Taking painkillers during pregnancy could affect the fertility of the unborn child in later life, University of Edinburgh research suggests. These drugs may also affect the fertility of future generations, by leaving marks on DNA. The findings add to a growing body of evidence that certain medicines, including paracetamol, should be used with caution during pregnancy.
Researchers stress that advice for pregnant women remains unchanged. Current guidelines say that, if necessary, paracetamol – also known as acetaminophen – should be used at the lowest possible dose for the shortest possible time. Ibuprofen should be avoided during pregnancy.
Scientists at the university looked at the effects of paracetamol and ibuprofen on samples of human foetal testes and ovaries. They found similar effects using several different experimental approaches, including lab tests on human tissue samples and animal studies.
Human tissues exposed to either drug for one week in a dish had reduced numbers of cells that give rise to sperm and eggs, called germ cells, the study found. Ovaries exposed to paracetamol for one week had more than 40% fewer egg-producing cells. After ibuprofen exposure, the number of cells was almost halved. Experts say this is important because girls produce all of their eggs in the womb, so if they are born with a reduced number it could lead to an early menopause.
Painkiller exposure during development could have effects on unborn boys too, the study found. Testicular tissue exposed to painkillers in a culture dish had around a quarter fewer sperm-producing cells after exposure to paracetamol or ibuprofen.
The team also tested the effects of painkiller treatment on mice that carried grafts of human foetal testicular tissue. These grafts have been shown to mimic how the testes grow and function during development in the womb. After just one day of treatment with a human-equivalent dose of paracetamol, the number of sperm-producing cells in the graft tissue had dropped by 17%. After a week of drug treatment, there were almost one third fewer cells.
Previous studies with rats have shown that painkillers administered in pregnancy led to a reduction in germ cells in female offspring. This affected their fertility and the fertility of females in subsequent generations.
The scientists found that exposure to paracetamol or ibuprofen triggers mechanisms in the cell that make changes in the structure of DNA, called epigenetic marks. These marks can be inherited, helping to explain how the effects of painkillers on fertility may be passed on to future generations.
Painkillers' effects on germ cells are likely caused by their actions on molecules called prostaglandins, which have key functions in the ovaries and testes, the researchers found.
The study was funded by the Medical Research Council, Wellcome and the British Society of Paediatric Endocrinology and Diabetes.
Dr Rod Mitchell, who led the research at the University of Edinburgh's MRC Centre for Reproductive Health, said: "We would encourage women to think carefully before taking painkillers in pregnancy and to follow existing guidelines – taking the lowest possible dose for the shortest time possible."
Background: Analgesic exposure during pregnancy may affect aspects of fetal gonadal development that are targeted by endocrine disruptors.
Objectives: We investigated whether therapeutically relevant doses of acetaminophen and ibuprofen affect germ cell (GC) development in human fetal testes/ovaries using in vitro and xenograft approaches.
Methods: First-trimester human fetal testes/ovaries were cultured and exposed to acetaminophen or ibuprofen (7 d). Second-trimester human fetal testes were xenografted into mice and exposed to acetaminophen (1 or 7 d), or ibuprofen (7 d). To determine mechanism of action, a human GC tumor–derived cell line (NTera2) exhibiting fetal GC characteristics was used in addition to in vitro and in vivo rat models.
Results and Discussion: Gonocyte (TFAP2C+) number was reduced relative to controls in first-trimester human fetal testes exposed in vitro to acetaminophen (–28%) or ibuprofen (–22%) and also in ovaries exposed to acetaminophen (–43%) or ibuprofen (–49%). Acetaminophen exposure reduced gonocyte number by 17% and 30% in xenografted second-trimester human fetal testes after treatment of host mice for 1 or 7 d, respectively. NTera2 cell number was reduced following exposure to either analgesic or prostaglandin E2 (PGE2) receptor antagonists, whereas PGE2 agonists prevented acetaminophen-induced reduction in NTera2 cell number. Expression of GC pluripotency genes, and genes that regulate DNA/histone methylation, also differed from controls following analgesic and PGE2 receptor antagonist exposures. Gene expression changes were observed in rat fetal testis/ovary cultures and after in vivoacetaminophen exposure of pregnant rats. For example, expression of the epigenetic regulator TET1, was increased following exposure to acetaminophen in human NTera2 cells, rat fetal testis/ovary cultures, and in fetal testes and ovaries after in vivoexposure of pregnant rats, indicating translatability across experimental models and species.
Conclusions: Our results demonstrate evidence of PGE2-mediated effects of acetaminophen and ibuprofen on GC/NTera2 cells, which raises concerns about analgesic use during human pregnancy that warrant further investigation.
Pablo Hurtado-Gonzalez, Richard A Anderson, Joni Macdonald, Sander van den Driesche, Karen Kilcoyne, Anne Jørgensen, Chris McKinnell, Sheila Macpherson, Richard M Sharpe, Rod T Mitchell
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[link url="https://ehp.niehs.nih.gov/ehp2307/"]Environmental Health Perspectives abstract[/link]