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

Polycyclic aromatic hydrocarbons (PAHs) are toxic chemicals released into t he environment by fossil fuel combustion. Moreover, a primary route of huma n exposure to PAHs is tobacco smoke(1,2). Oocyte destruction and ovarian fa ilure occur in PAH-treated mice(1,2), and cigarette smoking causes early me nopause in women(1,3). In many cells, PAHs activate the aromatic hydrocarbo n receptor (Ahr), a member of the Per-Arnt-Sim family of transcription fact ors(4,5). The Ahr is also activated by dioxin, one of the most intensively studied environmental contaminants. Here we show that an exposure of mice t o PAHs induces the expression of Bax in oocytes(6), followed by apoptosis. Ovarian damage caused by PAHs is prevented by Ahr or Bax inactivation. Oocy tes microinjected with a Bax promoter-reporter construct show Ahr-dependent transcriptional activation after PAH, but not dioxin, treatment, consisten t 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 flankin g each Ahr response element in the Bax promoter. Oocytes in human ovarian b iopsies grafted into immunodeficient mice also accumulate Bax and undergo a poptosis after PAH exposure in vivo. Thus, Ahr-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsib le for environmental toxicant-induced ovarian failure.