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.

Quantifying injury to common bottlenose dolphins from the Deepwater Horizon oil spill using an age-, sex- and class-structured population model

“…However, this scenario is premised on the assumption that new births contribute to an unexposed class, and that the unexposed class into which new births feed truly is physiologically unaffected by the DWH spill. In actuality, effects on offspring later in life following in utero exposure and even transgenerational effects have been reported for petroleum-associated compounds (Jurisicova et al 2007, Mohamed et al 2010, Perera & Herbstman 2011, and we cannot rule out the possibility of greater susceptibility to disease or reproductive impairment in the offspring of exposed individuals. Such effects were not included in our current model due to lack of available information to estimate factors for reduced reproduction or survival for In (a) solid red: exposed class; blue hatched: unexposed class.…”

The role of BH3-only proteins in apoptosis within the ovary

“…E15.5-PN1) or in the adult ovary, leaving open the possibility of a role for HRK in the mediation of apoptosis within the ovary. In this regard, Jurisicova et al (2007) showed that polycyclic aromatic hydrocarbons (PAH), such as those found in cigarette smoke, can induce the expression of HRK mRNA and HRK protein in primordial and primary follicles. Furthermore, elimination of HRK in mice conferred protection against PAH-induced primordial and primary follicle depletion (Jurisicova et al 2007).…”

“…In this regard, Jurisicova et al (2007) showed that polycyclic aromatic hydrocarbons (PAH), such as those found in cigarette smoke, can induce the expression of HRK mRNA and HRK protein in primordial and primary follicles. Furthermore, elimination of HRK in mice conferred protection against PAH-induced primordial and primary follicle depletion (Jurisicova et al 2007). Maternal exposure to cigarette smoke has also been recently shown to upregulate the expression of HRK mRNA in the human foetal ovary (Fowler et al 2014).…”

Endocrine-disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling

“…Animal studies also showed that PAHs destroy ovarian follicles via the AHR signaling pathway in rat and mice . Maternal exposure to PAHs before pregnancy and/or during lactation (cumulative dose of 12 mg/kg), compromises ovarian reserve of female offspring (Jurisicova et al 2007). Further studies show that PAHs activate the AHR signaling pathway and induce the expression of pro-apoptotic genes, thus, accelerating germ cell depletion in mice (Pru et al 2009).…”