Prenatal perfluorooctanoic acid exposure and glutathione s-transferase T1/M1 genotypes and their association with atopic dermatitis at 2 years of age
Prenatal perfluorooctanoic acid exposure and glutathione s-transferase T1/M1 genotypes and their association with atopic dermatitis at 2 years of age
Hui-Ju WenID 0 3
Shu-Li Wang 0 1 3
Pau-Chung Chen 2 3
Yue Leon Guo 0 2 3
0 National Institute of Environmental Health Sciences, National Health Research Institutes , Miaoli , Taiwan
1 Department of Public Health, National Defense Medical Center , Taipei, Taiwan , 3 Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health , Taipei , Taiwan
2 Department of Environmental and Occupational Medicine, National Taiwan University (NTU) College of Medicine and NTU Hospital , Taipei, Taiwan , 5 Department of Public Health, National Taiwan University College of Public Health , Taipei , Taiwan
3 Editor: Susan M. Pinney, University of Cincinnati , UNITED STATES
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Funding: This study was funded by the Ministry of
Science and Technology, Taiwan, grant numbers
MOST106-3114-B400-002 -, and MOST 107-2321-B-400-010 -. The
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of
using a birth cohort study.
From 2001 to 2005, 1,264 mother?newborn pairs were recruited from eight Taiwanese
maternity hospitals. PFAS levels and Genotypes were analysed from cord blood.
Information on children?s health status including AD occurrence was obtained via phone interviews
at 6 months and 2 years. Cord plasma concentrations of nine PFASs were measured via
ultra-high performance liquid chromatography/tandem mass spectrometry. GSTT1/M1 was
genotyped (null/present) via polymerase chain reaction. Environment-gene interaction
effects on AD were assessed using multiple logistic regression analysis.
Overall, 839 mother?newborn pairs completed all measurements. The prevalence of ever
having physician-diagnosed AD by 2 years of age was 5.4%. Among PFASs,
perfluorooctanoic acid (PFOA) was positively associated with AD adjusted for potential confounders.
After grouping PFOA levels into three groups: undetected, below and above the median in
Competing interests: The authors have declared
that no competing interests exist.
those with detected, children in above the median group who had the GSTT1-null, or
GSTM1-null genotype exhibited a higher odds ratio for AD (OR [95%CI] = 3.45 [1.26?9.99]
and 2.92 [1.12?7.91], respectively) as compared to the undetected group.
Our data demonstrated that in-utero PFOA exposure with GSTT1/M1 null genotype were
associated with AD. Minimizing early-life PFAS exposure may help against AD
development, especially in genetically susceptible individuals.
Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are widespread and persistent synthetic
chemicals in the environment and humans. PFASs are composed of highly stable
carbon-fluorine bonds and provide high chemical and thermal stability, durability, and strength [
are widely applied in many products used in daily life including clothing, food packaging,
carpets, furniture, and fire-fighting foams [
]. The health concerns for PFAS exposure are owing
to their bioaccumulation and persistence [
Atopic dermatitis (AD) is a common childhood chronic skin inflammation disorder that
has profound effects on the quality of life of the affected children and their families, especially
in those with severe symptoms [
]. In Taiwan, the prevalence of physician-diagnosed AD
among school-age children increased from 1.57% in 1995?96 to 2.79% in 2001[
] and among
preschool-age children was 8.7% in 2008 [
]. AD is usually the first manifestation in the atopic
march, which means that AD could be a significant predictor for other allergic disease such as
asthma and allergic rhinitis [
]. Most AD symptoms occur in early life. Approximately half of
children with AD have symptoms within the first 6 months of life and nearly 85% of affected
children develop symptoms before the age of 5 years [
]. The identification of early risk factors
of AD may allow for potential prevention against atopic disease development. Previously, we
found environmental factors to be important components for development of AD . Thus,
we attended to define specific environmental factors considering genetics.
