Prenatal exposure for endocrine disrupting chemicals and its importance for child
neurodevelopment.
Doctoral project Maria Marinopoulou
Background
Endocrine disrupting chemicals
Today we know that the endocrine system is of greatest importance for a healthy development - from
the time of conception until death - for both animals and humans. It is therefore of global concern that
the entire human population, foetuses, infants, children and adults, are constantly exposed to low levels
of anthropogenic chemicals, some of which are endocrine disrupting chemicals (EDCs) that may interact with our natural endocrine functions with adverse health effects as result. Everyone is exposed, as
supported by global bio-monitoring data showing that EDCs and/or their metabolites are routinely detected in human fluids such as urine, blood, breast milk, and recently in amniotic fluid showing that
they pass placenta and exposing the fetus at vulnerable developmental stages. Exposure to EDCs during windows of susceptibility during fetal development, even at low doses and in complex mixtures,
is of particular concern for developmental programming and trans-generational effects on the proteome, transcriptome and epigenome. These changes underlie disorders that may manifest in adult life and
contribute to a multitude of chronic diseases (Bergman, Heindel, Jobling, Kidd, & Zoeller, 2013).
SELMA study
The SELMA study (http://selmastudy.se/) is a population-based, longitudinal pregnancy cohort study
being conducted in the county of Värmland (Bornehag et al.,2012). The study is investigating prenatal
and postnatal exposure for EDCs – both as single compounds and as mixtures – for health outcomes
and development in four different domains in children including sexual development, neurodevelopment and behavior, metabolism and growth, and asthma and allergy, and to examining mode of actions
including inflammation and epigenetic mechanisms. SELMA is currently following 1.951 mother child
pairs from 1st trimester of pregnancy over birth and up in school age. Within SELMA we are examining both non-persistent organic compounds and persistent organic pollutants, all with documented
EDC properties, known as additives in materials of common consumer products, known to occur in the
general environment and detected in humans globally. All these compounds or metabolites of them can
be analysed in human fluids. An extensive health and neurodevelopmental examination of the children
is going to be conducted when they are 7 years of age.
Neurodevelopment and neurodevelopmental disorders
The prenatal period is of crucial importance for brain development. A great and rapid growth and development occurs during this period, manifested as cell birth, migration and differentiation, dendrite
and axonal growth, formation of synapses, pruning and myelogenesis. Several factors can influence
this development contributing to obvious or less pronounced deficits (Kolb & Whishaw, 2009). Hormones such as thyroxin, testosterone and estrogen are important for normal brain development. The
most sensitive window of exposure to EDCs is during critical periods of development, such as fetal
development and puberty (Bergman et al., 2013). Today we have neuropsychological test instruments
to measure neurodevelopmental outcomes by assessing cognitive functions such as intellectual functioning, language, attention and executive functioning. Cognitive functions are considered to be normally distributed in the general population.
The term neurodevelopmental disorders refer to a group of conditions affecting several areas of cognitive functioning and behavior, such as autism spectrum disorder (ASD), ADHD and intellectual disability. Comorbidity and overlapping symptoms are common. The first symptoms, for example motor
problems, language delay or hyperactive behavior, are apparent in early childhood indicating the need
for further examination. Symptoms in one developmental domain often indicate significant developmental problems within the same or other domains later on and a possible diagnosis of neurodevelopmental disorder. The term ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental
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Clinical Examinations) has been coined to stress the importance of early assessment and treatment
(Gillberg, 2010). Children with neurodevelopmental disorders are often found to have impairments in
some cognitive functions, as displayed by test results on the lower, left end of the normal distribution
curve.
Epidemiological studies report an increased prevalence of ASD, from 0,05% in the 1980s to 1,5% in
2010 (CDC, 2014) and up to 2,4%-2,6% in certain age groups (Idring et al., 2014; Kim Y. S. et al,
2011). Changes in diagnostic awareness and procedures explain a large share of the observed increase,
yet a true increase cannot be ruled out (Idring et al., 2014). Prevalence of ADHD is considered to be
stable over time, even if there has been an increasing rate of ADHD diagnosis and treatment (Polanczyk, Willcutt, Salum, Kieling, & Rohde 2014). Twin studies show a high heritability of about 7080% for ADHD (Faraone et al., 2005). Earlier studies estimated that the heritability of ASD was about
80-90%. However, recent studies show an estimated heritability of about 37-50 % (Hallmayer et al.,
2011; Sandin et al., 2014), suggesting that environmental factors contribute to ASD etiology in greater
proportion than previously thought.
