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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Perturbateurs endocriniens, liste des substances anthropiques

Office parlementaire d’évaluation des choix scientifiques et technologiques, Rapport 2011

En 2011, à l’occasion d’une proposition de loi visant à interdire le Bisphénol A dans les plastiques alimentaires, l’Office parlementaire d’évaluation des choix scientifiques et technologiques a été saisi pour réaliser une étude portant sur la question des perturbateurs endocriniens et l’état des recherches.

Les substances anthropiques représentent des milliers de produits et comprennent des produits de l’industrie chimique (phtalates, bisphénol A, métaux lourds, etc.) et les produits phytosanitaires utilisés en agriculture (herbicides, fongicides, insecticides, etc.).

PRINCIPALES SOURCES DES PERTURBATEURS ENDOCRINIENS CONFIRMÉS OU POTENTIELS

Produits pharmaceutiques

  • DES (Distilbène), éthynil-oestradiol (contraceptif), kétokonazole (traitement du pityriasis, pommade)…

Produits dentaires

  • Bisphénol A

Produits vétérinaires

  • DES, trenbolones (augmentent la masse musculaire)…

Produits de combustion

  • Dioxines, furanes, HAP (hydrocarbure aromatique polycyclique)…
  • Produits à usage industriel ou domestique
  • Phtalates, bisphénol A, styrène (polystyrène)…
  • Polybromodiphényl éthers (PBDE), polychlorobiphényls, organoétains…
  • Alkylphénols, parabens (conservateurs dans les produits de beauté)…
  • Arsenic, cadmium…

Produits phytosanitaires

  • Organochlorés (DDT, chlordécone…)
  • Vinchlozoline (retirée en avril 2007), linuron (herbicide)…

Phytooestrogènes

  • Isoflavones (soja, trèfle)…

Mycotoxines

  • Zéaralénone…

Perturbateurs endocriniens, le temps de la précaution

Le Distilbène DES, en savoir plus

60 MiNueTs : Toxic Bodies

UCSF Program on Reproductive Health and the Environment, 2017

The University of California San Francisco (UCSF) Program on Reproductive Health and the Environment (PRHE)’s mission is to create a healthier environment for human reproduction and development through advancing scientific inquiry, clinical care and health policies that prevent exposures to harmful chemicals in our environment.

PRHE is housed within the Department of Obstetrics, Gynecology and Reproductive Sciences, in the UCSF School of Medicine, one of the nation’s most prestigious medical schools. The Department is renowned for promoting cutting-edge reproductive science research, extending the frontiers of multidisciplinary women’s health care and professional education, advocating for women’s health at local, state and national levels, and engaging community involvement.

More Information

Phthalates and Thyroid Function in Preschool Age Children: Sex Specific Associations

Household Chemicals May Impair Thyroid in Young Girls

Early childhood exposures to specific phthalates are associated with depressed thyroid function in girls at age 3, according to a May 2017 study conducted by scientists at Columbia University’s Mailman School of Public Health. Image credit columbia.edu.

Highlights

  • In a study of inner-city mothers and their children, we measured metabolites of several phthalates in maternal prenatal urine and child urine collected at age 3.
  • We also measured serum free thyroxine and thyroid stimulating hormone in the children at age 3.
  • We found inverse and sex specific associations between specific phthalate metabolites measured in children at age 3 and free thyroxine.
  • The associations were limited to girls.
  • Maternal prenatal urine concentrations of MEHP, a metabolite of DEHP, were associated with increases in free thyroxine in children at age 3.
  • No associations were found between phthalate metabolites and thyroid stimulating hormone.

Abstract

Background
Research relating either prenatal or concurrent measures of phthalate exposure to thyroid function in preschool children is inconclusive.

Methods
In a study of inner-city mothers and their children, metabolites of di-n-butyl phthalate, butylbenzyl phthalate, di-isobutyl phthalate, di(2-ethylhexyl) phthalate, and diethyl phthalate were measured in a spot urine sample collected from women in late pregnancy and from their children at age 3 years. We measured children’s serum free thyroxine (FT4) and thyroid stimulating hormone (TSH) at age 3. Linear regression models were used to investigate the associations between phthalate metabolites, measured in maternal urine during late pregnancy and measured in child urine at age 3 and thyroid function measured at age 3.

Results
Mean concentrations (ranges) were 1.42 ng/dL (1.02–2.24) for FT4, and 2.62 uIU/mL (0.61–11.67) for TSH. In the children at age 3, among girls, FT4 decreased with increasing loge mono-n-butyl phthalate [estimated b = − 0.06; 95% CI: (− 0.09, − 0.02)], loge mono-isobutyl phthalate [b = − 0.05; 95% CI: (− 0.09, − 0.01)], loge monoethyl phthalate [b = − 0.04; 95% CI: (− 0.07, − 0.01)], and loge mono(2-ethyl-5-hydroxyhexyl) phthalate [b = − 0.04; 95% CI: (− 0.07, − 0.003)] and loge mono(2-ethyl-5-oxy-hexyl) phthalate [b = − 0.04; 95% CI: (− 0.07, − 0.004)]. In contrast, among boys, we observed no associations between FT4 and child phthalate metabolites at age 3. On the other hand, in late gestation, FT4 increased with increasing loge mono-(2-ethylhexyl) phthalate [estimated b = 0.04; 95% CI: (0.02, 0.06)] and no sex difference was observed. We found no associations between phthalate biomarkers measured in either the child or prenatal samples and TSH at age 3.

