Offspring had fewer egg follicles, mouse study shows
WEDNESDAY, Nov. 21 (HealthDay News) -- Researchers have identified the chemical pathway by which a mother's smoking before and after pregnancy might reduce her daughter's fertility by as much as two-thirds.
Cigarette smoking during pregnancy has been shown in retrospective studies to affect the fertility of a woman's offspring, but this is the first study to offer an explanation of the biology behind the effect, the Canadian scientists claim.
A team at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto investigated the impact of polycyclic aromatic hydrocarbons (PAH), a byproduct of smoking, on mouse fertility.
Researchers injected three groups of female mice with a low-dose mixture of PAH: One group received PAH before conception and again when they were providing milk for their pups; one group received PAH only before conception; and the third group received PAH only during lactation. A fourth control group did not receive PAH but were mated at the same time as the others. The total amount of PAH given to each mouse over the three-week injection cycle was equivalent to 25 packs of cigarettes, according to the researchers. The exposed mice did not have fewer pups in their own litters, but when researchers investigated the number of eggs in their female offspring, they found about 70 percent fewer follicles available to produce eggs.
"Mothers, mice in this case, exposed to PAHs -- environmental pollutants found in cigarette smoke, car exhaust, smoke produced by fossil fuel combustion, as well as in smoked food --before pregnancy and/or during breast-feeding, but not during pregnancy, can cause a reduction in the number of eggs in the ovaries of their female offspring by two-thirds. This limits the window in which the daughter will be able to reproduce," explained lead researcher Dr. Andrea Jurisicova.
Further analysis indicated that the effects of PAHs on the number of follicles in female offspring were mediated through a receptor that affects the expression of a gene that makes a protein that causes cells to die. The researchers then demonstrated similar effects in human ovarian tissue transplanted into immunocompromised mice.
Jurisicova described the process: "Toxic compounds were injected under the skin of mice and were picked up by the bloodstream and carried throughout the body until they reached the ovaries. Once at the ovaries, they passed through the cell membrane and bound to the receptor. When this happens, it activates the receptor, which then enters the cell nucleus. The receptor then finds a specific DNA sequence that turns on the gene, which accumulates and eventually kills the eggs."
"This study now is providing a chemical pathway, which is very nice," said Dr. Norman Edelman, consultant for scientific affairs with the American Lung Association. The new data provides biological support for epidemiological results, such as the previously observed reduction in fertility among daughters of smoking women, he added.
Whether the news will have an impact on a woman's decision to smoke is another question, said Edelman.
"If we do our job right and these results get good press, this data could remind women of what they are doing to their unborn fetuses," Edelman said.
Another expert noted this latest finding adds to a growing body of evidence that shows a strong connection between smoking and fertility.
"I think it is an interesting study, but it doesn't add much new. Other studies have shown similar outcomes. The theory is that smoking could affect the follicles or the fallopian tubes," said Dr. Amos Grunebaum, director of obstetrics at New York Weill Cornell Medical Center, in New York City. "We have known for many years that smoking affects fertility on many levels."
"The key is women should quit smoking before they are thinking of getting pregnant," Grunebaum said.
The Canadian researchers did offer some good news in their report, published in the Dec. 3 edition of the Journal of Clinical Investigation. Injecting resveratrol in the mice who were exposed to PAH prevented the reduction in egg follicles in their offspring. Resveratrol is a naturally occurring antioxidant found in wine and grape skins. However, that reversal of damage does not mean that women who smoke can counter the effects with a nutritional supplement or a glass of red wine, the researchers stressed.
"We have found that oral consumption of resveratrol as a food supplement, at least in mice, is not effective, as levels of resveratrol do not reach sufficient amount in the bloodstream to provide protection," Jurisicova said.
Although the findings do not define the length of time between quitting smoking and healthier fertility in offspring, Jurisicova noted that previous studies have shown that women who smoke have better results with in vitro fertilization one year after they quit smoking. The mice in the current study conceived up to two weeks after their final PAH injection, which is approximately equivalent to three menstrual cycles in women.
The effect of a mother's cigarette smoking is not limited to her female children. A study published in the Jan. 1 issue of the American Journal of Epidemiology suggested that the male offspring of mothers who smoke have lower sperm counts.
There is still more research to be done, Jurisicova noted.
"We hope to continue studying the female offspring to see if they enter the mouse version of menopause earlier than mice whose mothers were not exposed to PAHs," Jurisicova said. "We also hope to study if their reduced fertility passes on to subsequent generations, and if the granddaughters are predisposed to similar problems."
SOURCES: Norman H. Edelman, M.D., consultant, scientific affairs, American Lung Association; Andrea Jurisicova, M.D., assistant professor, University of Toronto, and Canada Research Chair, Molecular and Reproductive Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto; Amos Grunebaum, M.D., director, obstetrics, New York Weill Cornell Medical Center, New York City; Dec. 3, 2007, Journal of Clinical Investigation
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