Maternal exposure to ibuprofen can affect the programming of the hypothalamus of the male offspring

Balin, Paola da Silva; Jorge, Bárbara Campos; Leite, Andressa Rejani Ribeiro; Borges, Cibele dos Santos; Oba, Eunice; Silva, Erick J. R.; Barros, Aline Lima de; Júnior, José de Anchieta Castro Horta; Arena, Arielle Cristina

doi:10.1016/j.yrtph.2020.104576

Cited by 19 publications

(19 citation statements)

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“…Overall, these studies strongly suggest that NSAIDs and analgesic drugs can target Leydig cells and alter their ability to regulate hormone levels, particularly testosterone, as reported in ex vivo (Kristensen et al, 2012;Albert et al, 2013;van Den Driesche et al, 2015;Gaudriault et al, 2017;Maamar et al, 2017), in utero (da Silva Balin et al, 2020), and in vitro (Passoni et al, 2018) studies. In support of these effects, several studies reported alterations of steroidogenic enzymes (Wang et al, 2003;van Den Driesche et al, 2015;Maamar et al, 2017;Kristensen et al, 2018;Passoni et al, 2018).…”

Section: Studies From Human-derived Modelsmentioning

confidence: 74%

“…Despite some effects observed in rats with in-utero exposure of NSAID diclofenac sodium on Sertoli cell number and the morphology of the tubules, there were no alterations in Sertoli cell ratio observed in human testes explants. Other studies that evaluated effect of NSAIDs on the testes found no changes in Sertoli cell number ( van Den Driesche et al, 2015 ; Maamar et al, 2017 ; Rossitto et al, 2019 ; da Silva Balin et al, 2020 ), despite some decreases in AMH protein and mRNA levels and Sox9 levels ( Maamar et al, 2017 ; Kristensen et al, 2018 ). Therefore, further studies will need to be conducted on Sertoli cell models to gain a more complete understanding of the effect of NSAIDs and analgesic drugs on early male reproductive development.…”

Section: Eicosanoid System In Male Reproductive Developmentmentioning

confidence: 94%

“…In a separate study, in utero exposure of rats to 10–60 mg/kg of ibuprofen from GD15 to PND21 was found to lower volumes of Leydig cell nuclei by PND90, with a concomitant decrease in testosterone levels in the highest dose group. LH and FSH levels were similar between groups, and no alterations in spermatogenesis or Sertoli cell dynamics were observed ( da Silva Balin et al, 2020 ). When fetal rat testes at GD14.5 were exposed to acetaminophen (1 μM) or aspirin (1 and 10 μM) for 24–72 h ex vivo , 1 uM acetaminophen reduced testosterone production and dose dependent reductions were observed with aspirin as well, with a significant reduction at the 10 μM dose ( Kristensen et al, 2011 ).…”

Section: Eicosanoid System In Male Reproductive Developmentmentioning

confidence: 99%

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Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Tran-Guzman

Culty

2022

Front. Toxicol.

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Increasing rates of infertility associated with declining sperm counts and quality, as well as increasing rates of testicular cancer are contemporary issues in the United States and abroad. These conditions are part of the Testicular Dysgenesis Syndrome, which includes a variety of male reproductive disorders hypothesized to share a common origin based on disrupted testicular development during fetal and neonatal stages of life. Male reproductive development is a highly regulated and complex process that relies on an intricate coordination between germ, Leydig, and Sertoli cells as well as other supporting cell types, to ensure proper spermatogenesis, testicular immune privilege, and endocrine function. The eicosanoid system has been reported to be involved in the regulation of fetal and neonatal germ cell development as well as overall testicular homeostasis. Moreover, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics with abilities to block eicosanoid synthesis by targeting either or both isoforms of cyclooxygenase enzymes, have been found to adversely affect male reproductive development. This review will explore the current body of knowledge on the involvement of the eicosanoid system in male reproductive development, as well as discuss adverse effects of NSAIDs and analgesic drugs administered perinatally, focusing on toxicities reported in the testis and on major testicular cell types. Rodent and epidemiological studies will be corroborated by findings in invertebrate models for a comprehensive report of the state of the field, and to add to our understanding of the potential long-term effects of NSAID and analgesic drug administration in infants.

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Section: Studies From Human-derived Modelsmentioning

confidence: 74%

Section: Eicosanoid System In Male Reproductive Developmentmentioning

confidence: 94%

Section: Eicosanoid System In Male Reproductive Developmentmentioning

confidence: 99%

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Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Tran-Guzman

Culty

2022

Front. Toxicol.

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“…In males exposed to IBU, body weight and AGD were decreased, and testis descent and preputial separation (puberty onset) were delayed. In adult age, serum testosterone levels and the percentage of sperm with normal morphology were decreased, but fertility and male behavior were normal ( Balin et al, 2020 ). Exposure of female rats to APAP (350 mg/kg/day during gestation and lactation) did not affect the AGD and preputial separation (at 21 dpp) and testosterone production and sperm parameters (in adulthood) in their male offspring.…”

Section: In Vivo Experiments In Rodents To Elucidate the Imp...mentioning

confidence: 99%

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

et al. 2022

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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.

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“…Expression of female-typical behavior in adult male: 15 days after the evaluation of male sexual behavior, the same rats were pretreated with estradiol 17-benzoate (20 μg/kg; i.p. ), 24 h before the evaluation of female sexual behavior (lordosis) (Balin et al, 2020).…”

Section: Male Copulatory Behaviormentioning

confidence: 99%

Lactational exposure to venlafaxine provokes late repercussions on reproductive parameters in male rat offspring

Moreira

Manoel

Inácio

et al. 2022

J of Applied Toxicology

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Exposure to selective serotonin reuptake inhibitors can affect hormone-dependent processes, such as the brain sexual differentiation. Because the use of these antidepressants cause concern during lactation, we evaluated the possible effects of venlafaxine on lactational exposure and its late repercussions on reproductive parameters in male rats. Lactating rats were exposed to venlafaxine (3.85, 7.7, or 15.4 mg/kg/ body weight; gavage), from lactational day 1 to 20. Venlafaxine and Odesmethylvenlafaxine residues were found in all milk samples of dams treated, demonstrating the lactational transfer of this antidepressant to the offspring. Although the maternal behavior was normal, the dams presented an increase in urea and uric acid levels in the groups treated with 7.7 and 15.4, respectively, as well as a spleen weight increased in the 3.85 and 15.4 groups. The male offspring showed a decrease in play behavior parameters in the intermediate dose group. Sperm analysis indicated a reduction in sperm motility in all treated groups. The androgen receptor expression in the hypothalamus was decreased in the highest dose group, although the sexual behavior had not been affected. In conclusion, venlafaxine was transferred through breast milk and promoted changes in play behavior, sperm quality, and hypothalamic androgen receptor (AR) content, which may indicate an incomplete masculinization of the brain of male offspring.

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Maternal exposure to ibuprofen can affect the programming of the hypothalamus of the male offspring

Cited by 19 publications

References 65 publications

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

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

Lactational exposure to venlafaxine provokes late repercussions on reproductive parameters in male rat offspring

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