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Induction of Proapoptotic Gene Expression and Recruitment of p53 Herald Ovarian Follicle Loss Caused by Polycyclic Aromatic Hydrocarbons

Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, and Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts

Tomoko Kaneko-Tarui, MD, PhD

Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, and Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts

Andrea Jurisicova, PhD

Department of Obstetrics and Gynecology, University of Toronto, and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

Aki Kashiwagi, MD

Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, and Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts

Kaisa Selesniemi, PhD

Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, and Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts

Jonathan L. Tilly, PhD

Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, and Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts

Activation of the aryl hydrocarbon receptor (AHR) by polycyclic aromatic hydrocarbons (PAH), a ubiquitous class of environmental and occupational biohazards, accelerates germ cell depletion in female mice during prenatal and postnatal life. Like AHR, BAX is also functionally required for PAH to kill oocytes. Here, we show that PAH upregulates ovarian expression of not just Bax but a large cassette of proapoptotic genes that function at multiple steps of the cell death signaling pathway. We further show that ovarian expression of p53 and several proapoptotic genes that are known transcriptional targets of p53 are increased by PAH treatment, and that mice lacking functional p53 are resistant to the ovotoxic effects of in vivo PAH exposure. This study provides further mechanistic insights into how PAH accelerate oocyte depletion in females and adds p53 to the list of genes whose functional importance to PAH-induced ovotoxicity has been demonstrated by gene knockout technology.

Key Words: Apoptosis • AHR • BAX • cell death • oocyte • ovary • p53 • DNA damage • PAH.

This version was published on April 1, 2009

Reproductive Sciences, Vol. 16, No. 4, 347-356 (2009)
DOI: 10.1177/1933719108327596


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