Smoking can lead to premature ovarian failure, or early menopause, and scientists at Massachusetts General Hospital (MGH) have discovered how. The work published in the August issue of Nature Genetics - and available online on July 16th - could eventually have implications for fertility, menopause and overall women's health.
"We've uncovered a mechanism to explain why premature ovarian failure occurs following exposure to toxic chemicals in the environment.," says principal investigator Jonathan Tilly, PhD, of the MGH Vincent Center for Reproductive Biology. "Women who smoke undergo menopause earlier, and we've correlated this with exposure to a class of chemicals in tobacco smoke that accelerate the death of egg cells in the ovaries."
Tilly and his group found that cigarette smoke-derived chemicals called polycyclic aromatic hydrocarbons (PAHs) bind to a receptor called the AHR inside egg cells of the ovaries. This binding triggers the expression of a gene called Bax within an egg's nucleus. The elevated level of Bax then initiates a suicide command and the egg undergoes programmed cell death. Using mouse models, Tilly's team also found that eggs with inactivated Ahr or Bax genes were resistant to PAH-induced death, indicating the functional importance of these two players in premature ovarian failure resulting from exposure to these toxic chemicals.
To demonstrate the relevance of their findings to humans, Tilly and his colleagues grafted human ovarian tissue under the skin of mice. After treating the mice with PAHs, they showed that Bax expression and programmed cell death indeed occurred in the human eggs within the grafts in a manner identical that that observed in mouse ovaries.
Because of the prevalence of PAHs in tobacco smoke, the current data strongly support the hypothesis that the early onset of menopause in women smokers is at least partly due to PAH-induced egg cell death, according to Tilly. His group's work has defined the actual molecular mechanism that triggers inappropriate death of eggs after exposure to PAHs. "We need to get people away from thinking that toxic chemicals cause general harm. Here we have mapped how a chemical, through several discrete steps, influences specific genetic events that lead to cell death," he says.
Tilly hopes this new human-graft mouse model will also allow researchers to conduct studies of other potential biohazards and drugs for their effects on the health of women's eggs. "For the first time, we have the right population of human eggs, in a natural, nourishing, living environment - not in a petri dish in the lab," says Tilly.
The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.