Ibuprofen results in alterations of human fetal testis development

Maamar, Millissia Ben; Lesné, Laurianne; Hennig, K; Desdoits-Lethimonier, Christèle; Kilcoyne, Karen; Coiffec, Isabelle; Rolland, Antoine; Chevrier, Cécile; Kristensen, David M.; Lavoué, Vincent; Antignac, Jean-Philippe; Bizec, Bruno Le; Dejucq-Rainsford, Nathalie; Mitchell, Rod; Mazaud-Guittot, Séverine; Jégou, Bernard

doi:10.1038/srep44184

Cited by 68 publications

(81 citation statements)

References 69 publications

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“…This wealth of clinical experience has also suggested that ibuprofen may have other effects. There is emerging evidence that ibuprofen may in certain specific situations act as an endocrine disrupter [118,119]. The role of ibuprofen in cancer is currently being discussed in the literature, because ibuprofen offers antiproliferative benefits in some situations [120][121][122].…”

Section: Discussionmentioning

confidence: 99%

Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review

Varrassi¹,

et al. 2019

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Ibuprofen first came to market about 50 years ago and rapidly moved to over-thecounter (OTC) sales. In April 2019, the National Agency for the Safety of Medicines and Health Products (ANSM) of France issued a warning for NSAID uses by patients with infectious diseases based on an analysis of 20 years of real-world safety data on ibuprofen and ketoprofen. Nevertheless, ibuprofen remains a mainstay in the analgesic armamentarium and with numerous randomized clinical trials, head-to-head studies, and decades of clinical experience. The authors offer a review of the safety of ibuprofen and how it may differ from other NSAIDs. Ibuprofen is associated with certain well-known gastrointestinal adverse effects that are related to dose and patient population. Among nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen has a comparatively low risk of cardiovascular adverse effects. It has been associated with renal and hepatic adverse effects, which appear to depend on dose, concomitant medications, and patient population. The association of ibuprofen with infections is more complex in that it confers risk in some situations but benefits in others, the latter in cystic fibrosis. Emerging interest in the literature is providing evidence of the role of ibuprofen as a possible endocrine disrupter as well as its potential antiproliferative effects for cancer cells. Taken altogether, ibuprofen has a favorable safety profile and is an effective analgesic for many acute and chronic pain conditions, although it-like other NSAIDs-is not without risk. After 50 years, evidence is still emerging about ibuprofen and its unique safety profile among NSAIDs.

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Section: Discussionmentioning

confidence: 99%

Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review

Varrassi¹,

et al. 2019

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“…APAP, ASA, and IBU stock solutions (500, 277, and 219 mM, respectively) (MilliporeSigma, Burlington, MA, USA) were prepared in ethanol and 10-fold diluted with PBS before oral administration between 10.5 and 13.5 dpc. For experiments with single drugs, 30 mg/kg APAP, 50 mg/kg ASA, and 15 mg/kg IBU (19,20,27,39) or 9.7% ethanol (control) were administered daily at 2 times (150 ml by gavage, 6 h apart) (n = 6 experiments with 2 pregnant females for each condition). For experiments with 2 drugs [30 mg/kg/d APAP + 50 mg/kg/d ASA, and 30 mg/kg/d APAP + 15 mg/kg/d IBU or ethanol and APAP + APAP (60 mg/kg/d) as controls], the same doses for each drug were alternately administrated every 3 h (4 times, 150 ml by gavage) (n = 4 experiments with 2 pregnant females for each condition).…”

Section: Animals and Experimental Protocolsmentioning

confidence: 99%

“…Furthermore, in a large population-based mother-child cohort, an association between simultaneous maternal use of both APAP and NSAID and shorter anogenital distance was found, whereas APAP use alone did not affect anogenital distance in the male offspring (12). Experimental in vivo/ex vivo investigations in rodents (13)(14)(15)(16) and ex vivo studies using human testicular explants (17)(18)(19)(20) showed that nontherapeutic doses of these drugs cause mild or contradictory effects on testosterone secretion. Also, when administered to adult men, IBU disrupts the hypothalamus-pituitary-gonad axis, inducing an increase in LH secretion and a decrease in testosterone production; ex vivo studies using adult testicular explants confirmed the antiandrogenic action of IBU (21).…”