Conclusions
The data show inverse and sex specific associations between specific phthalate metabolites measured in children at age 3 and thyroid function in preschool children. These results may provide evidence for the hypothesis that reductions in thyroid hormones mediate associations between early life phthalate exposure and child cognitive outcomes.

The impact of chemicals on children’s brain development

A cause for concern and a need for action

No Brainer

Science has shown that many thousands of people have been exposed to now mostly banned chemicals such as lead and PCBs at high enough levels to have had their brain development negatively affected. This report finds that there are other chemicals which are still in routine use in our homes where there is evidence of similar developmental neurotoxic (DNT) properties, and also identifies huge gaps in our knowledge of the impacts of other chemicals on brain development. It also points out the unpleasant reality that we are constantly exposed to a cocktail of chemicals, something which is still largely ignored by chemical safety laws.

In spite of the lessons of the past, regulators are continuing to only regulate after harm is caused, instead of acting to effectively protect the most precious of things; children’s developing brains.

In June 2007 CHEM Trust wrote the briefing Chemicals Compromising Our Children, which highlighted growing concerns about the impacts of chemicals on brain development in children. Almost 10 years later, CHEM Trust has revisited the issue with this report, which includes contributions from two of the most eminent scientists in this area, Professor Barbara Demeneix (Laboratory of Evolution of Endocrine Regulations, CNRS, Paris) and Professor Philippe Grandjean (Department of Environmental Medicine, University of Southern Denmark, Denmark & Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, USA), who also peer reviewed the report.

Our brain and its development

Download the full report “No Brainer, The impact of chemicals on children’s brain development: a cause for concern and a need for action”, chemtrust, 2017.

Our brains are astoundingly complex, made up of over 85 billion neurons, which have grown, developed and interconnected during our lives. The brain is the organ that takes the longest to develop, with initial stages of cell division, creation of neurons and their migration taking place from the first hours after fertilisation and throughout the foetus’ time in the womb. However, brain development does not stop at birth – it’s not until our twenties that neurons are fully developed with their myelin coats.

Throughout this complex developmental process a range of signalling chemicals and other processes operate in order to control what happens. The thyroid hormone system is intimately involved in brain development and function, yet it is well established that this system can be disrupted – for example by a lack of iodine (essential to make thyroid hormone) or by certain chemicals. If developmental processes are disrupted, this most often creates permanent problems.

The complexity of brain development and function means that deficits can be very subtle – small reductions in IQ, disabilities that exist with a broad spectrum of seriousness such as autism, or in some cases conditions which do not have fully agreed diagnostic criteria.

Disruption of brain development by chemicals

Disruption of brain development by chemicals

We are all exposed to hundreds of man-made chemicals in our daily life, coming from everyday products including food, furniture, packaging and clothes. Many of these chemicals will have no negative effects on us, but it is now well established that some are able to disrupt normal development of the brain. Chemicals with long established DNT properties such as lead, PCBs and methylmercury, have been joined by others where DNT effects have been identified more recently, and which are being used in everyday products. There are also rising concerns about chemicals that are very similar to chemicals that have had their use restricted, but which we continue to use as there isn’t sufficient information about their toxic effects. We know even less about thousands of other chemicals in routine use, which have had no testing for DNT properties.

Chemical exposures are so ubiquitous that experts have recognized that babies are born “pre-polluted”. Scientific paediatric and gynaecology & obstetrics societies have consistently warned about chronic health implications from both acute and chronic exposure to chemicals such as pesticides and endocrine disruptors.

The report identifies evidence of DNT properties for the following chemicals:

  • Bisphenol A (BPA)
    a chemical that was used to make baby bottles, is currently being phased out of till receipts (in the EU), but is still used in the making of food can linings and many polycarbonate plastics. There are also concerns about closely related chemicals that are not restricted, including Bisphenol S.
  • Brominated Flame Retardants (BFRs)
    a group of chemicals added to furniture, electronics and building materials. The evidence for neurodevelopmental effects is strongest for the PBDE (polybrominated diphenyl ether) group of BFRs, which are already banned or nearly banned in the EU, though they are still in furniture in our homes, and in dust. However, other BFRs are now being found in dust and human blood serum, with concerns that these BFRs might have similar effects.
  • Phthalates
    a group of chemicals used as plasticisers in PVC and in other products. Some chemicals in this group are now banned in the EU, but many others are still in use.
  • Per- and poly-fluorocarbons (PFCs)
    used as non-stick coatings or breathable coatings, are a large group of chemicals, a few of which are in the process of being restricted by the EU. There is evidence that some PFCs can disrupt the action of the thyroid hormone. PFCs are very persistent in the environment, and many of them can accumulate in our bodies – they are routinely found in blood.
  • Perchlorate
    a contaminant of food, related to the use of certain fertilisers and hypochlorite bleach, and is known to disrupt the thyroid hormone system.

