Allergy Asthma Immunol Res AAIR Allergy, Asthma & Immunology Research 2092-7355 2092-7363 The Korean Academy of Asthma, Allergy and Clinical Immunology; The Korean Academy of Pediatric Allergy and Respiratory Disease 10.4168/aair.2016.8.1.41 Original Article The Interaction Between Prenatal Exposure to Home Renovation and Reactive Oxygen Species Genes in Cord Blood IgE Response is Modified by Maternal Atopy Yu Jinho 1 http://orcid.org/0000-0001-7751-9829 Ahn Kangmo 2 Shin Youn Ho 3 Kim Kyung Won 4 Suh Dong In 5 Yu Ho-Sung 6 Kang Mi-Jin 6 Lee Kyung-Shin 6 Hong Seo Ah 7 Choi Kil Yong 6 Lee Eun 1 Yang Song-I 1 Seo Ju-Hee 8 Kim Byoung-Ju 9 Kim Hyo-Bin 10 Lee So-Yeon 11 Choi Suk-Joo 12 Oh Soo-Young 12 Kwon Ja-Young 13 Lee Kyung-Ju 14 Park Hee Jin 14 Lee Pil Ryang 15 Won Hye-Sung 15 Hong Soo-Jong 1 COCOA Study Group Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Department of Pediatrics, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea. Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea. Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea. Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea. ASEAN Institute for Health Development, Mahidol University, Nakhonpathom, Thailand. Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Korea. Department of Pediatrics, Inje University Haeundae Paik Hospital, Busan, Korea. Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Korea. Department of Pediatrics, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea. Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Korea. Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea. Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Correspondence to: Soo-Jong Hong, MD, PhD, Department of Pediatrics, Childhood Asthma Atopy Center, Research Center for Standardization of Allergic Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: +82-2-3010-3379; Fax: +82-2-473-3725; sjhong@amc.seoul.kr 01 2016 30 07 2015 8 1 41 48 15 01 2015 18 04 2015 14 05 2015 Copyright © 2016 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose

Although home renovation exposure during childhood has been identified as a risk factor for the development of allergy, there is limited information on the association between prenatal exposure to home renovation and cord blood (CB) IgE response. The aims of this study were to identify the effect of prenatal exposure to home renovation on CB IgE levels, and to investigate whether this exposure interacts with neonatal genes and whether the effect can be modified by maternal atopy.

 Methods

This study included 1,002 mother-neonate pairs from the COhort for Childhood Origin of Asthma and allergic diseases (COCOA). Prenatal environmental factors were collected using a questionnaire. The levels of CB IgE were measured by the ImmunoCAP system, and DNA was extracted from CB.

 Results

Exposure to home renovation during the prenatal period was associated with significantly higher levels of CB IgE only in neonates from atopic mothers, and the effect of renovation exposure on CB IgE levels persisted from 31 months before birth. Furthermore, prenatal exposure to home renovation increased the risk of CB IgE response interacting with polymorphisms of NRF2 and GSTP1 genes only in neonates from atopic mothers.

 Conclusions

Maternal atopy modified the effect of prenatal exposure to home renovation on CB serum IgE response as well as the interaction between the exposure and neonatal genes involved in the oxidative stress pathway. These findings suggest that the genetically susceptible offspring of atopic mothers may be more vulnerable to the effect of prenatal exposure to home renovation on the development of allergy.

 Cord blood gene-environment interaction IgE prenatal reactive oxygen species renovation single nucleotide polymorphism Korea Centers for Disease Control & Prevention 2013-E51011-00 INTRODUCTION

Epidemiologic studies have reported that exposure to home renovation increases the risk of allergic diseases during childhood.12 However, there is limited information on the association between exposure to home renovation during the prenatal period and the development of childhood allergy. In a previous study, home redecoration during pregnancy was not associated with wheezing during early childhood, although redecoration during the first or second year of life increased the risk of wheezing during the same period.1 By contrast, the Lifestyle-Immune System-Allergy (LISA) birth cohort study reported that exposure to indoor volatile organic compounds (VOCs) during pregnancy is associated with cord blood (CB) immune status.3 Significantly elevated levels of VOCs in indoor air have been found in new and renovated buildings.345

