Researchers Figure Out Link Between Popular Painkillers and Inheritable Infertility

Ibuprofen and paracetamol taken during pregnancy can cause epigenetic changes in the fetus' ovarian or testicular tissues, damaging their fertility in adulthood

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Taking certain painkillers - ibuprofen and paracetamol - over a long time has been associated with a sperm count impairment in men and fertility problems in daughters of women who took the pills.
PainCredit: Dan Keinan

Headache is bad for procreation and it isn't because the afflicted refuse sex. It's because when pregnant women take popular painkillers like ibuprofen and paracetamol, the fertility of their children may be damaged, by changing the DNA in the fetal cells that eventually give rise to sperm and eggs, scientists at the University of Edinburgh report Monday in Environmental Health Perspectives.

It's ironic that advances in contraception for men, if they don't mind the side effect of weight gain, are concurrent with a marked deterioration in global male fertility. There is no single reason for it, but the fact is that sperm counts halved or worse in the last 40 years. Everything from pesticides to pollution to phones has been blamed (at least coffee's off the hook). Analgesics taken by the mother had been added to the list, and now the paper explains how this happens: not mutation, but epigenetic change.

"Analgesic exposure in utero affects germ cells in the testis of the male fetus, and ovaries of female fetuses. Both could have impaired fertility in adulthood," lead writer Dr. Rod Mitchell tells Haaretz. 

Just this year new research, albeit on a small study group, suggested that that long-term ibuprofen use (six weeks in the test) can disrupt hormone production in men, resulting in reduced sperm production; meanwhile in women, protracted use during the first six months of pregnancy may decrease the number of eggs in their daughters – in effect, impairing the fertility of the next generation.

Epigenetic changes are modifications of DNA by the environment, not mutation: the genetic code stays, but its expression can change.

"Epigenetic marks stick to DNA and permanently alter the expression of the gene," explains Mitchell. "Epigenetic marks are permanent within that individual cell and also when the cell divides."

Exposure to these drugs in the womb is likely to matter much more than exposure in adulthood, he says.

"Fetal life is the period when your future reproductive development potential is established. Failure of normal reproductive development during this period results in disorders that are present at birth (including undescended testis,  genital abnormalities) or do not become apparent until adulthood (testis cancer and infertility)," Mitchell explains. "Fetal life is the period when epigenetic marks are erased and re-established, so this is the critical time for reproductive development."

Born that way

While studying epigenetic expression is all the rage, it has been hyped. The inheritability of an individual's biochemical reaction to environmental conditions is hard to prove. For example, the theory that Holocaust trauma is inheritable through epigenetics has been widely critiqued: it's difficult to weed out biochemical effects from the impact of decades of horror stories.

But there are studies that demonstrated, for instance, correlation between a grandfather's diet and the risk of diabetes and cardiovascular disease in the grandchildren – an epigenetic effect passing down multiple generations.

What exactly are paracetamol and ibuprofen doing to us? In both male and female human tissues exposed to either drug for one week – the result was reduced numbers of cells that give rise to sperm and eggs, called germ cells, the study found.

DrugsCredit: Srdjan Zivulovic, Reuters

In the fetal tissue, exposing testicular tissue to paracetamol or ibuprofen in the lab resulted in 25 percent fewer sperm-producing cells, says the new paper by Dr. Rod Mitchell and colleagues.

Women are born with all their eggs, and make no more after their birth. Analgesics wouldn't affect their eggs. But because they are "making" their daughters' eggs while pregnant with them, heavy analgesic use in the first two trimesters may result in their daughters being born with fewer eggs, previous studies indicated.This new research showed that ovarian tissue exposed to paracetamol for one week had more than 40 percent fewer egg-producing cells, the group reported. After ibuprofen exposure, the number of cells was almost halved.

Rat studies done separately have shown that painkillers administered in pregnancy led to a reduction in germ cells in female pups – in other words, the damage to fertility reached subsequent generations.

The studies were done on human tissues, not human beings.

As Mitchell points out, this sort of thing is difficult to demonstrate in people, due to challenges in accurately recording analgesic exposure in large populations of pregnant women. Also, measuring fertility in large human populations is equally challenging. "However, the majority of epidemiological studies in humans do show an association between in-utero analgesic exposure and reproductive disorders in males born to those mothers," he says.

The doses involved in the tests were not disproportionate, but were the same as those normally used by humans, he says.

Advice for pregnant women remains unchanged, the researchers stress: paracetamol, also known as acetaminophen, should be used at the lowest possible dose for the least possible time, and ibuprofen is best avoided during pregnancy. Throughout the whole nine months? "The effects occur with just short term exposure during fetal life, and this results in effects on germ cells that persist post-natally," Mitchell told Haaretz. "There may be more sensitive periods during pregnancy, although our studies so far have shown effects following short term exposure of human fetal testes and ovaries in either the first or second trimester."

The researchers didn't mention a recommendation for men who wish to be fruitful and multiply, so Haaretz asked if they should eschew the headache drugs. While epigenetic changes in the fetus are expected to remain for life, any effects ibuprofen and paracetamol have on adult men and their procreative ability is more likely to be fleeting.

"Adulthood is not the period when epigenetic changes occur," Mitchell says. "Other recent studies have looked at this and shown that there may be effects on the testis when adult males take analgesics. But these are likely to be transient. It is fetal exposure that is more likely to result in permanent effects."