PFASs have been suggested to exhibit immunotoxicity from animal studies via altered cytokine
production, inflammatory responses, and innate and adaptive immune responses [
have also been reported to associate with the development of atopic diseases in animals and
humans. The immune responses in atopic diseases are found to be skewed toward a T-helper
(Th) 2 phenotype with elevated levels of serum interleukin (IL)-4 and immunoglobulin E (IgE)
]. Notably, Dong et al. found that perfluorooctane sulfonate (PFOS), one of the most common
PFASs, was associated with increased secretion of IgE and Th2-type cytokines (IL-4 and IL-10)
and decreased secretion of Th1-type cytokines (interferon [INF]-? and IL-2) in mice [
Perfluorooctanoic acid (PFOA) was shown to be associated with increased IgE levels in a murine
]. In a case?control study, PFASs were shown to be associated with childhood asthma.
Higher IgE concentrations were also found in children with higher PFAS levels [
the association between PFASs and childhood AD is still unclear and controversial. Okada et al.
found that the risk of developing eczema decreased in children with lower prenatal
perfluorotridecanoic acid exposure [
], whereas no association was found between PFAS exposure and AD in
a study by Wang et al [
]. Thus, observation of a large number of children is necessary.
Genetic variation may play an important role in individual susceptibility to environmental
pollutants. In the human body, glutathione S-transferase (GST) plays an essential role in
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chemical detoxification. GST genotypes are known to associate with the health effects of
exposure to environmental pollutants including ambient air pollutants, smoke, metal, and
pesticides. Chen et al. found that children carrying the GSTM1-null genotype had significant
PM2.5-related increment in neutrophils and leukocytes in nasal lavage as determined by a
longitudinal study of schoolchildren [
]. Wang et al. found that GSTM1-null and GSTP1 Ile/Ile
genotypes were associated with a significant increase in the risk of AD in children with
prenatal smoke exposure [
]. Additionally, incense burning was reported to have a joint effect with
GSTT1 genotype and to associate with current asthma and wheezing in children [
Although genetic and environmental factors both likely contribute to the development of
AD and PFAS exposure is known to be associated with atopic diseases, the effect of PFAS
exposure and GST genotype on AD remains unclear. The current study aimed to investigate
the effect of PFAS exposure and GSTT1/M1 genotype on childhood AD from a 2-year
followup birth cohort study.
Materials and methods
Study population and data acquisition
A longitudinal birth cohort study was conducted among pregnant women who had undergone
prenatal examinations at eight selected private maternity hospitals located in seven areas,
including one in Taipei, one in eastern Taiwan, and five in the south part of Taiwan. The newborns
born after July 2001 were consecutively recruited . After providing written informed
consent, the pregnant women in their third trimester of gestation were asked to complete a
structured questionnaire. Venous blood of the women and umbilical cord blood of newborns were
obtained by a nurse. Blood specimens were centrifuged to obtain plasma and stored at ?80?C
until analysis. In total, 1,264 mother?newborn pairs were recruited between July 2001 and July
2005. Our protocols were approved by the National Cheng Kung University Hospital
Institutional Review Board and the National Taiwan University Hospital Institutional Review Board.
Pregnant women were asked about their demographic characteristics, environmental factors
at home (such as environmental tobacco smoke, cockroaches, incense burning, carpets, pets,
or fungi on walls), family history of allergic diseases (atopic dermatitis, asthma, and allergic
rhinitis), and neonate birth order. Maternal self-reported mental status during pregnancy was
also included in the prenatal questionnaire. Newborn birth outcomes (gestational weeks,
height, weight, and head circumference) were collected from hospital records by nurses.
Children were followed up via phone interview by well-trained interviewers at the ages of 6
and 24 months. After permission was obtained, mother or main caregiver was asked about the
child?s growth situation, diet habit, health status, and environmental exposure. Children were
considered as with- or without-AD according to the response to the question ?Did your child
ever have physician-diagnosed atopic dermatitis?? and ?Did your child ever have symptoms of
itching and scratching of the skin and have a rash characteristic in arm folds and behind the
knees?? The answer of ?Yes? to both questions in either of the two follow-up interviews was
considered positive that the child had AD before 2 years of age.