Maternal exposure to environmental factors, including cigarette smoke and microbials, is known to alter fetal immune function and increase the risk of allergic disease in children.678 Lower interferon γ (INF-γ) levels or a reduced number of T regulatory cells (Treg) in neonates was reported to induce T helper (Th) 2-skewed immune response, which is a main pathogenesis of development of allergic diseases during childhood.910 These data suggest that prenatal environmental factors are important in programming neonatal immune response and in the subsequent development of allergic diseases. Recently, CB immune response was reported to be modifiable by maternal atopy.11 Furthermore, the levels of maternal inflammatory cytokines during pregnancy are associated with corresponding cytokines in infants at the age of 1 year.12 These data suggest that maternal immune status may provide an intrauterine environment that influences the development of the immune system, having effects beyond the fetus stage. However, to the best of our knowledge, no studies have evaluated the effect of prenatal environmental factors on CB immune response in relation to maternal immune status.

Although genome-wide association studies have identified several genes associated with allergic diseases, especially asthma, the results do not account for the significant trait variation observed.13 Gene-environment interaction can explain some of this missing heritability. Exposure to environmental factors in early life increases the risk for allergic disease in individuals with a susceptible genotype.14151617 However, there is limited information on the interaction between environmental factors in prenatal periods and genes that affect CB immune response.

The aims of this study were to investigate the association between maternal exposure to prenatal home renovation and CB IgE response in a prospective birth cohort and to assess whether this exposure interacts with genetic variants in neonates and whether this association can be modified by maternal atopy.

 MATERIALS AND METHODS Study design

The COhort for Childhood Origin of Asthma and allergic Diseases (COCOA) study is an ongoing prospective longitudinal birth cohort one.18 A total of 1,369 pregnant women were recruited at 26 weeks of pregnancy from 4 tertiary hospitals (Asan Medical Center, Samsung Medical Center, Severance Hospital, and CHA Gangnam Medical Center) and 7 public health centers in Seoul, Republic of Korea. The study methods have been described in detail elsewhere.18 A total of 1,200 neonates born to those mothers were enrolled after exclusion of neonates who were premature or who had a major congenital anomaly or birth asphyxia, and after withdrawals from participation. Neonates with no information available on prenatal home renovation exposure, maternal atopic status, or CB IgE levels were also excluded. Finally, 444 neonates were included in the analysis (Figure). The study protocol was approved by the institutional review boards of Asan Medical Center (IRB No. 2008-0616), Samsung Medical Center (IRB No. 2009-02-021), Yonsei University (IRB No. 4-2008-0588), and CHA Medical Center (IRB No. 2010-010). Informed consent was confirmed by each IRB and obtained from the parents of each infant.

 Prenatal exposure and maternal atopy

Standardized questionnaires were administered during pregnancy (at week 26) and included information on demographic data, social economic status, family history of allergic disease, and history of home renovation. Questions about home renovation were as follows: "Have you ever renovated your home where you are resident?", "If you answer yes, when did you renovate it? (describe the renovation date as a year and a month.)"

Maternal atopy was assessed by a skin prick test (SPT) within 6 months after birth. SPT was performed on the backs of the mothers using standard methods. Commercial extracts of the following common allergens were used: mites (D. pteronyssinus and D. farinae), molds (Alternaria and Aspergillus), pollens (grasses, trees I and II, ragweed, mugwort, oak, and elder), animal dander (dog and cat), and cockroach. Histamine and isotonic saline were used as positive and negative controls, respectively. A positive SPT was defined by a mean wheal diameter of ≥3 mm and at least as large as that of the positive control. Atopy was defined as the presence of at least 1 positive SPT result.

 Cord blood IgE

The methods for measuring CB IgE levels have been described in detail elsewhere.19 Briefly, CB samples were collected from the umbilical cord vein, and the total IgE level (cutoff, 0.001 kU/L) was measured by the ImmunoCAP system (ThermoFisher, Uppsala, Sweden).