Previous studies
A recent review of epidemiological studies shows that prenatal phthalate exposure may have a negative impact on the developing brain as displayed by associations between exposure and child cognitive,
motor and behavioural development (Miodovnik, Edwards, Bellinger, & Hauser, 2014), see table 1.
Sex-specific effects are often seen, with males more affected than females, but masculinization of female behaviour has also been reported.
Table 1. Epidemiological studies on phthalate exposure and neurodevelopment (adapted from Miodovnik et al., 2014).
Author
Exposure
Study design
period
(No of children)
Neonatal and Infant Neurological Status
Engel et al. 2009
25-40 week
Prospective study
(n=295)
Yolton et al. 2011
Two times
Prospective study
16/26
(n=350)
weeks
Mental and Psychomotor Development
Kim Y. et al. 2011
35-41
Prospective study
weeks
(n=460)
Whyatt et al. 2012
33.1
±3
Prospective study
weeks
(n=319)
Téllez-Rojo et al. 2013
third
triProspective study
mester
(n=135 girls)
Age
of
children
Instrument and type of
measurement
Outcome
infant/
neonate
BNBAS; Brazelton Neonatal
Behavioral Assessment Scale
LMWP: ↑motor performance in boys
HMWP:↓orientation and quality of alertness in girls
5 weeks
NNNS, NICU Network Neurobehavioral Scale
∑DBP: ↓arousal and ↓special handling required; ↑selfregulation and movement quality
∑DEHP: ↑nonoptimal reflexes in males
6 months
3 years
BSID-II
Bayley Scales of Infant Development
BSID-II
2-3 years
BSID-II
MEHHP, MEOHP, and MBP: ↓ Mental Development
Index (MDI) and PDI Psychomotor Developmental
Index (PDI) for boys
MnBP: ↓MDI scores for girls
MnBP and MiBP: ↓PDI and ↑odds of psychomotor delay
MEHP, MEHHP, MEOHP, MECPP and ∑DEHP:
↓MDI scores for girls
Cho et al. 2010
Cross-sectional study
(621)
Behavior and Emotional problems
8-11 years
WISC Wechsler
Full-Scale Verbal and performance IQ
Engel et al. 2010
Prospective study
(n=171)
mean
of
31.2 weeks
Follow up
btw 4 and
9 years
LMWP: ↑aggression, attention problems, conduct
problems, depression, and Behavior Symptoms Index
in boys
Whyatt et al. 2012
Prospective study
(n=319)
Play behavior
Swan et al. 2010
Multi-center prospective
study
(n=145)
Social Impairment
third
trimester
BASC-PRS
Behavior Assessment System for Children-Parent Rating Scales
CBCL Childhood Behavior
Checklist
Parent rating of behavior
4-7 years
PSAI Pre-School Activities
Inventory
Parents report of play behavior
MnBP and ∑DBP metabolites: ↓masculine composite
scores in boys
MEOHP, MEHHP and ∑DEHP metabolites:
↓masculine subscale scores in boys
Miodovnik et al. 2011
Prospective study
(n=137)
ADHD
Kim et al. 2009
Cross-sectional
(n=261)
third
trimester
7-9 years
SRS Social Responsiveness
Scale
LMWP: ↑(worse) total score and subdomain scores for
Social Cognition, Social Communication, and Social
Awareness scales
-
8-11 years
MEHP and MEOP: ↑teacher-rated ADHD symptoms
Chopra et al. 2014
Cross sectional
-
ARS ADHD Rating Scale
Teachers
rating ADHD
symptoms
CPT continuous performance
test
Parent reported
ADD/ADHD diagnosis
mean
weeks
28
6-15
years
MBzP and MCPP: ↑PDI in boys
MEHP and ∑DEHP: ↓vocabulary subscale scores in
boys
MnBP: ↑internalizing behaviors in boys
MBzP: ↑internalizing behaviors in girls
MnBP: ↑computerized omission and commission errors
DEHP and HMWP: ↑ odds of ADD/ADHD
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HMWP: High molecular weight phthalate metabolites (MBzP, MECPP, MEHHP, MEOHP, MEHP, MCPP). LWMP: Low molecular weight phthalate metabolites (MMP, MEP, MnBP, MiBP). Engel 2009, 2010 and Miodovnik were based on the same pregnancy cohort study.