mentioning

confidence: 99%

Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen

et al. 2018

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Nonsteroidal antiinflammatory drugs and analgesic drugs, such as N-acetyl- p-aminophenol (APAP; acetaminophen, paracetamol), are widely used by pregnant women. Accumulating evidence has indicated that these molecules can favor genital malformations in newborn boys and reproductive disorders in adults. However, the consequences on postnatal testis development and adult reproductive health after exposure during early embryogenesis are still unknown. Using the mouse model, we show that in utero exposure to therapeutic doses of the widely used APAP-ibuprofen combination during the sex determination period leads to early differentiation and decreased proliferation of male embryonic germ cells, and early 5-methylcytosine and extracellular matrix protein deposition in 13.5 d postcoitum exposed testes. Consequently, in postnatal testes, Sertoli-cell maturation is delayed, the Leydig-cell compartment is hyperplasic, and the spermatogonia A pool is decreased. This results in a reduced production of testosterone and in epididymal sperm parameter defects. We observed a reduced sperm count (19%) in utero-exposed (F0) adult males and also a reduced sperm motility (40%) in their offspring (F1) when both parents were exposed, which leads to subfertility among the 6 mo old F1 animals. Our study suggests that the use of these drugs during the critical period of sex determination affects the germ-line development and leads to adverse effects that could be passed to the offspring.-Rossitto, M., Marchive, C., Pruvost, A., Sellem, E., Ghettas, A., Badiou, S., Sutra, T., Poulat, F., Philibert, P., Boizet-Bonhoure, B. Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen.

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“…Concomitant reductions in prostaglandin levels, COX activity and COX gene expression have not been found in fish (Flippin et al, 2007;Lister & Van Der Kraak, 2008;Morthorst et al, 2013) and this could indicate that prostaglandin inhibitors influence the prostaglandin synthesis without affecting expression of the COX genes. That mild analgesics display a wide diversity in their responses is demonstrated in an ex vivo human foetal testis system (Ben Maamar et al, 2017). The effects on e.g.…”

Section: Accepted Manuscriptmentioning

confidence: 95%

“…14 anti-androgenic effect of mild analgesics has been demonstrated in ex vivo foetal testes of rats and humans (Kristensen et al, 2012;Ben Maamar et al, 2017), but the mechanism of action is likely to be uncoupled from the inhibition of the prostaglandin synthesis. How the inhibition of prostaglandin synthesis is related to steroids levels, steroidogenesis and reproduction remains unknown.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Two common mild analgesics have no effect on general endocrine mediated endpoints in zebrafish (Danio rerio)

Morthorst¹,

Lund

Holbech

et al. 2018

Comparative Biochemistry and Physiology Part C: Toxicology &

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Mild analgesics such as acetylsalicylic acid (ASA) and acetaminophen (APAP) exert their pain-relieving effect in humans by inhibition of prostaglandin synthesis. Prostaglandins play key roles in developmental and reproductive processes in vertebrates, and in recent years, it has been suggested that weak analgesics might also act as endocrine disrupters. In a set of experiments we investigated if ASA and APAP affect well-established endocrine endpoints in zebrafish (Danio rerio), which is a commonly used model organism in the investigation of endocrine disrupting chemicals. Zebrafish were exposed to APAP (0.22, 2.3, and 30mgL) or ASA (0.2, 0.5, 1.7, and 8.2mgL) from hatch to sexual maturity in a test design resembling the OECD Fish Sexual Development Test. No effects on sex ratio and vitellogenin levels were observed. Adult zebrafish were exposed to high concentrations (mgL) of ASA or APAP for eight or 14days. ASA reduced the levels of prostaglandin E, but had no effect on the concentration of 11-ketotestosterone and vitellogenin. Overall, ASA decrease prostaglandin E concentrations, but well-established endpoints for endocrine disruption in zebrafish are generally not affected by aquatic exposure neither during development nor adulthood. According to the WHO/IPCS definition of an endocrine disrupter, the present results do not define APAP and ASA as endocrine disrupters.

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Ibuprofen results in alterations of human fetal testis development

Cited by 68 publications

References 69 publications

Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review

Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review

Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen

Two common mild analgesics have no effect on general endocrine mediated endpoints in zebrafish (Danio rerio)

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