 Genotyping Analysis

DNA from CB mononuclear cells was isolated using the Gentra Puregene® Blood kit (Qiagen, Germantown, MD, USA) and screened for single nucleotide polymorphisms (SNPs) of IL-13 (rs20541), toll-like receptors 4 (TLR4) (rs1927911), CD14 (rs2569190), N-acetyltransferase 2 (NAT2) (rs4271002), nuclear factor erythroid 2-related factor 2 (NRF2) (rs6726395), and Glutathione-S-transferase P1 (GSTP1) (rs1695) by using the TaqMan assays. Assay ID numbers for SNPs are C_2259921_20, C_11722141_10, C_16043997_10, C_31028511_10, C_155538 _10, and C_3237198_20, respectively (ABI, Foster City, CA, USA). The final polymerase chain reaction (PCR) volume was 5 µL, containing 10 ng of genomic DNA, 2.5 µL of TaqMan Universal PCR Master Mix, and 0.13 µL of 40× assay mix. All PCRs were performed on 384-well plates and using a 384-Well Veriti thermal cycler (ABI). The endpoint fluorescent readings were performed on an ABI PRISM 7900 HT Sequence Detection System (ABI). Duplicate samples and negative controls were included to ensure genotyping accuracy.

 Statistical analysis

Associations between the levels of CB IgE and the general characteristics of the study subjects were assessed by the χ2 test or t test, as appropriate. The effect of prenatal home renovation exposure on CB IgE response was assessed according to the time of prenatal renovation in each atopic or non-atopic mother using analysis of variance by the LSMEANS procedure, adjusted for maternal age at birth, maternal education level, gender of neonates, maternal total serum IgE levels, and birth weight. The interaction of prenatal home renovation exposure and genetic polymorphisms on CB IgE response was investigated in subjects from each atopic or non-atopic mother by the LSMEANS approach. Statistical analyses were conducted with SAS for Windows (version 9.3). A P value of <0.05 was considered statistically significant.

 RESULTS CB IgE levels according to maternal and neonatal general characteristics

The general characteristics of mothers and neonates included in this analysis were not different from those of subjects not included for analysis, except for maternal education, maternal diagnosis of allergic disease, maternal serum total IgE level, and birth weight (Table 1 and Table S1).

The levels of CB IgE according to maternal and neonatal general characteristics are summarized in Table 2. CB IgE levels were higher in mothers who were older than 40 years at birththan in other age groups (P=0.020). Atopic mothers had a higher CB IgE level than non-atopic mothers (P=0.0002). Male neonates had a higher CB IgE level than female neonates (P= 0.036).

 CB IgE levels, prenatal home renovation exposure, and maternal atopic status

Among all subjects, CB IgE levels were not significantly different between the groups with exposure and non-exposure to prenatal home renovation (geometric mean [range of 1SD], 0.31 kU/L [0.23-0.41] and 0.30 kU/L [0.23-0.39], respectively). When subjects were divided according to the period from birth to home renovation (tertiles), the levels of CB IgE were not significantly different among the 3 groups (Table 3).

When all subjects were classified into 2 groups according to maternal atopy, higher levels of CB IgE in the exposure group compared to the non-exposure group were only seen in neonates with atopic mothers (0.74 kU/L [0.50-1.09] and 0.46 kU/L [0.32-0.65], respectively, P=0.026). However, no such difference between the exposure and non-exposure groups was noted in neonates with non-atopic mothers. In terms of the renovation timing, the levels of CB IgE were significantly higher in atopic mothers in the exposure group in the first and second tertiles compared to the non-exposure group, while no difference was seen among subjects classified into the third tertile (first tertile 0.76 [0.49-1.19], P=0.038, second tertile 0.96 [0.62-1.49]), P=0.039, and third tertile 0.41 [0.24-0.68]). However, there was no significant difference in CB IgE levels between the exposure and non-exposure groups in any of the 3 tertiles when considering only non-atopic mothers.

When the levels of maternal IgE were compared between the non-exposure group and each tertile exposure group, no significant differences were seen in atopic or non-atopic mothers (Table S2).

 Interaction of prenatal home renovation exposure and neonatal genes on CB IgE response

We chose SNPs for IL-13 rs20541, TLR4 rs1927911, CD14 rs2569190, NAT2 rs4271002, NRF2 rs6726395, and GSTP1 rs1695 as candidate genes based on the results of our previous studies162021 to evaluate the interaction between prenatal exposure to home renovation and neonatal genes on CB IgE response. No SNP interacted with renovation exposure in any subjects. When the subjects were classified into 2 groups according to maternal atopy, SNPs for polymorphisms of NRF2 and GSTP1 interacted with renovation in subjects from atopic mothers, but did not have any interaction with renovation in subjects from non-atopic mothers (Table 4). There was no interaction between SNPs for IL-13, TLR4, or CD14 and renovation exposure in subjects from either atopic or non-atopic mothers (Table S3).

