Bisphenol A modulates germ cell differentiation and retinoic acid signaling in mouse ES cells

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2012-11, Vol.34 (3), p.463-470
• Main Authors: Aoki, Tomohiro, Takada, Tatsuyuki
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Benzhydryl Compounds - toxicity; Biological and medical sciences; Bisphenol A; Cell Differentiation - drug effects; Cell Line; Embryology: invertebrates and vertebrates. Teratology; Embryonic stem cell; Embryonic Stem Cells - cytology; Embryonic Stem Cells - drug effects; Embryonic Stem Cells - metabolism; Endocrine disruptor; Endocrine Disruptors - toxicity; Estrogens, Non-Steroidal - toxicity; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Germ cell; Germ Cells - cytology; Germ Cells - drug effects; Male; Medical sciences; Mice; Mice, Inbred ICR; Phenols - toxicity; Proteins - genetics; Retinoic acid; Signal Transduction - drug effects; Stra8; Teratology. Teratogens; Toxicology; Tretinoin - metabolism
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2012.06.001

► We investigated the effect of BPA on germ cell marker genes during ES cell differentiation. ► BPA up-regulated germ cell markers and Stra8 showed the most prominent up-regulation. ► BPA showed synergistic effect with retinoic acid on Stra8 expression. ► BPA up-regulated ovarian markers and suppressed testicular markers. ► BPA might have a feminizing effect on gonadal development in mammals. Bisphenol A (BPA) has been reported to have an adverse effect on mammalian reproduction and recognized as an endocrine disruptor. However, the molecular mechanism that causes impaired development of germ cells remains elusive. In this study, we investigated the effect of BPA using in vitro differentiation of embryonic stem (ES) cells focusing on the expression of germ cell marker genes. We found that the BPA-treated embryoid bodies (EBs), exhibited the most prominent up-regulation of meiotic entry gene Stra8 and induction mechanism appeared to be different from that of retinoic acid. Localization of aggregated Sycp3 signal in nuclei, characteristic to leptotene of meiosis, was also detected. In addition, up-regulation of ovarian markers (Foxl2 and Wnt4) and suppression of testicular markers (Sox9 and Fgf9) were observed. These results suggest that BPA might affect testicular and ovarian development as well as germ cell differentiation, and appears to induce genes responsible for ovary development.