To the Editor:
We previously reported that inner-city childhood asthma was independently associated with measures of early childhood exposure to bisphenol A (BPA)1 and prenatal, but not childhood, exposures to di-n-butyl phthalate and butylbenzyl phthalate (BBzP). 2 Here, we evaluate whether these 2 classes of endocrine-disrupting chemicals interact to increase the risk of asthma.

We evaluated 292 inner-city women and their children aged 5 to 11 years from the Columbia Center for Children's Environmental Health birth cohort of pregnant women who delivered between 1998 and 2006. Enrollment, exclusion criteria, and a description of the cohort have been reported previously.3 Subjects were selected for the present study on the basis of the availability of (1) measurements of phthalates in spot urine collected from the mother during pregnancy (33.9 ± 3.1 weeks' gestation) and BPA in child urine at ages 3 (n = 237), 5 (259), and/or 7 (n = 161) years; (2) data on child asthma and wheeze-related outcomes; and (3) availability of model covariates. Demographic characteristics of Columbia Center for Children's Environmental Health subjects are provided in Table E1 in this article's Online Repository at www.jacionline.org. All participants gave written informed consent

Calafat, Antonia M.

Donohue, Kathleen M.

Hoepner, Lori A.

Just, Allan C.

Miller, Rachel L.

Perera, Frederica P.

Perzanowski, Matthew S.

Rundle, Andrew G.

Whyatt, Robin M.

Journal of Allergy and Clinical Immunology

English

PubMed

Robin M. Whyatt

Andrew G. Rundle

Matthew S. Perzanowski

Allan C. Just

Kathleen M. Donohue

Antonia M. Calafat

Lori Hoepner

Frederica P. Perera

Rachel L. Miller

Crossref

Prenatal phthalate and early childhood bisphenol A exposures increase asthma risk in inner-city children

