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Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance.

ABSTRACT: Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for quality and data extracted for analysis. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. The search yielded 6 relevant human studies and 19 animal studies. Meta-analysis of 5 human observational prospective cohort studies showed that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in boys (-4.07 [CI, -6.49 to -1.66] % decrease per log10 rise in DEHP metabolites). Meta-analysis and meta-regression of the 19 experimental animal studies found reduced AGD with DEHP treatment, with a dose-response gradient, and with heterogeneity explained by species and strain. There is a moderate level of evidence from human investigations and a high level of data from animal studies that in utero exposure to DEHP decreases AGD. Based upon the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans on the basis of effects on AGD.

SUBMITTER: Dorman DC

PROVIDER: S-EPMC6786271 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance.

Dorman David C DC Chiu Weihsueh W Hales Barbara F BF Hauser Russ R Johnson Kamin J KJ Mantus Ellen E Martel Susan S Robinson Karen A KA Rooney Andrew A AA Rudel Ruthann R Sathyanarayana Sheela S Schantz Susan L SL Waters Katrina M KM

Journal of toxicology and environmental health. Part B, Critical reviews 20180910 4

Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Sea ...[more]

PMID: 30199328

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Project description:Study questionWhat is the relationship between maternal paracetamol intake during the masculinisation programming window (MPW, 8-14 weeks of gestation) and male infant anogenital distance (AGD), a biomarker for androgen action during the MPW?Summary answerIntrauterine paracetamol exposure during 8-14 weeks of gestation is associated with shorter AGD from birth to 24 months of age.What is already knownThe increasing prevalence of male reproductive disorders may reflect environmental influences on foetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces foetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism.Study design, size, durationProspective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 676 delivered male infants and completed a medicine consumption questionnaire.Participants/materials, setting, methodMothers self-reported medicine consumption during pregnancy by a questionnaire administered during the perinatal period. Infant AGD (measured from 2006 onwards), penile length and testicular descent were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between paracetamol intake during three gestational periods (<8 weeks, 8-14 weeks and >14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of six hundred and eighty-one male infants were exposed to paracetamol during pregnancy, of whom sixty-eight were reported to be exposed during 8-14 weeks. AGD measurements were available for 434 male infants.Main results and the role of chanceParacetamol exposure during 8-14 weeks of gestation, but not any other period, was associated with shorter AGD (by 0.27 SD, 95% CI 0.06-0.48, P = 0.014) from birth to 24 months of age. This reduction was independent of body size. Paracetamol exposure was not related to penile length or testicular descent.Limitations, reasons for cautionConfounding by other drugs or endocrine-disrupting chemicals cannot be discounted. The cohort was not fully representative of pregnant women in the UK, particularly in terms of maternal ethnicity and smoking prevalence. There is likely to have been misclassification of paracetamol exposure due to recall error.Wider implications of the findingsOur observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development.Study funding/competing interestsThis work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation for Disabled Children, the Evelyn Trust, the Mothercare Group Foundation, Mead Johnson Nutrition, and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. The authors declare no conflict of interest.

Project description:BackgroundAnogenital distance (AGD), the distance between the anus and genitals, is in rodents a well-established marker of early androgen action and has been suggested to be so in humans as well. Thus, a link between human AGD and semen quality and potentially fecundity may exist.ObjectiveThe aim of this study was to assess the association between AGD and male factor infertility and among proven fertile men also time to pregnancy (TTP).Material and methodsAll included men were recruited from and examined at Copenhagen University Hospital - Rigshospitalet, Denmark (N = 388). Men with impaired semen quality were included from infertile couples (N = 128), and men with naturally conceived pregnant partners were invited to participate when their partners had their routine second trimester examination (N = 260). All men underwent a physical examination, completed a questionnaire (including TTP for the fertile men), delivered a semen sample and had a blood sample drawn. The primary exposure was AGDAS measured from the centre of the anus to the posterior base of the scrotum. Associations between AGD and fertility status as well as between AGD and TTP among the fertile men were calculated using multiple logistic regression adjusted for covariates.ResultsAGD did not show a statistically significant association with fertility status. In adjusted logistic regression models, the odds of infertility per 1 cm increase in AGDAS were 1.02 (95% confidence interval [CI]: 0.88; 1.19). Among fertile men, a 1-cm increase in AGDAS was associated with an 8% non-statistically significantly reduced odds of having a longer (>3months) TTP (adjusted odds ratio (OR) = 0.92, 95% CI: 0.76-1.11).ConclusionOur study showed that the clinical application of AGD as a predictor of fertility and fecundity seems to be limited as no associations were observed between AGD and fertility status, nor was the decreased risk of experiencing a longer TTP with longer AGDAS statistically significant.

