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The Possible Impact of Antenatal Exposure to Ubiquitous Phthalates Upon Male Reproductive Function at 20?Years of Age.

ABSTRACT: Phthalates are ubiquitous environmental endocrine-disrupting chemicals suspected to interfere with developmental androgen action leading to adverse effects on male reproductive function. Prenatal exposure studies in rodents show cryptorchidism, hypospadias and reduced testicular volume (TV), testosterone and anogenital distance in males. It is postulated that there is a developmental window in utero when phthalate exposure has the most potent adverse effects. Some human studies show associations between prenatal phthalate exposure and reduced calculated "free" serum testosterone in infant boys and shorter anogenital distance. However, there are no data available yet which link antenatal exposure to long-term effects in men. We aimed to correlate antenatal phthalate exposure with adult TV, semen parameters and serum reproductive hormone concentrations. 913 men from the Western Australian (Raine) Pregnancy Cohort were contacted aged 20-22?years. 423 (56%) agreed to participate; 404 underwent testicular ultrasound examination; 365 provided semen samples, and reproductive hormones were measured in 384. Maternal antenatal serum phthalate metabolite measurements were available for 185 and 111 men, who provided serum and semen, respectively. Maternal serum collected at 18 and 34?weeks gestation, stored at -80°C, was pooled and analyzed for 32 phthalate metabolites by liquid chromatography-tandem mass spectrometry. TV was calculated, semen analysis performed by WHO approved methods, and serum concentrations of gonadotrophins, inhibin B, and testosterone measured. Eleven phthalate metabolites were detected. Primary and secondary metabolites of di-(2-ethyl-hexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP) were positively correlated. After correction for adult height, BMI, presence of a varicocele and exposure to maternal smoking mono-iso-nonyl phthalate (MiNP) (r?=?-0.22) and sums of DEHP and DiNP metabolites (r?=?-0.24) and the sum of the metabolites of the high molecular weight phthalates (r?=?-0.21) were negatively correlated with TV (all p?r?=?0.26), MiNP (r?=?0.18), the sum of metabolites for DEHP (r?=?0.21) and DiNP (r?=?0.18), and the sum of high molecular phthalates (r?=?0.20) (p?=?0.0005 to p?=?0.02). Given sample size, storage duration and confounding through postnatal exposures, further studies are required.

SUBMITTER: Hart RJ

PROVIDER: S-EPMC5996240 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Possible Impact of Antenatal Exposure to Ubiquitous Phthalates Upon Male Reproductive Function at 20 Years of Age.

Hart Roger J RJ Frederiksen Hanne H Doherty Dorota A DA Keelan Jeffrey A JA Skakkebaek Niels E NE Minaee Noviani S NS McLachlan Robert R Newnham John P JP Dickinson Jan E JE Pennell Craig E CE Norman Robert J RJ Main Katharina M KM

Frontiers in endocrinology 20180604

Phthalates are ubiquitous environmental endocrine-disrupting chemicals suspected to interfere with developmental androgen action leading to adverse effects on male reproductive function. Prenatal exposure studies in rodents show cryptorchidism, hypospadias and reduced testicular volume (TV), testosterone and anogenital distance in males. It is postulated that there is a developmental window <i>in utero</i> when phthalate exposure has the most potent adverse effects. Some human studies show assoc ...[more]

PMID: 29922230

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Project description:BackgroundPrevious reports suggest that prenatal phthalate exposure is associated with lower scores on measures of motor skills in infants and toddlers. Whether these associations persist into later childhood or preadolescence has not been studied.MethodsIn a follow up study of 209 inner-city mothers and their children the concentrations of mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monomethyl phthalate (MEP), mono-carboxy-isooctyl phthalate (MCOP), and four di-2-ethylhexyl phthalate metabolites (ΣDEHP) were measured in spot urine sample collected from the women in late pregnancy and from their children at ages 3, 5, and 7 years. The Bruininks-Oseretsky Test of Motor Proficiency short form (BOT-2) was administered at child age 11 to assess gross and fine motor skills.ResultsThe total number of children included in the study was 209. Of the 209 children, 116(55.5%) were girls and 93 were (45%) boys. Among girls, prenatal MnBP(b=-2.09; 95%CI: [-3.43, -0.75]), MBzP (b=-1.14; [95%CI: -2.13, -0.14]), and MiBP(b=-1.36; 95%CI: [-2.51, -0.21] and MEP(b=-1.23 [95%CI: -2.36, -0.11]) were associated with lower total BOT-2 composite score. MnBP (b= -1.43; 95% CI: [-2.44, -0.42]) was associated with lower fine motor scores and MiBP(b = -0.56; 95% CI: [-1.12, -0.01]) and MEP (b = -0.60; 95% CI: [-1.14, -0.06])was associated with lower gross motor scores. Among boys, prenatal MBzP (b = -0.79; 95% CI: [-1.40, -0.19]) was associated with lower fine motor composite score. The associations between MEP measured at age 3 and the BOT-2 gross motor, fine motor and total motor score differed by sex. In boys, there was an inverse association between ΣDEHP metabolites measured in childhood at ages 3 (b = -1.30; 95% CI: [-2.34, -0.26]) and 7 years (b = -0.96; 95% CI: [-1.79, -0.13]), and BOT-2 fine motor composite scores.ConclusionsHigher prenatal exposure to specific phthalates was associated with lower motor function among 11- year old girls while higher postnatal exposure to ΣDEHP metabolites was associated with lower scores among boys. As lower scores on measures of motor development have been associated with more problems in cognitive, socioemotional functioning and behavior, the findings of this study have implications related to overall child development.

Project description:BackgroundEmerging evidence suggests that phthalate exposure may be associated with behavior problems in children and that these associations may be sex specific.MethodsIn a follow up study of 411 inner-city minority mothers and their children, mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monethyl phthalate (MEP) and four di-2-ethylhexyl phthalate metabolites (DEHP) were quantified in maternal urine samples collected during the third trimester and in child urine samples at ages 3 and 5 years. The Conners' Parent Rating Scale-Revised: Long Form (CPRS) and Child Behavior Checklist (CBCL) were administered to the mothers to assess children's behavior problems at 7 years of age. The analysis included children with available measures of CBCL, CPRS and phthalates measured in maternal urine. We performed both Quasi-Poisson regression and a mixture analysis using Weighted Quantile Sum(WQS) regression to assess the risk for CPRS scores and for internalizing and externalizing behaviors (from the CBCL) following intra-uterine exposure to the phthalate metabolites for boys and girls separately.ResultsAmong boys, increases in in anxious-shy behaviors were associated with prenatal exposure to MBzP (Mean Ratio [MR] = 1.20, 95%CI 1.05-1.36) and MiBP (Mean Ratio (MR) = 1.22, 95%CI 1.02-1.47). Among girls, increases in perfectionism were associated with MBzP (MR = 1.15, 95%CI 1.01-1.30). In both boys and girls, increases in psychosomatic problems were associated with MiBP (MR = 1.28, 95%CI 1.02-1.60), and MnBP (MR = 1.28, 95%CI 1.02-1.59), respectively. Among girls, decreased hyperactivity was associated with two DEHP metabolites, mono(2-ethyl-5-oxohexyl) phthalate (MR = 0.83, 95%CI 0.71-0.98) and mono(2-ethyl-5-hydroxyhexyl) phthalate (MR = 0.85, 95%CI 0.72-0.99). Using weighted Quantile Sum logistic regression, no associations were found between the Weighted Quantile Sum (WQS) of phthalate metabolites and CPRS scores or externalizing and internalizing behaviors. Nonetheless, when the analysis was performed separately for DEHP and non-DEHP metabolites significant associations were found between the WQS of DEHP metabolites and social problems in boys (OR = 2.15, 95%CI 1.13-4.06, p-value = 0.02) anxious-shy problems in girls (OR = 2.19, 95%CI 1.15-4.16, p = 0.02), and emotional lability problems in all children (OR = 0.61, 95%CI 0.38-0.97, p = 0.04). MEHP and MEOHP were the most highly weighted DEHP metabolites in WQS mixture. The analysis performed with CBCL scale corroborated these associations.ConclusionConcentration of non-DEHP metabolites was associated with anxious-shy behaviors among boys. DEHP phthalate metabolites were associated with decreased hyperactivity and impulsivity among girls on CPRS scores. These findings lend further support to the adverse associations between prenatal phthalate exposure and childhood outcomes, and clearly suggest that such associations are sex and mixture specific.

Project description:BACKGROUND:There are concerns that developmental exposure to endocrine disrupting chemicals such as phenolic compounds and phthalates could affect child cognitive function. Epidemiological studies tackling this question have mainly focused on phthalate metabolites and bisphenol A, but not on the other phenolic compounds. Our study aimed to assess the relationship between in-utero exposure to phthalates, bisphenol A and other phenolic compounds (parabens, triclosan, dichlorophenols and benzophenone-3) and the Intelligence Quotient (IQ) of boys at 5-6 years. METHODS:In 452 mother-son dyads from the French EDEN cohort, we measured 11 phthalate metabolites and 9 phenolic compounds (4 parabens, benzophenone-3, bisphenol A, 2 dichlorophenols and triclosan) in spot urine samples collected between 22 and 29 gestational weeks. Verbal and performance IQ of children were assessed at 5-6 years by a psychologist using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI). We used adjusted Structural Equation Models (SEM) combined with Benjamini and Hochberg false discovery rate correction to assess the associations between maternal urine phenol and phthalate metabolite concentrations considered simultaneously and the boys' IQ. RESULTS:No phenol or phthalate metabolite concentration was negatively associated with the boys' verbal or performance IQ (uncorrected p-values ?0.09). Mono(3-carboxypropyl) phthalate tended to be associated with increased verbal IQ (? = 0.136, 95% confidence interval, 0.01; 0.27). This association disappeared after correction for multiple comparison (corrected p-value, 0.71). CONCLUSION:Our results did not provide evidence of an inverse association between in-utero exposure to phenols or phthalates and verbal and performance IQ among boys. Since phenols and phthalates may have sex-specific effects, these null findings cannot be generalized to girls. Limitations included use of a single spot urine sample to assess exposures and lack of consideration of postnatal exposures.

Project description:The reproductive system is extremely susceptible to environmental insults, for example exogenous steroids during gestational development and differentiation. Experimental induction of androgen excess during prenatal life in female animal models reprograms their reproductive physiology, however the fetal programming of the male reproductive system by androgen excess has not been well studied. We aimed to determine the effect of prenatal exposure of two different doses of testosterone on different gestational days, on the male reproductive system using a rat model. Sixteen pregnant rats were randomly divided into two experimental groups and two control groups. Experimental group І were subcutaneously injected with 3 mg free testosterone on gestational days 16-19 and its controls received solvent for that time; experimental group П were subcutaneously injected with 20 mg free testosterone on day 20 of gestational period and its controls received solvent at the same time. The reproductive system morphology and function of 32 male offspring of these study groups were compared at days 6-30-60 of age and after puberty. The anogenital distance of the male offspring of both experimental groups had no significant differences on the different days of measurement, compared with controls. In the offspring of experimental group І, the testes weight, number of Sertoli, Spermatocyte and Spermatid cells, sperm count and motility and the serum concentration of testosterone after puberty were significantly decreased; except for reduction of sperm motility (p< 0.01), the other effects were not observed in the offspring of experimental group ІІ. In summary, our data show that prenatal exposure of male rat fetuses to excess testosterone disrupted reproductive function, an effect highly dependent on the time, duration and level of exposure. It seems that the reproductive system in individuals exposed to high levels of androgens during fetal life should be evaluated at puberty and likely to be treated.

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The Possible Impact of Antenatal Exposure to Ubiquitous Phthalates Upon Male Reproductive Function at 20?Years of Age.

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The Possible Impact of Antenatal Exposure to Ubiquitous Phthalates Upon Male Reproductive Function at 20 Years of Age.

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