Paracetamol, Aspirin, and Indomethacin Induce Endocrine Disturbances in the Human Fetal Testis Capable of Interfering With Testicular Descent

Mazaud-Guittot, Séverine; Nicolaz, Christophe Nicolas; Desdoits-Lethimonier, Christèle; Coiffec, Isabelle; Maamar, Millissia Ben; Balaguer, Patrick; Kristensen, David M.; Chevrier, Cécile; Lavoué, Vincent; Poulain, P.; Dejucq-Rainsford, Nathalie; Jégou, Bernard

doi:10.1210/jc.2013-2531

Cited by 137 publications

(132 citation statements)

References 46 publications

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“…The interindividual variations in the levels of INSL3, the other Leydig cell hormone investigated, were greater than those of testosterone, as generally observed (Ivell et al, 2013;Mazaud-Guittot et al, 2013). This and the NMDR also often encountered with this hormone complicated the interpretation of our data.…”

Section: Inhibin Bmentioning

confidence: 49%

Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis

et al. 2017

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WHAT IS KNOWN ALREADY:The few epidemiologic studies performed suggest that bisphenols have potential endocrine disruptive properties, but they did not identify clear and direct patterns of endocrine disruption. STUDY DESIGN, SIZE, DURATION:Adult human testis explants in culture were exposed to BPA and the analogs bisphenol F (BPF), bisphenol S (BPS), bisphenol E (BPE), bisphenol B (BPB), and bisphenol A diglycidyl ether (BADGE) at 10 -9 to 10 -5 M for 24 h or 48h.PARTICIPANTS/MATERIALS, SETTING, METHODS: Human adult testes were obtained from prostate cancer patients who had no hormone therapy, or from multiorgan donors. After ex vivo exposure to the investigated bisphenols, the measured outcomes were related to histopathology (gross morphology and germ cell viability determined by anti-caspase 3 immunohistochemistry), and the levels of testosterone, insulin-like fator 3 and inhibin B were measured using immunoassays. The levels of mRNA encoding key enzymes of bisphenol biotransformation were investigated by quantitative PCR: UGT2B15 UDP (glucuronosyltransferase two family, polypeptide B15), GUSB (glucuronidase beta), SULT1A1 and 3 (sulfotransferase family 1 A member 1 and 3) and STS (steroid sulfatase). MAIN RESULTS AND THE ROLE OF CHANCE: A significant dose-dependent inhibition wasfound between testosterone levels measured in the culture medium and concentrations of BPA The active concentrations of BPA and BPA-A used in the study were higher than those found in human biological fluids. WIDER IMPLICATIONS OF THE FINDINGS:Under our experimental conditions, direct exposure to BPA or BPA-A can result in endocrine disturbance in the adult human testis.

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Section: Inhibin Bmentioning

confidence: 49%

Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis

et al. 2017

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“…It may be due to male germ-line epigenetic effects as described in endocrine disruption effects of acetaminophen on the human testis. 15,16 At least 3 plausible hypotheses are proposed to explain the association between maternal acetaminophen use and ADHD. First, neonatal exposure to acetaminophen changes the levels of brain-derived neurotropic factor in mice and results in altered behavior, lowered fear responses, and reduced learning abilities in adulthood.…”

Section: Figurementioning

confidence: 99%

“…However, acetaminophen and endocrine disruptors have been shown to have potential for transgenerational disease transmission effects in mouse models via male germ-line epigenetic effects, and endocrine disruption effects of acetaminophen have been shown in the human testis. 15,16 It is therefore important to estimate the effect of paternal prepregnancy use.…”

