title: Bisphenol A disrupts Notch signaling by inhibiting gamma-secretase activity and causes eye dysplasia of Xenopus laevis.
abstract: Bisphenol A (BPA) is being recognized as an endocrine-disrupting chemical (EDC). Recently, several reports indicated that BPA affects the central nervous system (CNS) during embryonic development. However, the molecular mechanism of BPA in the CNS is not well known. Here, we show that BPA affected Notch signaling by inhibiting the activity of the Notch intracellular domain (NICD) cleavage-related enzyme, gamma-secretase (gamma-secretase), at the neurula stage of the Xenopus laevis. BPA caused various morphologic aberrations including scoliosis, eye dysplasia, and loss of pigments in the X. laevis tadpole. These abnormalities were seen whenever BPA was used at the neurula stage. In addition, the expression levels of several marker mRNAs at the neurula stage were investigated by RT-PCR, and we found that the mRNAs expression of ectodermal marker, Pax6, CNS marker, Sox2, and neural crest marker, FoxD3, were decreased by treatment with BPA. These genes contribute to the neural differentiation at the neurula stage, and also the downstream factors of Notch signaling. Injection of NICD but not a Notch ligand, delta 1, rescued the abnormalities caused by BPA. We subsequently assayed the inhibition of the activities of NICD cleavage-related enzymes, tumor necrosis factor alpha converting enzyme, and gamma-secretase, by BPA and found that BPA inhibited the gamma-secretase activity. Furthermore, we expressed presenilin, a main component of gamma-secretase, in Escherichia coli and found the direct binding of BPA with presenilin. These results suggest that BPA affected the neural differentiation by inhibiting gamma-secretase activity, leading to neurodevelopmental abnormalities.
authors.affiliation: Department of Bioscience, Nanobiotechnology Research Center, School of Science and Technology, Kwansei Gakuin University, Sanda, Japan.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Baba
authors.forename: Kazushi
authors.initials: K
authors.lastname: Okada
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Susumu
authors.initials: S
authors.lastname: Imaoka
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000187:drug effects; D052244:Endocrine Disruptors / Q000633:toxicity*; D005128:Eye Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D017403:In Situ Hybridization; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000633:toxicity*; D053763:Presenilins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051880:Receptors, Notch / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects; D020349:Surface Plasmon Resonance; D014982:Xenopus laevis; D000098826:Bisphenol A Compounds
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D010636:Phenols; D053763:Presenilins; D012333:RNA, Messenger; D051880:Receptors, Notch; C006780:bisphenol A; D000098826:Bisphenol A Compounds