Chemical Driven Premature Ovarian Failure

Jonathan Tilly
Harvard Medical School
R01ES08430

Background: The ovaries are unique because at birth they house a finite and irreplaceable stockpile of germ cells (oocytes) enclosed within support structures termed follicles. Normal growth and maturation of these follicles is required for both fertility and the maintenance of a proper endocrine environment in the body. In laboratory animals, polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke cause oocyte destruction and ovarian failure. Likewise, women who smoke are at increase risk for early menopause. PAHs as well as dioxins activate the Ah receptor, however, dioxin is not toxic to oocytes. Ah receptor deficiency helps to maintain oocytes as does a deficiency of another related protein known as Bax.

Advance: These investigators have shown that oocytes have Ah receptor-dependent transcriptional activation after PAH exposure but not after dioxin treatment and that this difference is a function of a single base-pair difference adjacent to the Ah receptor response element in the Bax promoter. Dioxin cannot activate the Bax gene, and therefore it does not cause the apoptotic loss of oocytes.

Implication: As the world's consumption of fossil fuels increases causing further increases in air pollution and exposure to PAHs, the risk of PAH-induced reproductive failure increases. These studies show that PAH compounds signal through the Ah receptor/Bax-regulated pathway leading to oocyte death. Future research aimed at finding natural substance that will bind to the Ah receptor may lead to methods to prevent oocyte loss and prolong the reproductive lifespan of women.

Citation: Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY, Laine J, Sakai T, Korsmeyer SJ, Casper RF, Sherr DH, Tilly JL. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet. 2001 Aug;28(4):355-60.