Project description:Exposure to phthalates has been shown to impede the human endocrine system, resulting in deleterious effects on pregnant women and their children. Phthalates modify DNA methylation patterns in infant cord blood. We examined the association between prenatal phthalate exposure and DNA methylation patterns in cord blood in a Korean birth cohort. Phthalate levels were measured in 274 maternal urine samples obtained during late pregnancy and 102 neonatal urine samples obtained at birth, and DNA methylation levels were measured in cord blood samples. For each infant in the cohort, associations between CpG methylation and both maternal and neonate phthalate levels were analyzed using linear mixed models. The results were combined with those from a meta-analysis of the levels of phthalates in maternal and neonatal urine samples, which were also analyzed for MEOHP, MEHHP, MnBP, and DEHP. This meta-analysis revealed significant associations between the methylation levels of CpG sites near the CHN2 and CUL3 genes, which were also associated with MEOHP and MnBP in neonatal urine. When the data were stratified by the sex of the infant, MnBP concentration was found to be associated with one CpG site near the OR2A2 and MEGF11 genes in female infants. In contrast, the concentrations of the three maternal phthalates showed no significant association with CpG site methylation. Furthermore, the data identified distinct differentially methylated regions in maternal and neonatal urine samples following exposure to phthalates. The CpGs with methylation levels that were positively associated with phthalate levels (particularly MEOHP and MnBP) were found to be enriched genes and related pathways. These results indicate that prenatal phthalate exposure is significantly associated with DNA methylation at multiple CpG sites. These alterations in DNA methylation may serve as biomarkers of maternal exposure to phthalates in infants and are potential candidates for investigating the mechanisms by which phthalates impact maternal and neonatal health.

Project description:ImportancePrenatal exposure to phthalates has been associated with neurodevelopmental outcomes, but little is known about the association with language development.ObjectiveTo examine the association of prenatal phthalate exposure with language development in children in 2 population-based pregnancy cohort studies.Design, setting, and participantsData for this study were obtained from the Swedish Environmental Longitudinal Mother and Child, Asthma and Allergy (SELMA) study conducted in prenatal clinics throughout Värmland county in Sweden and The Infant Development and the Environment Study (TIDES) conducted in 4 academic centers in the United States. Participants recruited into both studies were women in their first trimester of pregnancy who had literacy in Swedish (SELMA) or English or Spanish (TIDES). This study included mothers and their children from both the SELMA study (n = 963) and TIDES (n = 370) who had complete data on prenatal urinary phthalate metabolite levels, language delay, and modeled covariables. For SELMA, the data were collected from November 1, 2007, to June 30, 2013, and data analysis was conducted from November 1, 2016, to June 30, 2018. For TIDES, data collection began January 1, 2010, and ended March 29, 2016, and data analysis was performed from September 15, 2016, to June 30, 2018.Main outcomes and measuresMothers completed a language development questionnaire that asked the number of words their children could understand or use at a median of 30 months of age (SELMA) and 37 months of age (TIDES). The responses were categorized as fewer than 25, 25 to 50, and more than 50 words, with 50 words or fewer classified as language delay.ResultsIn the SELMA study, 963 mothers, 455 (47.2%) girls, and 508 (52.8%) boys were included. In TIDES, 370 mothers, 185 (50.0%) girls, and 185 (50.0%) boys were included in this analysis. The prevalence of language delay was 10.0% in both SELMA (96 reported) and TIDES (37 reported), with higher rates of delay in boys than girls (SELMA: 69 [13.5%] vs 27 [6.0%]; TIDES: 23 [12.4%] vs 14 [7.6%]). In crude analyses, the metabolite levels of dibutyl phthalate and butyl benzyl phthalate were statistically significantly associated with language delay in both cohorts. In adjusted analyses, a doubling of prenatal exposure of dibutyl phthalate and butyl benzyl phthalate metabolites increased the odds ratio (OR) for language delay by approximately 25% to 40%, with statistically significant results in the SELMA study (dibutyl phthalate OR, 1.29 [95% CI, 1.03-1.63; P = .03]; butyl benzyl phthalate OR, 1.26 [95% CI, 1.07-1.49; P = .003]). A doubling of prenatal monoethyl phthalate exposure was associated with an approximately 15% increase in the OR for language delay in the SELMA study (OR, 1.14; 95% CI, 1.00-1.31; P = .05), but no such association was found in TIDES (OR, 0.98; 95% CI, 0.79-1.23).Conclusions and relevanceIn findings from this study, prenatal exposure to dibutyl phthalate and butyl benzyl phthalate was statistically significantly associated with language delay in children in both the SELMA study and TIDES. These findings, along with the prevalence of prenatal exposure to phthalates, the importance of language development, and the inconsistent results from a 2017 Danish study, suggest that the association of phthalates with language delay may warrant further examination.

Dataset Information

Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance.

Publications

Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance.

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