Analysis of PFASs
Cord plasma samples were sent to National Taiwan University for measurement of PFASs.
Altogether, nine PFASs were analysed: perfluorohexanoic acid (PFHxA), perfluoroheptanoic
acid (PFHpA), perfluorohexanesulfonic acid (PFHxS), PFOA, PFOS, perfluorononanoic acid
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(PFNA), perfluorodecanoic acid (PFDeA), perfluoroundecanoic acid (PFUnDA), and
perfluorododecanoic acid (PFDoDA). The analytical method was as described in a previous study
]. The detection of PFASs in plasma were performed on an Agilent-1200 high
performance liquid chromatography system (Agilent, Palo Alto, CA, USA) coupled with a
triplequadrupole mass spectrometer (Sciex API 4000, Applied Biosystems, Foster City, CA, USA).
The limit of quantitation values (LOQ) for serum PFASs were 0.25, 0.28, 0.08, 0.45, 0.10, 0.11,
0.19, 0.13, and 0.07 ng/mL for PFHxA, PFHpA, PFHxS, PFOA, PFNA, PFOS, PFDeA, PFUA,
and PFDoA, respectively. Participants? concentrations of PFASs below the detection limit were
replaced by half-of-detection-limit values.
Genomic DNA was extracted from umbilical cord blood cells using standard genomic DNA
extraction methods. The genotypes of GSTT1/M1 were determined using polymerase chain
reaction (PCR) assays as previously described [
]. GSTT1 and GSTM1 genotypes were
classified as present type (heterozygous or homozygous genotype for the gene presence) and null
type (homozygous deletion).
JMP version 5.0.1 (SAS Institute Inc., Cary, NC, USA) was used to perform all statistical
analyses. Geometric means of PFASs were calculated. Kruskal-Wallis tests was used to test for the
differences in PFAS concentrations between children with and without AD after excluding
outliers (S1 Table). Multiple logistic regression was also applied to test the association between
PFAS exposure parameters and AD in children. Odds ratio (OR) and 95% confidence interval
(95% CI) were used to assess the effects of PFAS exposure on AD. The stratified analysis by
GST genotypes was performed to evaluate the effect of PFAS exposure and GSTT1/M1
genotype on AD. P 0.05 was considered statistically significant.
In total, 1,264 mother?newborn pairs who completed the questionnaire interview and
specimen collection participated in the present study. After exclusion of 105 pairs because of
suspected cord blood contamination by maternal blood (N = 91 pairs), multiple birth (N = 13
pairs), and infant death (N = 1 pair), 1,159 pairs were recruited in follow-up phone interviews.
Among them, 264 pairs were lost to follow-up up to 2 years of age. We then excluded pairs
without PFAS concentration (N = 32 pairs) or GST genotype (N = 24 pairs) data, resulting in
839 pairs recruited in the final analysis (Fig 1).
The prevalence of ever having physician-diagnosed AD in 2-year-old children was 5.4%
(N = 45). For GSTT1/M1 genotypes, the frequency of the null genotype was 49.8% (N = 418)
for GSTT1 and 56.3% (N = 471) for GSTM1. Table 1 demonstrates the characteristics of
children and parents in children with and without AD. The children with and without AD did not
differ significantly regarding birth weight, gestational weeks, sex, birth order, maternal age
during pregnancy, paternal education, and family income. However, higher prevalence of
breastfeeding and parental atopy was found in children with AD. The characteristics of
children and parents between included pairs and excluded pairs are shown in S2 Table. No
significant difference was found between included and excluded pairs in birth weight, gestational
weeks, sex, birth order, maternal age during pregnancy, paternal education, family income, or
parental atopy. However, included pairs had higher education levels of the mothers than
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Fig 1. Flow chart of recruitment of mother-newborn pairs and data collection.
Table 2 demonstrates the concentrations of nine PFASs in the cord plasma. All detection
rates of PFASs were above 50% except PFHxA (3.33%), PFHpA (3.33%), and PFDeA (33.25%).