A recent study evaluating associations between prenatal phthalate exposure and intellectual function in
the early school years showed significant decrements in IQ associated with two specific phthalates
(Factor-Litvak et al., 2014). Another study suggests associations between higher levels of exposure to
certain phthalates in late pregnancy and behavioral problems in boys at 6-10 years of age (Kobrosly et
al., 2014). In the Dampness in Buildings and Health (DBH) Study PVC flooring especially in the parents’ bedroom when the children were 1-3 year old was associated with higher risk for ASD 5 years
later (Larsson, Weiss, Janson, Sundell, & Bornehag, 2009).
Aims




This doctoral project is part of the SELMA study aiming to determine the strength of associations between prenatal exposures to EDCs and 7 year neurodevelopmental outcomes. Specific aims are;
Aim 1. To examine if prenatal exposure to EDCs is associated with deficits in children’s cognitive
function at age 7 years.
Aim 2. To examine if prenatal exposure to EDCs is associated with deficits in sensorimotor function
in children at age 7 years.
Aim 3. To examine if prenatal exposure to EDCs is associated with impairments in social
interaction.
Aim 4. To examine whether sex modifies the associations found in specific aims above.
The following figure conceptualizes the areas of focus in this doctoral project:
Method
Participants and design
Active SELMA-participants (n=1.951) will be invited to the follow-up study when the children are 7
year old. We estimate that 1500 children will participate. The follow up examination will be conducted
during the period August 2015 to August 2017. The examination will take place in 5 locations i Värmland. The health and developmental examination will take four hours and include blood sampling,
physical examination and neuropsychological assessment of the child.
Data collection – EDC exposure
Data on EDC exposure has been collected and sampled during pregnancy, birth and infancy/childhood
period through biological sampling of blood and urine from the pregnant women and the infant/child.
The samples are biobanked. Our target EDCs are 20 non-persistent compounds representing phthalic
acid esters (“phthalates”) including DEP, DBP, BBzP, DEHP and DINP metabolites in urine, alkylphenols in urine (bisphenol A, triclosan), and polyfluorinated alkyl including PFOA and PFOS in
serum.
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Data collection - Neurodevelopment
Neuropsychological tests and questionnaires will be used to capture child neurodevelopment. Test selection criteria include (a) adequacy of psychometric properties and availability of standardized norms;
(b) sensitivity to EDCs and low-level toxic exposures; and (c) availability of continuous scores to
model degree of impairment. Measures to be used are the Wechsler Intelligence Scale for Children
(WISC-IV) (Wechsler, 2003), NEPSY-II (Korkman, Kirk, &Kemp, 2007), Behavior Rating Inventory
of Executive Function BRIEF (Gioia, Isquith, Guy, & Kenworthy, 2000), Five-to-Fifteen Questionnaire (5-15) (Kadesjo et al., 2004; Korkman, Jaakkola, Ahlroth, Pesonen, & Turunen, 2004), Social responsiveness scale (SRS) (Constantino, 2005) and the Strength and Difficulties Questionnaires (SDQ)
(Goodman, 1997). See table 2 for detailed information on measures of child neurodevelopment and
emotional/behavioral problems.
Table 2. Measures of child neurodevelopment and emotional/behavioral problems.
COGNITION
Global Intellectual Functioning
WISCIV
NEPSYII
BRIEF
SRS
5-15
SDQ
Full-Scale IQ
Attention
and Exexutive
Functioning
Working
Memory Index,
Processing
Speed Index
Design Fluency,
Animal
Sorting, Inhibition, Clocks
Behavioral
Regulation Index, Metacognition
Index,
Global Executive Composite
Language
Perception
Verbal Comprehension Index
Perceptual
Reasoning
Index
Learning
and
Memory
SENSORIMOTOR
FUNCTIONING
SOCIAL INTERACTION
Sensorimotor
tioning
Social Interaction
Func-
Emotional
and Behavioural problems
Information
(subtest)
Design
Copying,
Geometric
Puzzles
Sensorimotor domain
SRS Total
Executive
Functions (domain)
Language
main)
(do-
Perception
(domain)
Memory
(domain),
[Learing
(domain)]
Motor Skills (domain)
Social Skills (domain)
Emotional
Problems
(domain)
Prosocial
iour
Total Difficulties Score
Behav-
We will not perform diagnostic assessment of the children. However, information from some the instruments used may indicate symptoms of probable neurodevelopmental disorder as followed: a Total
T-score of SRS score above 60 indicating probable ASD (Constantino, 2005) and a percentile score
over 98 at the 5-15 domain attention and executive function indicating probable ADHD (Kadesjo et
al.,2004). A Full-Scale IQ under 70 indicates probable intellectual disability (APA,1994).
