Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin (acetylsalicylic acid), diclofenac and ibuprofen (IBU), and analgesic drugs, such as acetaminophen (APAP, or paracetamol), are widely used to treat inflammation and pain. APAP and IBU are over-the-counter drugs and are among the most commonly taken drugs in the first trimester of pregnancy, even in combination. Furthermore, these drugs and their metabolites are released in the environment, and can be frequently detected in wastewater, surface water, and importantly in drinking water. Although their environmental concentrations are much lower than the therapeutics doses, this suggests an uncontrolled low-dose exposure of the general population, including pregnant women and young children, two particularly at risk populations. Epidemiological studies show that exposure to these molecules in the first and second trimester of gestation can favor genital malformations in new-born boys. To investigate the cellular, molecular and mechanistic effects of exposure to these molecules, ex vivo studies with human or rodent gonadal explants and in vivo experiments in rodents have been performed in the past years. This review recapitulates recent data obtained in rodent models after in utero or postnatal exposure to these drugs. The first part of this review discusses the mechanisms by which NSAIDs and analgesics may impair gonadal development and maturation, puberty development, sex hormone production, maturation and function of adult organs, and ultimately fertility in the exposed animals and their offspring. Like other endocrine disruptors, NSAIDs and APAP interfere with endocrine gland function and may have inter/transgenerational adverse effects. Particularly, they may target germ cells, resulting in reduced quality of male and female gametes, and decreased fertility of exposed individuals and their descendants. Then, this review discusses the effects of exposure to a single drug (APAP, aspirin, or IBU) or to combinations of drugs during early embryogenesis, and the consequences on postnatal gonadal development and adult reproductive health. Altogether, these data may increase medical and public awareness about these reproductive health concerns, particularly in women of childbearing age, pregnant women, and parents of young children.

Highlights

  • Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac and ibuprofen (IBU), and analgesic drugs, such as acetaminophen (APAP, or paracetamol), are widely used to treat inflammation and pain

  • Epidemiological studies found that exposure to APAP alone (Berkowitz and Lapinski, 1996) or in combination with NSAIDs during the first and second trimester of pregnancy is associated with higher cryptorchidism rate [for review (Kristensen et al, 2016; Stukenborg et al, 2021)]

  • In 3,184 women, APAP intake in the second trimester of pregnancy [14–22 gestational weeks (GW)], but not during the periconception period and the first trimester of pregnancy, increased the risk of congenital cryptorchidism, but not of hypospadias (Snijder et al, 2012)

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Summary

NSAID and Analgesic Exposure in Humans

NSAIDs, such as aspirin (acetylsalicylic acid, ASA), diclofenac (DCF) and ibuprofen (IBU), and analgesic drugs, such as acetaminophen (APAP, or paracetamol), are widely used to treat inflammation and pain (Kristensen et al, 2016) Their regular use by the general population is considered safe, and self-medication with analgesics is widespread. In a large cohort of 150,000 pregnant women, 29% of them took one over-the-counter NSAID (IBU, ASA, DCF, or naproxen) or one analgesic (APAP) during the first trimester, and more than 18% of them used APAP alone (Zafeiri et al, 2021). 2-hydroxyibuprofen, the main IBU metabolite, has been detected in more than 5% of raw and treated water samples (~100 ng/L) (Han and Lee, 2017) This suggests an uncontrolled exposure of the general population, including pregnant women and young children, two at risk populations

NSAID and APAP Exposure and Congenital Defects in Humans
NSAIDs and Analgesics Are Endocrine Disruptors
NSAIDs and Analgesics Target Prostaglandins Production and Activity
Action on COX
Mouse in vivo
Human Testis xenograft
Mouse Mouse
Adult Reproductive Health and Reproductive Tract Disorders
EFFECTS OF EXPOSURE TO NSAIDS AND
Ex Vivo Culture of Rodent Fetal Gonads
Male Reproductive Health
Female Reproductive Health
Findings
CONCLUSION
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