Using Experimental Models to Decipher the Effects of Acetaminophen and NSAIDs on Reproductive Development and Health

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.

Cocktails of NSAIDs and 17α Ethinylestradiol at Environmentally Relevant Doses in Drinking Water Alter Puberty Onset in Mice Intergenerationally

“…Estrogens exert relevant roles in gonadotropin and testis physiology in mice and humans [ 130 ], and in utero exposure to BPA or other estrogen-like chemicals affects male reproductive developmental outcomes [ 131 , 132 ]. Moreover, the effects of NSAID exposure on female reproduction are well documented [ 5 , 133 ]. Altogether, these data suggest that this disturbed testicular and ovarian cell microenvironment may explain their altered maturation and physiology, and ultimately the early puberty of exposed females.…”

“…Moreover, synthetic hormones are widely used to treat acne, endometriosis, and ovarian cysts, and are also used in combination with progestins for contraception and for hormone replacement therapy [ 4 ]. NSAIDs exert their pharmacological effects by inhibiting one or both cyclooxygenase isoforms that are involved in the conversion of arachidonic acid for prostaglandin synthesis [ 5 ]. Like natural hormones, synthetic estrogens display estrogenic activity by binding to estrogen receptors a (ESR1) and b (ESR2).…”

“…The critical window of exposure is the onset of fetal gonadal sex determination that coincides with the period of epigenetic reprogramming in developing germ cells [ 27 , 28 ]. Many epidemiological studies on in utero exposure to therapeutic doses of aspirin, IBU, or acetaminophen during the first months of gestation [ 3 , 29 ], and ex vivo/in vivo studies using rodent models [ 5 ], identified these molecules as EDCs. In adult men, IBU alters the hypothalamic-pituitary-gonadal axis, leading to a decrease in testosterone production.…”

Effects of Acetaminophen on Reproductive Activities in Male Golden Hamsters

“…But overdoses or the long-term use of acetaminophen resulted in toxicity effects in the organs of liver, kidney, and testis and affected the blood chemistry and reproductive parameters (Olaleye & Rocha João, 2008;Luangpirom et al, 2012;Oyedeji et al, 2013;Khayyat, 2021). High doses of acetaminophen affected the male reproductive system, changing the semen quality, particularly the sperm morphology and fertilizing ability (Ratnasooriya & Jayakody, 2000;Luangpirom et al, 2012;Oyedeji et al, 2013;Banihani, 2018;Boizet-Bonhoure et al, 2022).…”

“…Recently, the effects of acetaminophen and NSAIDs on filial generation and on reproductive parameters have been reviewed (Boizet-Bonhoure et al, 2022;Tadokoro-Cuccaro et al, 2022). Generally exposure to NSAIDs was associated with the negative effects on the reproductive track development and function in prenatal and adult rodents.…”