 DISCUSSION

Prenatal exposure to home renovation increased the risk for CB IgE response only in subjects from atopic mothers. Exposure to renovation from 31 months before birth onward increased the risk of elevated CB IgE levels, while that before 31 months had no effect. Furthermore, prenatal home renovation exposure increased the risk of CB IgE response interacting with polymorphisms of reactive oxygen species genes only in subjects from atopic mothers.

Surprisingly, the effect of home renovation exposure on IgE response was prominent in the offspring from atopic mothers exposed to home renovation before fertilization, indicating that home renovation exposure can have an indirect effect on the fetus. Furthermore, these findings suggest that maternal exposure to home renovation may have important effects on CB immune response. Recently, maternal exposure to air pollution, including PM10 and benzene, 3 months before pregnancy as well as during pregnancy was reported to alter the percentage of CB Treg cells.22

Although IgE is not thought to cross the placenta, meaning that CB IgE is presumed to originate from fetal production, a recent study showed that increased CB IgE levels may be caused by maternofetal transfer, suggesting that measurement of IgA levels could be indicative of falsely elevated IgE levels in CB.23 In this study, CB IgE levels may have been contaminated by maternal IgE because maternal IgE levels were significantly correlated with CB IgE levels (r=0.328, P<0.0001, Fig. S1). However, we analyzed the association between prenatal exposure to home renovation and CB IgE levels after adjusting for maternal IgE levels. In addition, the levels of maternal IgE at birth did not differ according to exposure or time to renovation irrespective of maternal atopic status (Table S1). Although CB IgE level has not shown good sensitivity for predicting the development of allergic diseases during childhood,24 several studies found that elevated CB IgE levels are associated with aeroallergen sensitization and development of allergic diseases in children, particularly in those with a family history of atopy.2526

Which environmental factors related to home renovation could increase the risk for CB IgE response? Because exposure and time of renovation were recorded based on questionnaires, our results may be confounded by recall bias and unmeasured causes. According to previous studies, VOCs are emitted after renovation.45 Exposure to VOCs during pregnancy has been demonstrated to be associated with CB immune status and eosinophil/basophil progenitors in children diagnosed with cradle cap within the first year of life in LISA and Lifestyle and environmental factors and their Influence on Newborns Allergy risk (LINA) birth cohort studies.327

Our findings showed that maternal atopy modified the effect of prenatal exposure to home renovation on CB IgE response. Maternal atopy may provide the fetus with an intrauterine environment that affects fetal immune development, resulting in allergic predisposition in response to prenatal exposure to home renovation. A previous study reported that neonatal immune response to a TLR2 agonist was modified by maternal atopy.11 In addition, mothers with atopy have a genetic susceptibility to atopy, which can be inherited by the next generation, and may thus reflect a partly genetic susceptibility of neonates for allergy development.

When we evaluated whether renovation exposure, which affects CB IgE response, could interact with candidate genes in the offspring, we found an interaction between prenatal exposure to home renovation and polymorphisms of NRF2 and GSTP1 genes, which are involved in oxidative stress, on CB IgE response, only in offspring from atopic mothers, whereas no interaction was seen with genes for IL-13, TLR4, and CD14. To the best of our knowledge, this is the first study to prospectively show interactions between prenatal exposure to home renovation and neonate genes on CB IgE response. Previous epidemiologic study and in vitro and in vivo studies demonstrated that VOCs, which can be emitted following home renovation, induce T-cell differentiation toward a Th2 phenotype through oxidative stress.32829 Glutathione S-transferase (GST) is a well-known enzyme that acts as an antioxidant, and GSTP1 Ile105 Val polymorphism (rs 1695) lowers GST enzyme activity.30 High diesel exhaust particles increase the risk for wheezing only in children with the GSTP1 rs 1695 G allele.31 Our finding that prenatal exposure to home renovation elevated CB IgE levels in neonates with GSTP1 G or NRF2 A alleles from atopic mothers suggests that prenatal exposure to home renovation may in-duce T-cell differentiation to Th2 through oxidative stress. Interestingly, the finding that gene-environment interactions are only present in the offspring from atopic mothers suggests that the maternal atopic status may modify the interactions between genetic polymorphisms of reactive oxygen specifies and prenatal exposure to home renovation through another interaction with atopy-related genes of neonates inherited from atopic mothers or via the intrauterine environment provided by atopic mothers.