mentioning

confidence: 99%

Prenatal Exposure to Acetaminophen and Risk of ADHD

et al. 2017

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OBJECTIVES:To estimate the association between maternal use of acetaminophen during pregnancy and of paternal use before pregnancy with attention-deficit/hyperactivity disorder (ADHD) in offspring while adjusting for familial risk for ADHD and indications of acetaminophen use. We estimated hazard ratios (HRs) for an ADHD diagnosis by using Cox proportional hazard models. RESULTS:After adjusting for maternal use of acetaminophen before pregnancy, familial risk for ADHD, and indications of acetaminophen use, we observed a modest association between any prenatal maternal use of acetaminophen in 1 (HR = 1.07; 95% confidence interval [CI] 0.96-1.19), 2 (HR = 1.22; 95% CI 1.07-1.38), and 3 trimesters (HR = 1.27; 95% CI 0.99-1.63). The HR for more than 29 days of maternal acetaminophen use was 2.20 (95% CI 1.50-3.24). Use for <8 days was negatively associated with ADHD (HR = 0.90; 95% CI 0.81-1.00). Acetaminophen use for fever and infections for 22 to 28 days was associated with ADHD (HR = 6.15; 95% CI 1.71-22.05). Paternal and maternal use of acetaminophen were similarly associated with ADHD.CONCLUSIONS: Short-term maternal use of acetaminophen during pregnancy was negatively associated with ADHD in offspring. Long-term maternal use of acetaminophen during pregnancy was substantially associated with ADHD even after adjusting for indications of use, familial risk of ADHD, and other potential confounders.abstract NIH

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“…Although the exposure levels were chosen based on the estimated serum concentrations as that occurring after therapeutic use, the resulting testicular concentrations in adult men are unknown and rather difficult to determine. Mazaud-Guittot et al (2013) used an in vitro system based on the cell culture of human fetal testes exposed to NA4AP and its metabolite N-arachinodyl-4-phenolamine (AM404; see 'Metabolism of R108 H Modick and others acetaminophen and aniline' section) and other NSAIDs at concentrations ranging from 10 K4 to 10 K7 M. Endocrine-disrupting properties were investigated through measures of testosterone, anti-Mü llerian hormone (AMH), insulin-like factor 3 (INSL3), and PGs (PGD2 and PGE2) (Mazaud-Guittot et al 2013). The authors found significant inhibition of INSL3 production in samples exposed to NA4AP and AM404, with a significant dose-response relationship indicating a decrease in INSL3 production with an increasing dose of NA4AP.…”

Section: K5mentioning

confidence: 99%

Ubiquitous presence of paracetamol in human urine: sources and implications

Modick¹,

Weiß²,

Dierkes³

et al. 2014

Reproduction

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N-acetyl-4-aminophenol (acetaminophen/paracetamol, NA4AP) is one of the most commonly used over-the-counter analgesic and antipyretic drugs. Recent studies have reported anti-androgenic effects of NA4AP in vitro and possible associations between intrauterine exposure to NA4AP and the development of male reproductive disorders in humans. NA4AP is also a major metabolite of aniline (phenylamine), representing 75-86% of the aniline dose excreted in urine. Aniline is an important large-volume intermediate in several industrial processes. Besides individuals in various occupational settings with aniline exposure, the general population is also known to be ubiquitously exposed to aniline. In this article, we provide an overview of the recent literature concerning the intake of NA4AP during pregnancy and the possible anti-androgenic effects of NA4AP as well as literature concerning its known metabolic precursor aniline. We also present new research data, including the first human biomonitoring data on NA4AP excretion in urine, showing ubiquitous NA4AP body burdens in the general population at a wide range of concentrations. We found a small but significant impact of smoking on urinary NA4AP concentrations. We further present preliminary data on NA4AP excretion after therapeutic acetaminophen use, after aniline exposure in an occupational setting, and during a controlled fasting study (excluding oral exposure to both aniline and acetaminophen). Our findings indicate exposure to aniline (or aniline-releasing substances) as well as nutrition (next to the direct use of acetaminophen as medication) as possible sources of internal body burdens of NA4AP.Reproduction (2014) 147 R105-R117

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Paracetamol, Aspirin, and Indomethacin Induce Endocrine Disturbances in the Human Fetal Testis Capable of Interfering With Testicular Descent

Cited by 137 publications

References 46 publications

Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis

Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis

Prenatal Exposure to Acetaminophen and Risk of ADHD

Ubiquitous presence of paracetamol in human urine: sources and implications

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