Induction of proapoptotic gene expression and recruitment of p53 herald ovarian follicle loss caused by polycyclic aromatic hydrocarbons.
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.
Pru
James K
JK
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, USA.
Kaneko-Tarui
Tomoko
T
Jurisicova
Andrea
A
Kashiwagi
Aki
A
Selesniemi
Kaisa
K
Tilly
Jonathan L
JL
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015152:Blotting, Northern; D004247:DNA / Q000032:analysis; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D006080:Ovarian Follicle / Q000187:drug effects*; D010053:Ovary / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000235:genetics
D011084:Polycyclic Aromatic Hydrocarbons; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004247:DNA