There are some limitations in this study. Only 444 neonates were included in the analysis among 1,002 neonates enrolled, with the remaining neonates lacking information on prenatal exposure to home renovation, maternal atopic status, and/or CB IgE levels. However, we adjusted for confounding variables, including maternal education, maternal serum total IgE levels, and birth weight of neonates between subjects included in the analysis and those who were not. For gene-environment interactions, we chose only 6 SNPs for IL-13, TLR4, CD14, NAT2, NRF2, and GSTP1 as candidate genes. However, these candidate genes were chosen based on the results of our previous studies, which showed that these genes were associated with the development of allergy during childhood in Korea.162021 In addition, for the analysis of gene-environment interactions, we did not subclassify subjects into 3 tertile groups based on the period from renovation to birth due to the small sample size.

In conclusion, maternal atopy modified the effect of prenatal exposure to home renovation on CB IgE response and the interaction between home renovation exposure and genetic polymorphisms of oxidative stress genes in neonates. Our results indicate that the genetically susceptible offspring of atopic mothers may be more vulnerable to the effects of prenatal exposure to home renovation, even before pregnancy, on the development of allergy.

 ACKNOWLEDGMENTS

This research was supported by a fund (2013-E51011-00) from the Research of Korea Centers for Disease Control and Prevention.

There are no financial or other issues that might lead to conflict of interest.

