title: Ligand activation of the aromatic hydrocarbon receptor transcription factor drives Bax-dependent apoptosis in developing fetal ovarian germ cells.
abstract: We recently reported that a targeted disruption of the gene encoding the aromatic hydrocarbon receptor (AHR) in mice reduces fetal oocyte apoptosis, leading to a 2-fold increase in the number of primordial follicles endowed at birth. Although the identity of the natural ligand(s) for the AHR remains to be unequivocally established, these findings indicate that the level of AHR function is an important physiological determinant of how many oocytes will succumb to apoptosis during development of the fetal ovaries. Furthermore, the AHR is a well established receptor for polycyclic aromatic hydrocarbons (PAHs), a class of ubiquitous environmental chemicals known to cause the death of female germ cells in fetal life. Given the possibility that the AHR serves as a key mediator of fetal oocyte death under both physiological and pathological situations, this study was conducted to more fully examine the impact of PAH-AHR interaction on fetal ovarian germ cells. In addition, experiments were designed to begin identification of the mechanism(s) by which ligand activation of the AHR induces prenatal oocyte depletion after transplacental exposure of fetuses to PAHs in vivo. Embryonic d 13.5 murine fetal ovaries cultured in the presence of PAHs exhibited a high level of germ cell loss via apoptosis that was prevented by the selective AHR antagonist, alpha-napthoflavone (ANF). Immunohistochemical analysis revealed an accumulation of Bax protein in germ cells of fetal ovaries exposed to PAHs before the onset of apoptosis, whereas cotreatment with ANF inhibited the induction of Bax expression. The functional importance of increased Bax expression to the cytotoxic response was confirmed by findings that fetal ovarian germ cell loss caused by in utero exposure of wild-type female fetuses to PAHs was not observed in Bax-deficient female fetuses exposed in parallel. We conclude that a central role exists for the AHR in transducing the actions of PAHs in fetal ovarian germ cells, and that the proapoptotic Bcl-2 family member, Bax, is a required mediator of PAH-induced oocyte loss in female fetuses exposed to PAHs in utero.
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Matikainen
authors.forename: Toshitake
authors.initials: T
authors.lastname: Moriyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Morita
authors.forename: Gloria I
authors.initials: GI
authors.lastname: Perez
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: David H
authors.initials: DH
authors.lastname: Sherr
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Tilly
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D005333:Fetus; D005854:Germ Cells / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000187:drug effects; D010053:Ovary / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D008024:Ligands; D011084:Polycyclic Aromatic Hydrocarbons; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D015127:9,10-Dimethyl-1,2-benzanthracene