Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development

Kilcoyne, Karen; Mitchell, Rod T

doi:10.1136/archdischild-2016-311374

Cited by 18 publications

(13 citation statements)

References 87 publications

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“…18 This was supported by Sharpe and Skakkebaek,19 who subsequently proposed that hypospadias, cryptorchidism, poor semen quality, and testicular cancer are symptoms of one underlying entity with a common fetal origin. 20,21 Although an increasing number of studies of maternal lifestyle and health during pregnancy, such as maternal diet, alcohol consumption, smoking, medication use, and obesity support this fetal programming hypothesis, [22][23][24][25][26][27] large-scale epidemiological evidence is still lackingespecially regarding maternal exposure to endocrine disrupting chemicals at home and at work. 28 The limited body of evidence is likely explained by the complex logistics and high costs of establishing long-term longitudinal populationbased studies of male reproductive function, with information on exposures during early life, such as the need for detailed maternal information and bio-specimens stored for decades before follow-up.…”

Section: Introductionmentioning

confidence: 99%

<p>Fetal Programming of Semen Quality (FEPOS) Cohort – A DNBC Male-Offspring Cohort</p>

Hærvig

Bonde

Ramlau‐Hansen

et al. 2020

CLEP

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Background: Prenatal exposures may contribute to male infertility in adult life, but largescale epidemiological evidence is still lacking. The Fetal Programming of Semen quality (FEPOS) cohort was founded to provide means to examine if fetal exposures can interfere with fetal reproductive development and ultimately lead to reduced semen quality and reproductive hormone imbalances in young adult men. Methods: Young adult men at least 18 years and 9 months of age born to women in the Danish National Birth Cohort living in relative proximity to Copenhagen or Aarhus and for whom a maternal blood sample and two maternal interviews during pregnancy were available were invited to FEPOS. Recruitment began in March 2017 and ended in December 2019. The participants answered a comprehensive questionnaire and underwent a physical examination where they delivered a semen, urine, and hair sample, measured their own testicular volume, and had blood drawn. Results: In total 21,623 sons fulfilled eligibility criteria of whom 5697 were invited and 1058 participated making the response rate 19%. Semen characteristics did not differ between sons from the Copenhagen and Aarhus clinics. When comparing the FEPOS semen parameters to similar cohorts, the median across all semen characteristics was slightly lower for FEPOS participants, although with smaller variation. Conclusion: With its 1058 young adult men, the FEPOS cohort is the largest population-based male-offspring cohort worldwide specifically designed to investigate prenatal determinants of semen quality. Wide-ranging information on maternal health, lifestyle, socioeconomic status, occupation, and serum concentrations of potential reproductive toxicants during pregnancy combined with biological markers of fertility in their sons collected after puberty allow for indepth investigations of the 'fetal origins of adult disease hypothesis'.

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Section: Introductionmentioning

confidence: 99%

<p>Fetal Programming of Semen Quality (FEPOS) Cohort – A DNBC Male-Offspring Cohort</p>

Hærvig

Bonde

Ramlau‐Hansen

et al. 2020

CLEP

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“…analgesics, metformin and diethylstilboestrol) and lifestyle factors (e.g. diet, alcohol and smoking) (Habert et al , 2014; Kilcoyne and Mitchell, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the exposures used for these studies may not reflect the levels of exposure that are directly relevant to humans. Assessment of experimental studies using experimental animal models must take account of the variations in model systems ( in-vitro versus in-vivo ), exposure regimen and drug metabolism, whilst also accounting for the impact of species differences for each of these parameters (Kilcoyne and Mitchell, 2017). As a result, animal studies often report findings based on relative exposures which exceed human-relevant exposures, often by several orders of magnitude.…”

Section: Introductionmentioning

confidence: 99%

Effect of environmental and pharmaceutical exposures on fetal testis development and function: a systematic review of human experimental data

Kilcoyne

Mitchell

2019

Human Reproduction Update

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BACKGROUND Overall, the incidence of male reproductive disorders has increased in recent decades. Testicular development during fetal life is crucial for subsequent male reproductive function. Non-genomic factors such as environmental chemicals, pharmaceuticals and lifestyle have been proposed to impact on human fetal testicular development resulting in subsequent effects on male reproductive health. Whilst experimental studies using animal models have provided support for this hypothesis, more recently a number of experimental studies using human tissues and cells have begun to translate these findings to determine direct human relevance. OBJECTIVE AND RATIONALE The objective of this systematic review was to provide a comprehensive description of the evidence for effects of prenatal exposure(s) on human fetal testis development and function. We present the effects of environmental, pharmaceutical and lifestyle factors in experimental systems involving exposure of human fetal testis tissues and cells. Comparison is made with existing epidemiological data primarily derived from a recent meta-analysis. SEARCH METHODS For identification of experimental studies, PubMed and EMBASE were searched for articles published in English between 01/01/1966 and 13/07/2018 using search terms including ‘endocrine disruptor’, ‘human’, ‘fetal’, ‘testis’, ‘germ cells’, ‘testosterone’ and related search terms. Abstracts were screened for selection of full-text articles for further interrogation. Epidemiological studies involving exposure to the same agents were extracted from a recent systematic review and meta-analysis. Additional studies were identified through screening of bibliographies of full-texts of articles identified through the initial searches. OUTCOMES A total of 25 experimental studies and 44 epidemiological studies were included. Consistent effects of analgesic and phthalate exposure on human fetal germ cell development are demonstrated in experimental models, correlating with evidence from epidemiological studies and animal models. Furthermore, analgesic-induced reduction in fetal testosterone production, which predisposes to the development of male reproductive disorders, has been reported in studies involving human tissues, which also supports data from animal and epidemiological studies. However, whilst reduced testosterone production has been demonstrated in animal studies following exposure(s) to a variety of environmental chemicals including phthalates and bisphenol A, these effects are not reproduced in experimental approaches using human fetal testis tissues. WIDER IMPLICATIONS Direct experimental evidence for effects of prenatal exposure(s) on human fetal testis development and function exists. However, for many exposures the data is limited. The increasing use of human-relevant models systems in which to determine the effects of environmental exposure(s) (including mixed exposures) on development and function of human tissues should form an important part of the process for assessment of such exposures by regulatory bodies to take account of animal–human differences in susceptibility.

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“…All said, the subject is far from settled, stated the authors of a recent review of prenatal acetaminophen exposures and male reproductive effects. “It cannot be concluded that exposure to paracetamol is a direct cause of male reproductive disorders,” they wrote, “nor that analgesics should simply be avoided during pregnancy.” 19 …”

Section: Finding Fetal Impactsmentioning

confidence: 99%

Reproductive Headache? Investigating Acetaminophen as a Potential Endocrine Disruptor

Konkel¹

2018

Environ Health Perspect

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Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development

Cited by 18 publications

References 87 publications

<p>Fetal Programming of Semen Quality (FEPOS) Cohort – A DNBC Male-Offspring Cohort</p>

<p>Fetal Programming of Semen Quality (FEPOS) Cohort – A DNBC Male-Offspring Cohort</p>

Effect of environmental and pharmaceutical exposures on fetal testis development and function: a systematic review of human experimental data

Reproductive Headache? Investigating Acetaminophen as a Potential Endocrine Disruptor

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