Are we protected?

The EU has the most sophisticated regulations in the world for controlling chemical use. However, there are a number of key flaws in this system:

  • There is often inadequate safety information about individual chemicals, including a lack of information about neurodevelopmental effects.
  • The processes to ban chemicals are too slow, and the restrictions created often have big loopholes as a result of industry lobbying.
  • Chemicals are addressed one at a time, so one chemical may have its use restricted, but closely related chemicals remain in use.
  • We are always exposed to multiple chemicals, but regulations almost always assume we are only exposed to one at a time, even though numerous scientists have shown that chemical effects can add together in our bodies.

Policy recommendations

It is clear that our children are not currently being protected from chemicals that can disrupt brain development. We have identified a range of policy measures that could improve the situation, including:

  • Acting faster to ban chemicals of concern, including addressing groups of similar substances, not just those where we have the most information.
  • Ensuring that any safety testing of chemicals includes evaluation of DNT effects.
  • Ensuring better identification and regulation of neurodevelopmental toxic chemicals.
  • Ensuring that all uses of chemicals are properly regulated; for example there is a lack of effective regulation of chemicals in food packaging including paper, card, inks, glues and coatings.
  • The UK and Ireland should remove the requirement for an open flame test for furniture. This test is not required in the rest of the EU, and leads to increased use of flame retardant chemicals.

Finally, it is important to note that EU regulations have already controlled a number of chemicals of concern, and that EU laws provide a tool to address these problems. We therefore think it is vital for the UK Government to work to stay aligned with EU chemicals laws, whatever the eventual outcome of the UK’s Brexit process.

Though full protection will only come from proper regulation of chemicals, the report also includes a chapter with tips for reducing your and your family’s exposures in daily life.

Sources and More Information

  • Download the full report “No Brainer The impact of chemicals on children’s brain development: a cause for concern and a need for action”, chemtrust, 2017.
  • IT’S A NO BRAINER! Action needed to stop children being exposed to chemicals that harm their brain development!, chemtrust, MARCH 7, 2017.

Can common chemicals in the environment affect human foetal brain development ?

Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos

In a recent experiment conducted on tadpoles, researchers tested the hypothesis that common chemicals in the environment, singly and as a mixture, can interfere with human brain development.

2017 Study Abstract

Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure.

As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis.

We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses.

  • Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers.
  • Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size.
  • Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility.

In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.

Sources and Press Releases
  • Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos, Nature, doi:10.1038/srep43786, 07 March 2017.
  • Everyday chemicals may affect brain development, including foetal IQ, the conversation, May 11, 2017.
  • Image credit Benny Mazur.

Maternal Phthalate Exposure Promotes Allergic Airway Inflammation over Two Generations via Epigenetic Modifications

Phthalates increase the risk of allergies among children

Phthalates, which are used as plasticizers in plastics, can considerably increase the risk of allergies among children. According to a new study, an increased risk of children developing allergic asthma exists if the mother has been particularly heavily exposed to phthalates during pregnancy and breastfeeding.

2017 Study Abstract

Background
Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy-promoting effects in children due to exposure to plasticizers like phthalates, findings of previous studies are inconsistent and lack mechanistic information.

Objective
We investigated the effect of maternal phthalate exposure on asthma development in the subsequent generations and their underlying mechanisms including epigenetic alterations.

Methods
Phthalate metabolites were measured within the prospective mother-child cohort LINA and correlated with asthma development in the children. A murine trans-generational asthma model was used to identify involved pathways.

Results
In LINA maternal urinary concentrations of mono-n-butyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine trans-generational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease-promoting effect was mediated by a BBP-induced global DNA hypermethylation in CD4 T cells of the offspring as treatment with a DNA demethylating agent alleviated exacerbation of allergic airway inflammation. 13 transcriptionally down-regulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor Zfpm1 emerged as a potential mediator of the enhanced susceptibility for Th2-driven allergic asthma.

Conclusion
These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in Th2 differentiation via epigenetic alterations.

Sources and Press Releases
  • Maternal Phthalate Exposure Promotes Allergic Airway Inflammation over Two Generations Via Epigenetic Modifications, jacionline, DOI: 10.1016/j.jaci.2017.03.017, 1 March 2017.
  • Phthalates increase the risk of allergies among children, medicalxpress, May 3, 2017.
  • Image credit: UFZ/André KünzelmannIn the course of the LINA mother-child cohort study, UFZ scientists investigated the lifestyle and environmental factors of pregnant women and their influence on the allergy risk of infants.