These three PFASs were therefore excluded from further evaluation. A high correlation was
found among PFNA, PFUnDA, and PFDoA as shown in S3 Table. Cord plasma PFAS
concentrations among children with and without AD are reported in Table 3. Among the six PFASs,
children with AD had higher PFOA concentration and lower PFUnDA concentration than
those without AD.
We then grouped the PFOA concentrations into undetected and below and above the
median in those with detected exposure. The other five PFASs including PFHxS, PFNA,
PFOS, PFUA, and PFDoA were grouped by tertile. The associations between cord plasma
PFAS concentrations and AD are shown in Table 4 after adjustment for sex, family income,
maternal atopy, breast feeding, and maternal age during pregnancy. The results showed that
children in the highest PFOA group had a significantly higher risk of developing AD (OR
[95%CI] = 2.58 [1.27?5.32]) (Table 4). No significant association was found between the other
five PFASs and AD in children at the age of 2 years (Table 4).
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?P value was calculated by Kruskal-Wallis tests for continues variables and ?2 test for categorical variables as
compared between children with and without AD.
Some numbers do not add up to total n because of missing values.
Abbreviations: AD, atopic dermatitis; SD, standard deviation; USD, US dollars; ETS, environmental tobacco smoke.
PLOS ONE | https://doi.org/10.1371/journal.pone.0210708
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Abbreviations: AD, atopic dermatitis; GM, geometric mean; SD, standard deviation; IQR, interquartile range; PFAS, perfluoroalkyl and polyfluoroalkyl substance;
PFHxA, perfluorohexanoic acid; PFHpA, perfluoroheptanoic acid; PFHxS, perfluorohexane sulfonic acid; PFOA, perfluorooctanoic acid; PFNA, perfluorononanoic
acid; PFOS, perfluorooctane sulfonate; PFDeA: perfluorodecanoic acid; PFUnA, perfluoroundecanoic acid; PFDoDA, perfluorododecanoic acid
We then stratified children by GSTT1 and M1 genotype and evaluated the joint effect of
PFOA concentration and GSTT1/M1 genotype on AD. After adjustment for sex, family
income, maternal atopy, breast feeding, and maternal age during pregnancy, children with the
GSTT1-null genotype that were in the highest PFOA group had a higher risk of developing AD
(OR [95%CI] = 3.45 [1.26?9.99]). The result was similar for children with the GSTM1-null
genotype (OR [95%CI] = 2.92 [1.12?7.91]) (Table 5).
To our knowledge, this is the first study to investigate the effect of PFAS exposure and GST
genotype on childhood AD. We found that in-utero PFOA exposure was associated with AD
development in 2-year-old children and this effect was more prominent among children
carrying GSTT1-null or GSTM1-null genotypes.
Our result is consistent with the association between PFAS exposure and allergic diseases
reported previously. In a prospective birth cohort study in China, prenatal exposure to PFOA,
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?Adjusted OR (AOR) was adjusted by sex, family income, maternal atopy, breast feeding, and maternal age at
P < 0.05
P < 0.01.
Abbreviations: AD, atopic dermatitis; OR, odds ratio; CI, confident interval; AOR, adjusted OR; PFAS, perfluoroalkyl
and polyfluoroalkyl substance; PFHxS, perfluorohexane sulfonic acid; PFOA, perfluorooctanoic acid; PFNA,
perfluorononanoic acid; PFOS, perfluorooctane sulfonate; PFUnA, perfluoroundecanoic acid; PFDoDA,
PFHxS, PFDoA, and PFOA significantly increased the risk of AD in girls at the age before 2
years old [
]. In a case?control study of Taiwanese children, asthmatic children exhibited
significantly higher serum PFAS concentration than children without asthma [
]. PFOA is a
common PFAS. Specifically, Anderson-Mahoney et al. indicated that residents with prolonged
exposure to PFOA in drinking water had a higher prevalence of asthma than the general
population in West Virginia, United States [
]. In the National Health and Nutrition Examination
Survey (NHANES) study, PFOA was associated with ever having asthma among children at
12?19 years of age [
]. Notably, PFASs can cross the placental barrier, consequently
accumulating in the foetus and affecting newborn health. In the present study, we found that cord
serum PFOA was associated with childhood AD. This result was inconsistent with those of
previous birth cohort studies in Japan and Taiwan. Okada et al. reported no association
between maternal PFOA levels and eczema during the first 12 and 24 months [
]. Wang et al.