Data collection- Modifying factors
Information on modifying factors has been gathered by questionnaires during the mother’s pregnancy
(week 10 and 25) and annual questionnaire to the family after birth, and by access to the mother’s and
child’s medical records. Available data includes information on factors such as parental age, parental
education, smoking (cotinine in prenatal serum), alcohol consumption, use of medication etc. There
are also available data on parity, gestational age, the child’s birth weight, neurodevelopmental disorders in parents or siblings etc. In order to control for genetic factors the mother or the father will be
asked to complete a shortened version of Raven’s matrices (Van der Elst et al., 2013), a test of nonverbal intelligence.
Statistical analysis
Data on prenatal exposure and results from the neurodevelopmental examination will be used in biostatistical models. Data on modifying factors and potential confounders are available. Traditional general linear regression models including potential confounders will be used to assess associations between one chemical at a time (i.e., a traditional compound-by-compound approach) and different
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health outcomes with good statistical power due to the large sample size with outstanding possibilities
for needed stratifications and adjustments. Sample size considerations are based on the test for association between body burden of EDCs and prevalences of neurodevelopmental outcomes. We hypothesize
that the EDCs will be inversely associated with child mental and motor development – i.e., a one-sided
test. However, effects on behavior may be in both directions and will vary by sex. Sample size of 241
is associated with 90% power to detect a significant effect assuming a beta coefficient of -2.8 with 5%
significance using a two-sided test. However, a lower effect size can be detected with 80% power and
5% significance with a sample size of 266 per gender. We want a sample size large enough to test for
gender-specific effects and to split the data into discovery and validation datasets. A sample size of
500 (split into discovery and validation sets of 250) will provide 80% power or better at 5% significance using one- or two-sided tests in all but one scenario shown to evaluate sex-specific effects. Thus,
a total sample size of 1000 (i.e., 500 girls and 500 boys combined then randomly split into discovery
and validation sets) will provide adequate power.
PhD-student’s duties
The PhD student will participate in the planning and preparation of the neurodevelopmental examination, supervise the examinations conducted, conduct part of the examinations, conduct biostatistical
analyses, present and interpret results, and write scientific reports and articles together with other staff
in the SELMA study.
Scientific value
SELMA has - with its unique design, large size, homogenous population, large number of EDCs
measured, several health effects studied, etc. - the possibility to provide new and important knowledge
in the area of EDC exposure in early life and the impact on human health and development. Results of
this doctoral project will contribute with further knowledge about EDC’s and other prenatal factor’s influence on child neurodevelopment. Results can also be valuable for further research on risk assessment of chemicals as well as research on potential risk factors for neurodevelopmental disorders.
Ethics
Establishment of the SELMA-cohort and baseline data collection was approved by the Regional Ethical Review Board, Uppsala, Sweden (2007-05-02, Dnr: 2007/062). Ethics approval for the health examination of the children at age 7 years including neurodevelopmental outcomes has been applied to
The Regional Ethical Review Board of Uppsala in April 2015. All data to be collected will be coded
for de-identification before being entered into the research database. This means that all research staff
with access to the database will handle only no-identifiable data. Results will be published in reports
and peer review articles with no possibility to relate to identifiable information.
Timeline
The timeline to complete this doctoral project is 8 years, half-time combined with clinical praxis.
Funding
This doctoral project will be funded by the County Council of Värmland and external research grants.
Supervision
Principal supervisor for this doctoral project is associate professor Eva Billstedt (Institute of Neuroscience and Physiology, Gillberg Neuropsychiatry Centrum, University of Gothenburg). Assistant supervisors are M.D., PhD Maria Unenge Hallerbäck (County Council of Värmland and Department of
Health Sciences, Karlstad University) and professor Carl-Gustaf Bornehag (Department of Health Sciences, Karlstad University), principal investigator for the SELMA-study.
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