 Diez U Rehwagen M Rolle-Kampczyk U Wetzig H Schulz R Richter M Redecoration of apartments promotes obstructive bronchitis in atopy risk infants--results of the LARS Study Int J Hyg Environ Health 2003 206 173 179 Jaakkola JJ Parise H Kislitsin V Lebedeva NI Spengler JD Asthma, wheezing, and allergies in Russian schoolchildren in relation to new surface materials in the home Am J Public Health 2004 94 560 562 Lehmann I Thoelke A Rehwagen M Rolle-Kampczyk U Schlink U Schulz R The influence of maternal exposure to volatile organic compounds on the cytokine secretion profile of neonatal T cells Environ Toxicol 2002 17 203 210 Reitzig M Mohr S Heinzow B Knöppel H VOC emissions after building renovations: traditional and less common indoor air contaminants, potential sources, and reported health complaints Indoor Air 1998 8 91 102 Brown SK Volatile organic pollutants in new and established buildings in Melbourne, Australia Indoor Air 2002 12 55 63 Hylkema MN Blacquière MJ Intrauterine effects of maternal smoking on sensitization, asthma, and chronic obstructive pulmonary disease Proc Am Thorac Soc 2009 6 660 662 Noakes PS Holt PG Prescott SL Maternal smoking in pregnancy alters neonatal cytokine responses Allergy 2003 58 1053 1058 Roduit C Wohlgensinger J Frei R Bitter S Bieli C Loeliger S Prenatal animal contact and gene expression of innate immunity receptors at birth are associated with atopic dermatitis J Allergy Clin Immunol 2011 127 179 185 185.e1 Tang ML Kemp AS Thorburn J Hill DJ Reduced interferon-gamma secretion in neonates and subsequent atopy Lancet 1994 344 983 985 Smith M Tourigny MR Noakes P Thornton CA Tulic MK Prescott SL Children with egg allergy have evidence of reduced neonatal CD4(+)CD25(+)CD127(lo/-) regulatory T cell function J Allergy Clin Immunol 2008 121 1460 1466 1466.e1-7 Schaub B Campo M He H Perkins D Gillman MW Gold DR Neonatal immune responses to TLR2 stimulation: influence of maternal atopy on Foxp3 and IL-10 expression Respir Res 2006 7 40 Herberth G Hinz D Röder S Schlink U Sack U Diez U Maternal immune status in pregnancy is related to offspring's immune responses and atopy risk Allergy 2011 66 1065 1074 Weiss ST What genes tell us about the pathogenesis of asthma and chronic obstructive pulmonary disease Am J Respir Crit Care Med 2010 181 1170 1173 Lee YL Lee YC Guo YL Associations of glutathione S-transferase P1, M1, and environmental tobacco smoke with wheezing illness in school children Allergy 2007 62 641 647 Bieli C Eder W Frei R Braun-Fahrländer C Klimecki W Waser M A polymorphism in CD14 modifies the effect of farm milk consumption on allergic diseases and CD14 gene expression J Allergy Clin Immunol 2007 120 1308 1315 Kim WK Kwon JW Seo JH Kim HY Yu J Kim BJ Interaction between IL13 genotype and environmental factors in the risk for allergic rhinitis in Korean children J Allergy Clin Immunol 2012 130 421 426.e5 Yang SI Lee E Jung YH Kim HY Seo JH Kwon JW Effect of antibiotic use and mold exposure in infancy on allergic rhinitis in susceptible adolescents Ann Allergy Asthma Immunol 2014 113 160 165.e1 Yang HJ Lee SY Suh DI Shin YH Kim BJ Seo JH The Cohort for Childhood Origin of Asthma and allergic diseases (COCOA) study: design, rationale and methods BMC Pulm Med 2014 14 109 Kim HB Ahn KM Kim KW Shin YH Yu J Seo JH Cord blood cellular proliferative response as a predictive factor for atopic dermatitis at 12 months J Korean Med Sci 2012 27 1320 1326 Kang SH Jung YH Kim HY Seo JH Lee JY Kwon JW Effect of paracetamol use on the modification of the development of asthma by reactive oxygen species genes Ann Allergy Asthma Immunol 2013 110 364 369.e1 Lee SY Kang MJ Kwon JW Park KS Hong SJ Breastfeeding might have protective effects on atopy in children with the CD14C-159T CT/CC genotype Allergy Asthma Immunol Res 2013 5 239 241 Baïz N Slama R Béné MC Charles MA Kolopp-Sarda MN Magnan A Maternal exposure to air pollution before and during pregnancy related to changes in newborn's cord blood lymphocyte subpopulations. The EDEN study cohort BMC Pregnancy Childbirth 2011 11 87 Bønnelykke K Pipper CB Bisgaard H Transfer of maternal IgE can be a common cause of increased IgE levels in cord blood J Allergy Clin Immunol 2010 126 657 663 Edenharter G Bergmann RL Bergmann KE Wahn V Forster J Zepp F Cord blood-IgE as risk factor and predictor for atopic diseases Clin Exp Allergy 1998 28 671 678 Tariq SM Arshad SH Matthews SM Hakim EA Elevated cord serum IgE increases the risk of aeroallergen sensitization without increasing respiratory allergic symptoms in early childhood Clin Exp Allergy 1999 29 1042 1048 Halken S Early sensitisation and development of allergic airway disease - risk factors and predictors Paediatr Respir Rev 2003 4 128 134 Weisse K Lehmann I Heroux D Kohajda T Herberth G Röder S The LINA cohort: indoor chemical exposure, circulating eosinophil/basophil (Eo/B) progenitors and early life skin manifestations Clin Exp Allergy 2012 42 1337 1346 Lehmann I Röder-Stolinski C Nieber K Fischäder G In vitro models for the assessment of inflammatory and immuno-modulatory effects of the volatile organic compound chlorobenzene Exp Toxicol Pathol 2008 60 185 193 Bönisch U Böhme A Kohajda T Mögel I Schütze N von Bergen M Volatile organic compounds enhance allergic airway inflammation in an experimental mouse model PLoS One 2012 7 e39817 Watson MA Stewart RK Smith GB Massey TE Bell DA Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution Carcinogenesis 1998 19 275 280 Schroer KT Biagini Myers JM Ryan PH LeMasters GK Bernstein DI Villareal M Associations between multiple environmental exposures and Glutathione S-Transferase P1 on persistent wheezing in a birth cohort J Pediatr 2009 154 401 408 408.e1 Supplementary Materials Table S1

General characteristics of mothers and neonates

 Table S2

Association between maternal IgE levels and prenatal exposure to home renovation

 Table S3

Interaction of prenatal exposure to home renovation and neonate genes for IL-13, TLR4 and CD14 on cord blood IgE response

 Figure S1

Correlation of cord blood IgE and materal serum total IgE levels (n=428, r=0.328, P<0.0001).

