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Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals

Nature Genetics volume 28, pages 355–360 (2001)Cite this article

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are toxic chemicals released into the environment by fossil fuel combustion. Moreover, a primary route of human exposure to PAHs is tobacco smoke1,2. Oocyte destruction and ovarian failure occur in PAH-treated mice1,2, and cigarette smoking causes early menopause in women1,3. In many cells, PAHs activate the aromatic hydrocarbon receptor (Ahr), a member of the Per-Arnt-Sim family of transcription factors4,5. The Ahr is also activated by dioxin, one of the most intensively studied environmental contaminants. Here we show that an exposure of mice to PAHs induces the expression of Bax in oocytes6, followed by apoptosis. Ovarian damage caused by PAHs is prevented by Ahr or Bax inactivation. Oocytes microinjected with a Bax promoter–reporter construct show Ahr-dependent transcriptional activation after PAH, but not dioxin, treatment, consistent with findings that dioxin is not cytotoxic to oocytes. This difference in the action of PAHs versus dioxin is conveyed by a single base pair flanking each Ahr response element in the Bax promoter. Oocytes in human ovarian biopsies grafted into immunodeficient mice also accumulate Bax and undergo apoptosis after PAH exposure in vivo. Thus, Ahr-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsible for environmental toxicant-induced ovarian failure.

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Figure 1: Identification of Bax as a candidate target gene for the PAH-activated Ahr.
Figure 2: PAH-driven Bax protein accumulation and apoptosis in oocytes is Ahr antagonist-sensitive.
Figure 3: The Ahr is required for PAH-initiated oocyte destruction.
Figure 4: PAH-driven Bax transcription requires functional AHREs and Ahr.
Figure 5: Bax is required for PAH-induced oocyte destruction.
Figure 6: PAHs induce Bax production and apoptosis in human oocytes in vivo.

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Acknowledgements

We thank K.I. Tilly, X.-J. Tao and T. Manganaro for technical help, S. Riley for assistance with the image analysis, and I. Schiff for critical reading of the manuscript. This study was supported by the National Institutes of Health (R01-ES08430), the Canadian Toxic Substances Research Initiative, the Harvard Center of Excellence in Women's Health, and Vincent Memorial Research Funds. We conducted this work while T.M. and J.L. were Research Fellows supported by the Finnish Foundation for Pediatric Research and the Finnish Cultural Foundation, A.J. was a Research Fellow supported by the Canadian Institutes of Health Research, and J.K.P. was a Research Fellow supported by the Lalor Foundation.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital/Harvard Medical School, Boston, 02114, Massachusetts, USA

    Tiina Matikainen, Gloria I. Perez, Andrea Jurisicova, James K. Pru & Jonathan L. Tilly

  2. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Ontario, Canada

    Andrea Jurisicova & Robert F. Casper

  3. Department of Environmental Health, Boston University Schools of Medicine and Public Health, Boston, 02118, Massachusetts, USA

    Jennifer J. Schlezinger, Heui-Young Ryu & David H. Sherr

  4. Division of Immunology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, 02115, Massachusetts, USA

    Jarmo Laine

  5. Department of Preventive Medicine, Kyoto Prefectural University School of Medicine, Kyoto, 602-8566, Japan

    Toshiyuki Sakai

  6. Departments of Pathology and Medicine, Howard Hughes Medical Institute, Dana-Farber Cancer Institute/Harvard Medical School, Boston, 02115, Massachusetts, USA

    Stanley J. Korsmeyer

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  1. Tiina Matikainen
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Correspondence to Jonathan L. Tilly.

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Matikainen, T., Perez, G., Jurisicova, A. et al. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet 28, 355–360 (2001). https://doi.org/10.1038/ng575

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