Maternal exposure to polycyclic aromatic hydrocarbons diminishes murine ovarian reserve via induction of Harakiri
Andrea Jurisicova, … , Gabriel Nunez, Robert F. Casper
Andrea Jurisicova, … , Gabriel Nunez, Robert F. Casper
Published November 21, 2007
Citation Information: J Clin Invest. 2007;117(12):3971-3978. https://doi.org/10.1172/JCI28493.
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Maternal exposure to polycyclic aromatic hydrocarbons diminishes murine ovarian reserve via induction of Harakiri

Abstract

Maternal smoking during pregnancy is associated with a variety of adverse neonatal outcomes including altered reproductive performance. Herein we provide molecular evidence for a pathway involved in the elimination of the female germline due to prepregnancy and/or lactational exposure to polycyclic aromatic hydrocarbons (PAHs), environmental toxicants found in cigarette smoke. We show that ovaries of offspring born to mice exposed to PAHs contained only a third of the ovarian follicle pool compared with offspring of unexposed female mice. Activation of the cell death pathway in immature follicles of exposed females was mediated by the aryl hydrocarbon receptor (Ahr), as ovarian reserve was fully rescued by maternal cotreatment with the Ahr antagonist, resveratrol, or by inactivation of the Ahr gene. Furthermore, in response to PAHs, Ahr-mediated activation of the harakiri, BCL2 interacting protein (contains only BH3 domain), was necessary for execution of cell death. This pathway appeared to be conserved between mouse and human, as xenotransplanted human ovarian cortex exposed to PAHs responded by activation of the identical cell death cascade. Our data indicate that maternal exposure to PAHs prior to pregnancy and/or during lactation compromises ovarian reserve of female offspring, raising the concern about the transgenerational impact of maternal smoking on ovarian function in the human.

Authors

Andrea Jurisicova, Asako Taniuchi, Han Li, Yuan Shang, Monica Antenos, Jacqui Detmar, Jing Xu, Tiina Matikainen, Adalberto Benito Hernández, Gabriel Nunez, Robert F. Casper

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Figure 3

Ahr is involved in in vivo–induced follicle destruction in female offspring after maternal exposure to PAHs.

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Ahr is involved in in vivo–induced follicle destruction in female offspr...
(A) Schematic outline of putative XRE elements, identified by a MatInspector computer algorithm within 5,000 bp of murine Hrk promoter. (B) Ahr-deficient offspring born to mothers exposed to PAHs prior to pregnancy and during lactation retained a significantly larger primordial follicle pool than their wild-type sibling sisters. Quantitative representation of the morphometric analysis of the ovarian pool for nonapoptotic oocyte-containing primordial follicles is expressed as mean ± SEM. Each genotype group represents combined data from offspring born to mothers exposed to vehicle (Ahr+/+, n = 4; Ahr–/–, n = 3) or treated with PAH (Ahr+/+, n = 7; Ahr–/–, n = 3). A significant reduction of follicles was only observed in the wild-type ovaries (**P = 0.0003). (C) Ahr-deficient neonatal ovaries failed to upregulate Hrk transcript expression in response to PAHs over a 24-hour period. The expression data are shown as fold change in PAH-treated ovary compared with vehicle-treated ovary from the same female (mean ± SEM) and were obtained from 4 sets of independent ovaries per treatment/genotype. PAH induced a significantly different response in wild-type and Ahr-deficient ovaries (P = 0.007). (D) PAH treatment (1 μM DMBA/BaP each) induces expression of luciferase driven by Hrk promoter in transient transfection assay using HEK cells (*P < 0.01). Activity of the promoter was greatly reduced by mutation of all 3 XRE sites in the presence of vehicle, but no induction occurred after PAH exposure using mutated construct. Data are shown as mean ± SEM of 3 independent experiments performed in pentuplicate and are expressed as fold change of luciferase/β-galactosidase ratio.