 Enrollment and outcomes. General characteristics of mothers and neonates
Variables Included (n=444) Not included (n=558) P
mean±SD or n (%) mean±SD or n (%)
Maternal characteristics
 Age at birth (year) 32.1±3.4 32.5±3.3 0.0881
 BMI (kg/m2) 20.6±2.6 20.7±2.6 0.5396
 Maternal education
  ≤High school graduation 32/443 (7.2) 34/508 (6.7) 0.0157
  College or university graduation 288/443 (65.0) 372/508 (73.2)
  ≥Graduate school graduation 123/443 (27.8) 102/508 (20.1)
 Mode of delivery
  Vaginal 286/407 (70.3) 341/502 (67.9) 0.4478
  Caesarean section 121/407 (29.7) 161/502 (32.1)
 Parity
  No 99/358 (27.7) 120/456 (26.3) 0.6692
  Yes 259/358 (72.4) 336/456 (73.7)
 Renovation
  No 333/444 (75.0) 322/442 (72.9) 0.4662
  Yes 111/444 (25.0) 120/442 (27.2)
 Maternal diagnosis of allergic diseases*
  No 328/443 (74.0) 299/450 (66.4) 0.0131
  Yes 115/443 (26.0) 151/450 (33.6)
 Paternal diagnosis of allergic diseases*
  No 304/412 (73.8) 303/411 (73.7) 0.9834
  Yes 108/412 (26.2) 108/411 (26.3)
 Atopy
  No 276/444 (62.2) 146/245 (59.6) 0.5074
  Yes 168/444 (37.8) 99/245 (40.4)
 Serum total IgE (kIU/mL)** 428 41.2 (10.6-159.9) 427 49.6 (13.1-188.1) 0.0432
Infant characteristics
 Gender (male, %) 241/444 (54.3) 287/556 (51.6) 0.4024
 Birth weight 444 3.3±0.3 556 3.2±0.4 0.0296
 Season of birth
  Spring (March to May) 99/437 (22.7) 122/536 (22.8) 0.4378
  Summer (June to August) 103/437 (19.7) 120/536 (22.4)
  Autumn (September to November) 133/437 (30.4) 146/536 (27.2)
  Winter (December to February) 102/437 (23.3) 148/536 (27.6)
 Cord blood IgE (kIU/mL)** 444 0.27 (0.07-0.94) 286 0.27 (0.08-0.88) 0.8090

*Allergic diseases include asthma, allergic rhinitis, and atopic dermatitis; **Data are expressed as geometric mean (range of 1SD).

 Cord blood IgE according to maternal and neonatal general characteristics
Variables Cord blood IgE (kIU/mL)
n (%) Geometric mean (range of 1SD) P
Maternal characteristics
 Age at birth (year)
  20-29 109/444 (24.5) 0.32 (0.10-0.98) 0.0196
  30-39 324/444 (72.9) 0.25 (0.07-0.86)
  40+ 11/444 (2.4) 0.59 (0.07-4.58)
 Maternal education
  ≤High school graduation 32/443 (7.2) 0.28 (0.06-1.21) 0.8328
  College or university graduation 288/443 (65.0) 0.27 (0.08-0.91)
  ≥Graduate school graduation 123/443 (27.7) 0.25 (0.06-0.96)
 Parity (yes)
  No 99/358 (27.7) 0.27 (0.09-0.75) 0.6133
  Yes 259/358 (72.3) 0.25 (0.07-0.86)
 History of home renovation
  No 333/444 (75.0) 0.26 (0.08-0.84) 0.4311
  Yes 111/444 (25.0) 0.29 (0.06-1.28)
 Parental diagnosis of allergic diseases*
  No 221/419 (52.7) 0.25 (0.07-0.89) 0.1478
  Yes 198/419 (47.3) 0.29 (0.08-1.00)
 Maternal diagnosis of allergic diseases*
  No 328/443 (74.0) 0.25 (0.07-0.91) 0.0981
  Yes 115/443 (26.0) 0.32 (0.10-1.01)
 Paternal diagnosis of allergic diseases*
  No 304/412 (73.8) 0.27 (0.07-0.96) 0.7547
  Yes 108/412 (26.2) 0.26 (0.07-0.89)
 Atopy
  No 276/444 (62.2) 0.23 (0.07-0.75) 0.0002
  Yes 168/444 (37.8) 0.35 (0.09-1.30)
Infant characteristics
 Gender
  Male 241/444 (54.3) 0.30 (0.08-1.08) 0.0359
  Female 203/444 (45.7) 0.23 (0.07-0.78)
 Mode of delivery
  Vaginal 286/407 (70.3) 0.27 (0.08-0.86) 0.0956
  Caesarean section 121/407 (29.7) 0.22 (0.06-0.71)
 Birth weight (≤2.5 kg)
  No 435/443 (98.2) 0.27 (0.07-0.95) 0.3358
  Yes 8/443 (1.8) 0.17 (0.08-0.38)
 Season of birth (%)
  Spring (March to May) 99/437 (22.7) 0.25 (0.08-0.81) 0.5576
  Summer (June to August) 103/437 (23.6) 0.26 (0.06-1.09)
  Autumn (September to November) 133/437 (30.4) 0.30 (0.10-0.92)
  Winter (December to February) 102/437 (23.3) 0.25 (0.06-0.93)

