title: Benzo(a)pyrene causes PRKAA1/2-dependent ID2 loss in trophoblast stem cells.
abstract: Benzo(a)pyrene (BaP), a cigarette smoke component, is metabolized to diol esters (BPDE) that bind to DNA and form mutagenic BPDE-DNA adducts. BaP activates stress enzymes including stress-activated protein kinase/jun kinase (MAPK8/9) in embryos, AMP-activated protein kinase alpha1/2 subunits (PRKAA1/2) in somatic cells, and inhibits the proliferation of trophoblast cell lineages. The loss of transcription factor inhibitor of differentiation (ID)2 is required for the initial differentiation of mouse trophoblast stem cells (TSC) in implanting mouse embryo to produce the first placental hormone, chorionic sommatomammotropin (CSH)1. Here we demonstrate that BaP activates PRKAA1/2 and causes ID2 protein loss in TSC in a time- and dose-dependent manner. Although PRKAA1/2 was activated at low BaP doses, PRKAA1/2-dependent ID2 protein loss occurred at a dose that was similar to the threshold that results in a significant decrease in TSC accumulation and decreased fraction of proliferating TSC. This suggests a possible relationship between stress-induced declines in cell accumulation and stem cell differentiation when BaP levels are high. The threshold BaP dose that induces significant ID2 loss is in the range of a 2-3 pack/day habit, suggesting that this mechanism may be involved with implantation failure in smoking women.
authors.affiliation: CS Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.|Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Yufen
authors.initials: Y
authors.lastname: Xie
authors.affiliation: CS Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.|Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Mazen E
authors.initials: ME
authors.lastname: Abdallah
authors.affiliation: CS Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.|Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Awoniyi O
authors.initials: AO
authors.lastname: Awonuga
authors.affiliation: Program for Reproductive Sciences and/or Department of Physiology, Hospital, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Slater
authors.affiliation: CS Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.|Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Puscheck
authors.affiliation: CS Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.|Department of Ob/Gyn, Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, Michigan.|Program for Reproductive Sciences and/or Department of Physiology, Hospital, Wayne State University School of Medicine, Detroit, Michigan.|Institute for Environmental Health and Safety, Wayne State University School of Medicine, Detroit, Michigan.|Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.|Department of Biology University of Windsor, Windsor, Ontario, Canada.
authors.forename: Dan A
authors.initials: DA
authors.lastname: Rappolee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism*; D051379:Mice; D011247:Pregnancy; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014026:Nicotiana / Q000737:chemistry; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D051797:Inhibitor of Differentiation Protein 2; D021122:Protein Subunits; D001564:Benzo(a)pyrene; D055372:AMP-Activated Protein Kinases