found a positive correlation between cord blood IgE levels and cord serum PFOA in boys,
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GSTT1 present type
GSTM1 present type
?AOR was adjusted by sex, family income, maternal atopy, breast feeding, and maternal age at childbirth.
#P < 0.1
P < 0.05.
Abbreviations: AD, atopic dermatitis; OR, odds ratio; CI, confident interval; AOR, adjusted OR; PFOA,
perfluorooctanoic acid; GST, glutathione s transferase.
although no association was found between PFOA exposure and AD in children [
may have been due to insufficient samples for investigation (n = 244).
The biological mechanisms underlying the effects of PFAS exposure on AD development
remain unclear. Allergen-specific responses in AD are skewed toward a Th2 phenotype with
elevated serum IgE and IL-4 levels, whereas Fairley et al. reported that PFOA enhances the
hypersensitivity response to ovalbumin with increasing IgE levels in a murine model [
Singh et al. found that PFOA triggers mast cell-derived allergic inflammatory reactions by
histamine secretion and elevation of pro-inflammatory cytokines, including tumour necrosis
factor alpha, IL-1, IL-6, and IL-8 [
]. Additionally, prenatal PFOA exposure was positively
associated with cord blood IgE levels in a birth cohort study,[
] and a case?control study of
children reported a dose?response effect of PFOA concentration on increasing IgE levels [
Stein et al. indicated that total IgE levels might increase by 10% in children with doubled
PFOA exposure [
Another potential mechanism is through peroxisome proliferator-activated receptor
(PPAR) signalling pathways. Both PPAR-? and PPAR-? are potentially related to immune
function owing to their expression on monocytes or macrophages [
]. PPAR? agonists
inhibit interferon-? and enhance IL-4 levels [
]. PFOA is known as a peroxisome proliferator,
and binding to PPAR-? increased the activation of mouse and human PPAR-? in an in vitro
]. Specifically, a dose?response effect was found for mouse PPAR-? activated by
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PFOA and a positive association was also found for human PPAR-? treated with PFOA.
Moreover, this effect was inhibited by a PPAR-? antagonist [
]. PFOA may therefore potentially be
related to the immune function of children and associated with AD development through a
In our study, we also examined whether GST genetic variants comprised factors that
modified the relationship of PFAS exposure to AD and found that PFOA exposure was associated
with AD development, especially in children with GSTT1- or GSTM1-null genotypes. GST
genotypes have also been previously reported to modify the effect of environmental exposure
on allergic diseases. In a case?control study of Korean children, the GSTM1-null genotype was
significantly associated with childhood AD onset [
]. However, Chung et al. found that a
healthy dietary intake and the GSTM1-present genotype had a protective effect against AD
]. Furthermore, Carlsten et al. indicated that the GSTT1 genotype enhanced the ambient
diesel exhaust exposure-mediated increase in allergen-sensitized inflammation in airways
among atopic participants [
GSTs contribute to chemical detoxification by conjugation with glutathione, thereby
protecting cells from reactive oxygen species (ROS). Oxidative stress is associated with the
activation of inflammatory cells and production of pro-inflammatory cytokines and mediators .
ROS are known to associate with AD pathogenesis [
]. For example, a lower glutathione to
glutathione disulphide ratio, representative of higher oxidative stress induction, was found in
children with AD [
]. Additionally, PFOS and PFOA could induce ROS production and were
associated with reductions in the antioxidative responses of hepatocytes, leading to oxidative
]. Children with the GSTT1- or GSTM1-null genotype lose enzymatic activity and
may therefore be vulnerable to the impacts of oxidative stress. Thus, the combination of PFOA
exposure and GSTT1/M1-null genotypes is suspected to result in higher oxidative stress in
children. Accordingly, we found that the effect of PFOA exposure on AD was more obvious in
children with GSTT1- or GSTM1-null genotypes.
There are limitations in this study. The determination of childhood AD was based on
maternal or main caregiver?s report of physician-diagnosed AD, which might result in
misclassification. However, the validation of physician-diagnosed AD reported by mothers was
confirmed by clinical examination in a previous study [
]. Moreover, characteristic symptoms of
AD were described based on an international standard questionnaire, the ISAAC
questionnaire. Children were identified as having AD based on both physician-diagnosed AD and a
rash in a specific position, which might have reduced the level of misclassification. Second,
approximately 33.6% of mother?newborn pairs were excluded from the final analysis owing to
suspected cord blood contamination by maternal blood, loss of children to follow-up, and
children without data for both PFAS and GST genotypes. Selection bias might thus be a concern.
However, the characteristics of the children and mothers did not significantly differ between
included and excluded children, aside from maternal education (S2 Table). Moreover, as the
mothers and the interviewers were unaware of the research objective, selection bias caused by
differential participation was less likely. Third, our studied newborns were recruited from
eight private maternity hospitals located in seven areas. They may not be representative of all
newborns in Taiwan. Caution about the generalizability of our findings is warranted. An
external validation study in a more representative population is therefore warranted.
Despite these limitations, the study has several strengths. We enrolled a general population
of pregnant women in their third trimester throughout Taiwan. Second, using a birth cohort
design with longitudinal follow-up, we were able to clearly investigate the temporal sequence
between early life environmental exposure and disease occurrence. Additionally, the
prospective cohort design reduces recall bias. Finally, both PFAS concentrations and GSTT1/M1
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genotypes were measured using standard methods that therefore minimized the
misclassification of these measurements.
In conclusion, this study showed that in-utero PFOA exposure and neonatal GSTT1 or
GSTM1 genotype might have joint effects and be associated with childhood AD. Avoiding and
minimizing PFAS exposure in early life may be potentially helpful toward protecting against
S1 Table. Outlier points identified by Outlier analysis: Excluded data.
S2 Table. Characteristics of children and parents in included pairs (N = 839) and excluded
pairs (N = 320).
S3 Table. Spearmen?s correlation between cord plasma PFAS concentrations (ng/mL)
(N = 839).
The authors thank all the pairs of mothers and their children who participated in this
followup study. The authors thank the interviewers who supported the data collection and phone
interview. The authors also thank the collaborating hospitals? medical personnel who helped
with biological sample collection, including those from Kaohsiung Medical University
Hospital, Kaohsiung Chang Gung Memorial Hospital, and six other obstetrics and gynaecology
Conceptualization: Hui-Ju Wen, Yue Leon Guo.
Data curation: Hui-Ju Wen.
Formal analysis: Hui-Ju Wen.
Investigation: Hui-Ju Wen.
Methodology: Hui-Ju Wen, Pau-Chung Chen, Yue Leon Guo.
Project administration: Yue Leon Guo.
Resources: Hui-Ju Wen, Yue Leon Guo.
Supervision: Yue Leon Guo.
Validation: Hui-Ju Wen.
Visualization: Hui-Ju Wen.
Writing ? original draft: Hui-Ju Wen.
Writing ? review & editing: Shu-Li Wang, Yue Leon Guo.
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Wen HJ, Wang YJ, Lin YC, Chang CC, Shieh CC, Lung FW, et al. Prediction of atopic dermatitis in
2-yrold children by cord blood IgE, genetic polymorphisms in cytokine genes, and maternal mentality during
pregnancy. Pediatr Allergy Immunol. 2011; 22(7):695?703. https://doi.org/10.1111/j.1399-3038.2011.
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