*Allergic diseases include asthma, allergic rhinitis, and atopic dermatitis.

 Cord blood IgE according to the time of home renovation exposure and maternal atopic status
Variables Cord blood IgE (kIU/mL) n, geometric mean (range of 1SD)
Total Non-atopic mothers Atopic mothers
No renovation 333 0.30 (0.23-0.39) 212 0.27 (0.17-0.43) 121 0.46 (0.32-0.65)
Renovation Total 111 0.31 (0.23-0.41) 64 0.20 (0.13-0.33) 47 0.74 (0.50-1.09)*
1st tertile 34 0.35 (0.25-0.48) 17 0.23 (0.14-0.38) 17 0.76 (0.49-1.19)**
2nd tertile 34 0.37 (0.26-0.50) 18 0.19 (0.11-0.32) 16 0.96 (0.62-1.49)†
3rd tertile 32 0.25 (0.18-0.35) 22 0.22 (0.13-0.37) 10 0.41 (0.24-0.68)

First, second, and third tertiles indicated home renovation within 13 months before birth, between 14 months and 31 months before birth, and more than 31 months before birth, respectively.

*P=0.0262, compared to those not exposed to prenatal home renovation, and adjusted for maternal age at birth, maternal education level, gender of child, maternal total IgE level, and birth weight; **P=0.0375; †P=0.0393, compared to those not exposed to prenatal home renovation, and adjusted for multiple comparisons by Tukey-Kramer.

 Interaction of prenatal exposure to home renovation and neonate genes for reactive oxygen species on cord blood IgE response
Gene Genotype Renovation Cord blood IgE (kIU/mL) n, geometric mean (range of 1SD)
Total Non-atopic mothers Atopic mothers
NAT2 rs4271002 GG No 177 0.33 (0.28-0.38) 109 0.26 (0.22-0.32) 68 0.45 (0.35-0.57)
GG Yes 61 0.31 (0.26-0.38) 33 0.15 (0.12-0.20) 28 0.71 (0.53-0.96)
GC+CC No 141 0.35 (0.30-0.41) 95 0.27 (0.22-0.33) 46 0.49 (0.38-0.63)
GC+CC Yes 41 0.46 (0.37-0.58) 25 0.31 (0.23-0.41) 16 0.79 (0.56-1.13)
Nrf2 rs6726395 GG No 125 0.32 (0.27-0.38) 74 0.28 (0.23-0.35) 51 0.37 (0.29-0.47)
GG Yes 45 0.34 (0.27-0.43) 29 0.27 (0.20-0.35) 16 0.45 (0.31-0.64)
GA+AA No 200 0.34 (0.29-0.40) 134 0.26 (0.22-0.32) 66 0.52 (0.41-0.66)
GA+AA Yes 56 0.39 (0.32-0.48) 29 0.17 (0.13-0.22) 27 1.00 (0.76-1.31)*
GSTP1 rs1695 AA No 219 0.31 (0.27-0.36) 149 0.25 (0.20-0.30) 70 0.47 (0.37-0.60)
AA Yes 58 0.33 (0.27-0.40) 34 0.21 (0.16-0.27) 24 0.59 (0.44-0.80)
AG+GG No 106 0.39 (0.33-0.46) 59 0.32 (0.25-0.40) 47 0.49 (0.38-0.62)
AG+GG Yes 45 0.42 (0.34-0.53) 24 0.22 (0.16-0.29) 21 1.00 (0.72-1.39)**

*P=0.0023, compared to those not exposed to prenatal home renovation with the GG genotype; **P=0.0458, compared to those not exposed to prenatal home renovation with the AA genotype. All P values were adjusted for maternal age at birth, maternal education level, gender of child, maternal total IgE levels, and birth weight, and adjusted for multiple comparisons by Tukey-Kramer.