi
authors.initials: A
authors.lastname: Kannan
authors.affiliation: Department of Comparative Biosciences (Q.L., J.D., A.K., J.A.F., I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802.
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Flaws
authors.affiliation: Department of Comparative Biosciences (Q.L., J.D., A.K., J.A.F., I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802.
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.affiliation: Department of Comparative Biosciences (Q.L., J.D., A.K., J.A.F., I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802.
authors.forename: Indrani C
authors.initials: IC
authors.lastname: Bagchi
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D015536:Down-Regulation; D010064:Embryo Implantation / Q000187:drug effects*; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D011247:Pregnancy; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001559:Benzhydryl Compounds; D005346:Fibroblast Growth Factors; D020928:Mitogen-Activated Protein Kinases; D010636:Phenols; D011980:Receptors, Progesterone; C498766:Hand2 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds