Effect of environmental and pharmaceutical exposures on fetal testis development and function

A systematic review of human experimental data, 2019

Abstract

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. Image credit academic.oup.

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.

Prenatal and childhood exposure to phthalates and motor skills at age 11 years

Using Lipstick, Moisturizers During Pregnancy Linked To Motor Skill Deficiencies In Kids

2019 Study Highlights

  • Prenatal exposure to certain phthalates was associated with lower motor BOT-2 scores measured at 11 years of age among girls.
  • Postnatal exposure to certain phthalates was associated with lower motor proficiency among boys measured at 11 years of age.
  • The association between MEP measured at age 3 and motor performance at age 11 was different among girls and boys.

Abstract

Background
Previous 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.

Methods
In 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.

Results
The 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.

Conclusions
Higher 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.

Research communication. Press release. Image mamans.femmesdaujourdhui.be.

Do Harmful Chemicals in Health and Beauty Products Make Uterine Fibroids Grow ?

Phthalates exposure and uterine fibroid burden among women undergoing surgical treatment for fibroids: a preliminary study

A pilot study published in the journal Fertility and Sterility suggests that exposure to certain harmful chemicals called phthalates may lead to an increased burden of fibroids, uterine tumors that can cause heavy bleeding, pain, infertility, and other serious reproductive problems.

2019 Study Abstract

Objectives
To examine the association between phthalate exposure and two measures of uterine fibroid burden: diameter of largest fibroid and uterine volume.

Design
Pilot, cross-sectional study.

Setting
Academic medical center.

Patient(s)
Fifty-seven premenopausal women undergoing either hysterectomy or myomectomy for fibroids.

Intervention(s)
None.

Main Outcome Measure(s)
The diameter of the largest fibroid and uterine dimensions were abstracted from medical records. Spot urine samples were analyzed for 14 phthalate biomarkers using mass spectrometry. We estimated associations between fibroid outcomes and individual phthalate metabolites, sum of di(2-ethylhexyl) phthalate metabolites (∑DEHP), and a weighted sum of anti-androgenic phthalate metabolites (∑AA Phthalates) using linear regression, adjusting for age, race/ethnicity, and body mass index. Fibroid outcomes were also examined dichotomously (divided at the median) using logistic regression.

Results
Most women were of black ethnicity, overweight or obese, and college educated. In multivariable models, higher levels of mono-hydroxyisobutyl phthalate, monocarboxyoctyl phthalate, monocarboxynonyl phthalate, mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl phthalate) (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), ∑DEHP, and ∑AA Phthalates were positively associated with uterine volume. Associations were most pronounced for individual DEHP metabolites (MEHHP, MEOHP, MECPP), ∑DEHP, and ∑AA Phthalates. For example, a doubling in ∑DEHP and ∑AA Phthalates was associated with 33.2% (95% confidence interval 6.6–66.5) and 26.8% (95% confidence interval 2.2–57.4) increase in uterine volume, respectively. There were few associations between phthalate biomarkers and fibroid size.

Conclusions
Exposure to some phthalate biomarkers was positively associated with uterine volume, which further supports the hypothesis that phthalate exposures may be associated with fibroid outcomes. Additional studies are needed to confirm these relationships.

The George Washington University press release.

Components of plastic : experimental studies in animals and relevance for human health

You are what you eat, and drink

Abstract

Components used in plastics, such as phthalates, bisphenol A (BPA), polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A (TBBPA), are detected in humans. In addition to their utility in plastics, an inadvertent characteristic of these chemicals is the ability to alter the endocrine system. Phthalates function as anti-androgens while the main action attributed to BPA is oestrogen-like activity. PBDE and TBBPA have been shown to disrupt thyroid hormone homeostasis while PBDEs also exhibit anti-androgen action. Experimental investigations in animals indicate a wide variety of effects associated with exposure to these compounds, causing concern regarding potential risk to human health. For example, the spectrum of effects following perinatal exposure of male rats to phthalates has remarkable similarities to the testicular dysgenesis syndrome in humans. Concentrations of BPA in the foetal mouse within the range of unconjugated BPA levels observed in human foetal blood have produced effects in animal experiments. Finally, thyroid hormones are essential for normal neurological development and reproductive function. Human body burdens of these chemicals are detected with high prevalence, and concentrations in young children, a group particularly sensitive to exogenous insults, are typically higher, indicating the need to decrease exposure to these compounds.

General Conclusions

Exposure of humans to pharmaceuticals is deliberate, with the intention of achieving a desired effect. Development and testing of medications involves a series of evaluations culminating in human clinical trials before marketing is approved. This is quite different from the situation with chemicals, whose presence in biota and humans is inadvertent. In the field of toxicology, information regarding potential human health effects is mainly derived from experimental studies and, when available, from epidemiological studies. Difficulties are not only encountered with extrapolation from animal models to humans, but epidemiological studies are also thwarted by drawbacks such as controlling for confounding factors. In particular, subjects are exposed to an assortment of chemicals on a daily basis and, often, lack of data regarding the extent of exposure at what may have been the critical time frame. One of the goals of toxicology is to identify effects in animal models with the aim to lower the risks of negatively impacting human health. Implicit in this task is that toxicological data, derived from animal studies indicating a potential for adverse effects, serve as a basis to limit exposure before effects appear or are confirmed in humans. The evidence from animal studies on single exposures to the chemicals discussed here suggests the potential for risk to human health. Moreover, data derived from co-exposure studies support the contention that the assortment of chemicals to which we are exposed on a daily basis increases the likelihood of health effects. The high prevalence of body burdens of these chemicals and simultaneous exposure to a number of substances, in conjunction with the fact that the highest concentrations have been demonstrated in the developing young, a sensitive subpopulation of society, indicate the need to decrease the exposure to these compounds.

Read the full study (free access) on NCBI PubMed, 2009 Jul 27.

What are you putting on your baby? Or on your genitals?

Sanitary pads and diapers contain higher phthalate contents than those in common commercial plastic products

2019 Study Highlights

  • Three VOCs and 4 phthalates were measured in commercial sanitary pads and diapers.
  • Air in the packages of sanitary pads and diapers contained as high as 5.9 ppb of VOCs.
  • Sanitary pads and diapers contained as high as 8,014.9 ppb of phthalates.
  • VOCs and phthalates contained in the commercial products considerably vary among the brands.

Abstract

Sanitary pads and diapers are made of synthetic plastic materials that can potentially be released while being used. This study measured the amounts of volatile organic compounds (VOCs) (methylene chloride, toluene, and xylene) and phthalates (DBP, DEHP, DEP, and BBP) contained in sanitary pads and diapers. In sanitary pads, 5,900- and 130-fold differences of VOC and phthalate concentrations were seen among the brands. In the diapers, 3- and 63-fold differences of VOC and phthalate concentrations were detected among the brands. VOC concentrations from the sanitary pads and diapers were similar to that of the residential air. However, phthalate concentrations of sanitary pads and diapers were significantly higher than those found in common commercial plastic products. As sanitary pads and diapers are in direct contact with external genitalia for an extended period, there is a probability that a considerable amount of VOCs or phthalates could be absorbed into the reproductive system.

 

Impact of endocrine disrupting chemicals exposure on fecundity as measured by time to pregnancy

A systematic review;, Environmental research, 2018 Dec

Abstract

BACKGROUND
Emerging scientific evidence suggests that exposure to environmental pollutants is associated with negative effects on fecundity as measured by time to pregnancy (TTP).

OBJECTIVES
To conduct a systematic review of the literature on the association between selected endocrine disrupting chemicals (EDCs), and fecundity as measured by TTP in humans. Compounds included in this review are: brominated flame retardants (BFRs) such as hexabromocyclododecane, tetrabromobiphenol A and polybrominated diphenyl ethers; organophosphates flame retardants (OPFRs); and phthalates.

METHODS
Scopus, MEDLINE via Ebscohost and EMBASE databases were searched for articles exploring the relationships between selected EDCs and fecundity as measured by time to pregnancy. We assessed the quality of included studies and evidence for causality was graded using the criteria developed by the World Cancer Research Fund.

RESULTS
14 studies of 191 full-text articles assessed for eligibility were included for qualitative synthesis. Five studies examined BFRs and 10 studies examined phthalates. Among the fourteen, one study assessed both BFRs and phthalates. There were no studies which investigated fecundity as measured by TTP on HBCD, TBBPA, or OPFRs. We recorded plausible fecundity outcomes as measured by TTP related to some of these EDCs. BFRs or phthalates increased TTP. However, results were inconsistent.

CONCLUSION
We recorded mostly weak associations between exposure to selected EDCs and fecundity. However, evidence was considered limited to conclude a causal relationship due to inconsistency of results. The health risks posed by these chemicals in exposed populations are only beginning to be recognized and prospective measurement of the environmental effects of the chemicals in large cohort studies are urgently needed to confirm these relationships and inform policies aimed at exposure prevention

Prenatal Exposure to Phthalate connected to ADHD in Children

Prenatal Phthalates, Maternal Thyroid Function, and Risk of Attention-Deficit Hyperactivity Disorder in the Norwegian Mother and Child Cohort

Introduction

There is growing concern that phthalate exposures, particularly during the prenatal period, may have an impact on child neurobehavioral development. Prenatal exposure to phthalates has been associated with both externalizing and internalizing  behaviors using validated behavioral screening instruments, as well as with deficits in executive function as measured by both parental report and performance-based assessments , although not all studies have found evidence of associations. Among the neurobehavioral domains identified in multiple studies are inattention , aggression, conduct problems, and emotional reactivity/regulation, as well as impairments in working memory. Sex differences in the associations of phthalates with neurobehavioral end points have often been noted, although some studies have found stronger associations among boys, whereas others have found stronger associations among girls. The constellation of phthalate-associated behaviors highlighted across studies has led many researchers to note overlap with symptoms of attention-deficit hyperactivity disorder (ADHD).

Despite the observed overlap in affected neurobehavioral domains, there is less consensus on the specific phthalate responsible for neurodisruptive effects, and no prior study has accounted for the correlation among phthalates by mutual adjustment. Some studies have reported significant associations with dibutyl phthalates and/or di-2-ethylhexyl phthalate (DEHP) ; others have highlighted butyl benzyl phthalate (BBzP). Moreover, as of now there have been no studies with biomarkers of exposure in the prenatal period and access to clinically confirmed neurobehavioral end points, such as ADHD diagnoses from a clinical provider. Rather, the bulk of the literature relies on parent-reported symptoms. Because the ages of the children examined have varied substantially across and within studies, relying solely on parental reports to identify nonnormative behavior may be problematic.

A number of mechanisms have been proposed to explain how phthalates may negatively affect brain development, although few have been thoroughly examined in humans or in animal models. One prominent concern is phthalate-induced maternal thyroid hormone disruption. Phthalates have been associated with changes in circulating thyroid hormone levels in adults and in pregnant women. The most consistent finding across studies has been an inverse association between metabolites of DEHP and thyroxine and/or free thyroxine. Maternal prenatal thyroid hormone is essential for fetal neurodevelopment, and clinically diagnosed thyroid hormone disorders (hyperthyroidism and hypothyroidism) in the perinatal period have been linked with ADHD in offspring. Additionally, both higher and lower levels of thyroid hormone concentrations, even within population reference ranges, have been associated with ADHD-like behaviors. Perinatal phthalate exposure has also been associated with preterm delivery, which is itself a risk factor for ADHD.

A true causal association of phthalate exposure with child neurodevelopment would have major public health significance. Phthalates are ubiquitous in consumer products, are components of many food processing and packaging materials, and can be found in both pharmaceuticals, and personal care products. Therefore, to address this critically important public health question, we undertook a prospective, nested case–control study in the Norwegian Mother and Child Study (MoBa) to examine the hypothesis that prenatal biomarkers of phthalate exposure are associated with clinical ADHD in offspring. We further considered whether any associations were mediated by maternal thyroid function or preterm delivery or were modified by child sex.

Objectives

We undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case–control study of the Norwegian Mother and Child Cohort (MoBa) between the years 2003 and 2008.

Methods

Phthalate metabolites were measured in maternal urine collected at midpregnancy. Cases of ADHD (n=297) were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls (n=553) from the MoBa population was obtained.

Results

In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of ∑DEHP had almost three times the odds of an ADHD diagnosis as those in the lowest [OR=2.99 (95% CI: 1.47, 5.49)]. When ∑DEHP was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% [OR=1.47 (95% CI: 1.09, 1.94)]. We detected no significant modification by sex or mediation by prenatal maternal thyroid function or by preterm delivery.

Conclusions

In this population-based case–control study of clinical ADHD, maternal urinary concentrations of DEHP were monotonically associated with increased risk of ADHD. Additional research is needed to evaluate potential mechanisms linking phthalates to ADHD.

Phthalate prenatal exposure can affect mens’ fertility and reproductive capacity of several generations

Prenatal exposure to consumer product chemical may affect male fertility in future generations

Chicago, IL – Chemicals found in a variety of routinely used consumer products may be contributing to the substantial drop in sperm counts and sperm quality among men in recent decades, a new study in mice suggests.

The study found the effect of chemicals that disrupt the body’s hormones, called endocrine-disrupting chemicals, may extend beyond more than one generation. The research results was presented Monday, March 19, at ENDO 2018, the 100th annual meeting of the Endocrine Society, in Chicago, Ill.

“Sperm counts among men have dropped substantially over the last few decades, but the reason for such an alarming phenomenon is not known. These results suggest that when a mother is exposed to an endocrine disruptor during pregnancy, her son and the son’s future generations may suffer from decreased fertility or hormone insufficiency,”

said lead author Radwa Barakat, B.V.S.C., M.Sc., of the College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Ill.

The researchers studied the effect of di-(2-ethylhexyl) phthalate (DEHP), which is among the most widely used endocrine-disrupting chemicals. It is found in a wide array of industrial and consumer products, including polyvinyl chloride (PVC) piping and tubing, cosmetics, medical devices and plastic toys. The study found that male mice exposed to DEHP prenatally had significantly less testosterone in their blood and fewer sperm in their semen. Consequently, they lost fertility at an age when they normally would have been fertile.

“Most surprisingly, the male mice born to male mice that were exposed to DEHP also exhibited similar reproductive abnormalities—indicating prenatal exposure to DEHP can affect the fertility and reproductive capacity of more than one generation of offspring,” “Therefore, DEHP may be a contributing factor to the decreased sperm counts and qualities in modern men compared to previous generations.”

Barakat said.

Barakat and colleagues gave pregnant mice one of four doses of DEHP, or a type of corn oil, from 11 days after they conceived until birth.

Adult males born to these mice were bred with unexposed female mice, to produce a second generation of mice. Young adult males from this second generation were bred with unexposed females to produce a third generation. When each generation of mice was 15 months old, the researchers measured sex hormone levels, sperm concentrations and sperm motility, or movement (a potential sign of infertility).

In second-generation males, only those descended from mice in the highest DEHP exposure group had abnormal reproductive results—lower testosterone concentration, sperms levels and sperm motility. Third-generation males descended from DEHP-exposed mice also exhibited reproductive abnormalities at age 15 months, even those descended from mice that received a lower dose of the chemical. The researchers were surprised to find that the lowest DEHP dose group exhibited the greatest abnormalities.

“This study underscores the importance of educating public to try their best effort to reduce their exposure to this chemical and also the need to substitute this chemical with a safer one,”

Barakat said.

Cumulative effects of phthalates harm Leydig cells during fetal development

More bad news for sperm…

2018 Study Highlights

  • Phthalates dose-dependently cause fetal Leydig cell aggregation.
  • DEHP is more potent to inhibit testosterone production than DEP.
  • DEP and DEHP can elicit dose addition effect on FLC development

Abstract

Phthalate diesters, including di-(2-ethylhexyl) phthalate (DEHP) and diethyl phthalate (DEP), are chemicals to which humans are ubiquitously exposed. Humans are exposed simultaneously to multiple environmental chemicals, including DEHP and DEP. There is little information available about how each chemical may interact to each other if they were exposed at same time. The present study investigated effects of the combinational exposure of rats to DEP and DEHP on fetal Leydig cell development. The results showed that the gestational (GD12-20) exposure of DEP + DEHP resulted in synergistic and/or dose-additive effects on the development of fetal Leydig cell. The lowest observed adverse-effect levels (LOAEL) for fetal Leydig cell (aggregation and cell size), and StAR expressions were of 10 mg/kg and, lower than when these chemicals were exposed alone. Also, mathematical modeling the response curves supports the dose-addition model over integrated-addition model. Overall, these data demonstrate that individual phthalate with a similar mechanism of action can elicit cumulative, dose additive, and sometimes synergistic, effects on the development of male reproductive system when administered as a mixture.

Sources
  • In utero combined di-(2-ethylhexyl) phthalate and diethyl phthalate exposure cumulatively impairs rat fetal Leydig cell development, Science Direct, Volume 395, Pages 23–33, 15 February 2018.
  • Very high magnification micrograph of Leydig cells feature image wiki.

Waste-water analysis highlights exposure to endocrine-disrupting phthalate plasticisers

Wastewater-Based Epidemiology as a New Tool for Estimating Population Exposure to Phthalate Plasticizers

Researchers in Spain have analysed waste water to calculate levels of exposure to phthalates in individuals. The calculations showed that levels of four types of phthalate exceeded safe daily limits in some of the sites studied, with levels of exposure in children being of particular concern. Using the results of waste-water analysis in this way can identify areas where action may need to be taken to lower exposure.

2017 Study Abstract

This study proposes the monitoring of phthalate metabolites in wastewater as a nonintrusive and economic alternative to urine analysis for estimating human exposure to phthalates. To this end, a solid-phase extraction-liquid chromatography-tandem mass spectrometry method was developed, allowing for the determination of eight phthalate metabolites in wastewater (limits of quantification between 0.5 and 32 ng L-1). The analysis of samples from the NW region of Spain showed that these substances occur in raw wastewater up to ca. 1.6 μg L-1 and in treated wastewater up to ca. 1 μg L-1. Concentrations in raw wastewater were converted into levels of exposure to six phthalate diesters. For two of them, these levels were always below the daily exposure thresholds recommended by the U.S. Environmental Protection Agency and the European Food Safety Authority. For the other four, however, estimates of exposure surpassed such a threshold (especially the toddler threshold) in some cases, highlighting the significance of the exposure to phthalates in children. Finally, concentrations in wastewater were also used to estimate metabolite concentrations in urine, providing a reasonable concordance between our results and the data obtained in two previous biomonitoring studies.

More Information

  • Wastewater-Based Epidemiology as a New Tool for Estimating Population Exposure to Phthalate Plasticizers, Environmental science & technology, PMID: 28240866, 2017 Apr.
  • Waste-water analysis highlights exposure to endocrine-disrupting phthalate plasticisers, Science for Environment Policy, Issue 500, 11 January 2018.
  • Featured image credit degrootdesign

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