Columbia University Academic Commons

Letter to the EditorPrenatal phthalate and early childhood bisphe-nol A exposures increase asthma risk in inner-city childrenTo the Editor:We previously reported that inner-city childhood asthma wasindependently associated with measures of early childhoodexposure to bisphenol A (BPA)1 and prenatal, but not childhood,exposures to di-n-butyl phthalate and butylbenzyl phthalate(BBzP).2 Here, we evaluate whether these 2 classes of endocrine-disrupting chemicals interact to increase the risk of asthma.We evaluated 292 inner-city women and their children aged 5to 11 years from the Columbia Center for Children’s Environ-mental Health birth cohort of pregnant women who deliveredbetween 1998 and 2006. Enrollment, exclusion criteria, and adescription of the cohort have been reported previously.3 Subjectswere selected for the present study on the basis of the availabilityof (1) measurements of phthalates in spot urine collected from themother during pregnancy (33.96 3.1 weeks’ gestation) and BPAin child urine at ages 3 (n 5 237), 5 (259), and/or 7 (n 5 161)years; (2) data on child asthma and wheeze-related outcomes;and (3) availability of model covariates. Demographic character-istics of Columbia Center for Children’s Environmental Healthsubjects are provided in Table E1 in this article’s OnlineRepository at www.jacionline.org. All participants gave writteninformed consent.Samples were analyzed at the Centers for Disease Control andPrevention for concentrations of monobenzyl phthalate (MBzP,metabolite of BBzP), mono-n-butyl phthalate (MnBP, metaboliteof di-n-butyl phthalate), and BPA.4,5 Consistent with our previousapproach,1 mean urinary postnatal BPA concentrations werecalculated across samples of children aged 3 to 7 years, exceptfor a small subset (n 5 10) missing respiratory questionnairedata after age 6 years for whom the mean BPA was calculatedfor ages 3 to 5 years. Specific gravity was measured using a hand-held refractometer (Atago PAL 10-S, Bellevue, Wash) to controlfor urinary dilution.Repeat questionnaires, including the International Study ofAsthma and Allergies in Childhood, were administered to theparent at child ages 5, 6 7, 9, and 11 years (n 5 1202questionnaires, average 4.1 per child). Children with report inthe last 12 months of any of the following asthma-relatedsymptoms on 1 or more questionnaire were referred to an allergistor a pulmonologist for asthma diagnosis using standardizedcriteria: wheeze or whistling in the chest, a cough that lastedmore than a week, other breathing problems, and/or use of asthmarescue or controller medication.1 Children without any of theseasthma-related symptoms on the repeat questionnaires were clas-sified as nonasthmatic. Children were evaluated for persistentwheeze (>_ 3 reports of wheeze in the last 12 months on >_ 3 Inter-national Study of Asthma and Allergies in Childhood question-naires), exercise-induced wheeze (>_ 1 report in the last 12months of the child’s chest sounding wheezy during or after exer-cise), and report of emergency care visits in the last 12months to adoctor, clinic, or emergency room for asthma, wheeze, or otherbreathing problems on 1 or more repeat questionnaire.Variables assessed as potential confounders have beendescribed1,2 and were retained in the models if they weresignificant (P < .05) and/or their inclusion resulted in more than10% change in the predictor variables (see this article’s OnlineRepository at www.jacionline.org). Before statistical analyses,the 1 prenatal MBzP and 15 postnatal BPA concentrations belowthe limit of detection (0.22 mg/L [MBzP] and 0.4 mg/L [BPA])were assigned a value of half the limit of detection. Metaboliteconcentrations were right-skewed and transformed using the nat-ural logarithm. In analyses in which metabolites were catego-rized, we adjusted concentrations by specific gravity beforeranking as described previously.6 Consistent with our previousapproach,2 we used a modified Poisson regression to generaterelative risk (RR), and variance estimates for dichotomized out-comes (ie, child asthma) using the methods of Zou.7 Analyseswere conducted using SPSS 21 (IBM, Armonk, NY). Resultswere considered significant at P < .05.A total of 168 of 292 (57.5%) children had a history of asthma-related symptoms on repeat questionnaires. Of these, 142 wereevaluated by a study allergist or pulmonologist; 86 werediagnosed with current asthma and 56 with asthma-relatedsymptoms but without current asthma. The remaining 124children had no history of asthma-like symptoms and wereclassified as nonasthmatic. A total of 44 of 217 (20%) childrenhad persistent wheeze, 62 of 292 (21%) had exercise-inducedwheeze, and 98 of 292 (34%) had emergency care visits forasthma or other respiratory problems.A significant association between child (ln)BPA concentrationsand respiratory outcomes was observed only among thosechildren whose mothers had prenatal MBzP concentrations abovebut not below the median. For children with prenatal MBzPconcentrations above the median, the RR per log unit increase inchild BPA concentrations was 1.46 (95% CI, 1.14-1.87) for childcurrent asthma; 1.89 (95% CI, 1.29-2.78) for persistent wheeze;1.67 (95% CI, 1.17-2.40) for exercise-induced wheeze; and 1.47(95% CI, 1.13-1.89) for emergency care visits. The multiplicativeinteraction between child (ln)BPA and higher versus lowerprenatal MBzP was significant for asthma (P 5 .001) but notfor other outcomes (Fig 1).Table I presents associations between asthma and wheeze-related outcomes among children with both prenatal MBzP andchild BPA concentrataions above the median compared with chil-dren with one or bothmeasurements below the median. Therewasa highly significant increase in RR for all these outcomes amongchildren with both prenatal MBzP and child BPA above the me-dian. In contrast, there was no increase in RR if only one of theendocrine-disrupting chemicals but not both were above the me-dian (P values ranged from 0.12 to 0.94, data not shown). Therewere no significant interactions between (1) prenatal BPA andeither prenatal MBzP or MnBP concentrations or (2) prenatalMnBP and child BPA concentations on the risk of child asthma,frequent wheeze, exercised-induced wheeze, or emergency carevisits (data not shown).Using 2 analytic approaches, we found a novel and significantassociation between child BPA and risk of child asthma and otherwheeze-related symptoms among inner-city children whosemothers had higher but not lower prenatal measures of exposuresto BBzP. These findings suggest the possibility of a ‘‘multihit’’model such that higher prenatal BBzP exposures may render thechild more susceptible to adverse effects of BPA on the airways1FIG 1. Association between child (ln)BPA concentrations by strata of higher versus lower prenatal MBzP(above and below median) and child asthma (A), exercise-induced wheeze (B), persistent wheeze (C), andemergency care vists (D). Models controlled for maternal asthma, household smoke exposure, maternalprenatal BPA, maternal prenatal specific gravity, maternal prenatal demoralization, child age at asthmadiagnosis or classification as nonasthmatic (Fig 1, A), and child sex (Fig 1, B-D). Mutiplicative interactionsbetween postnatal (ln)BPA concentrations and higher versus lower prenatal MBzP were also evaluatedfor each outcome (Fig 1, A-D). *P < .01 and **P <_ .001.TABLE I. Asthma-related outcomes among children with bothmaternal prenatal MBzP and child BPA above the median versusone or both below the medianRelative risk (95% CI)Childhood asthma(n 5 210)Persistentwheeze(n 5 217)Exercise-inducedwheeze (n 5 292)Emergency carevisits (n 5 292)1.67 (1.25-2.23)* 2.02 (1.22-3.35) 1.76 (1.13-2.72) 1.71 (1.25-2.34)*Models controlled for maternal asthma, household smoke exposure, prenatal BPA,maternal prenatal specific gravity, maternal prenatal demoralization, child age (at thetime of asthma diagnosis included in asthma model only), and child sex (in models ofother asthma-related outcomes).*P <_ .001.P <_ .01.J ALLERGY CLIN IMMUNOLnnn 20142 LETTER TO THE EDITORduring early childhood. Although potential mechanisms for thishypothesis need to be evaluated and results require replication,findings are of concern given that exposures to these compoundsare ubiquitous in the United States and other countries.Robin M. Whyatt, DrPHaAndrew G. Rundle, DrPHa,bMatthew S. Perzanowski, PhDaAllan C. Just, PhDcKathleen M. Donohue, MD, MSa,dAntonia M. Calafat, PhDeLori Hoepner, MPHaFrederica P. Perera, DrPH, PhDaRachel L. Miller, MDa,d,fFrom athe Department of Environmental Health Sciences, Columbia Center for Chil-dren’s Environmental Health, Mailman School of Public Health, ColumbiaUniversity, New York, NY; bthe Department of Epidemiology, Mailman School ofPublic Health, Columbia University, New York, NY; cthe Department of Environ-mental Health, Harvard School of Public Health, Boston, Mass; dthe Division of Pul-monary, Allergy, and Critical Care, Department of Medicine, Columbia UniversityCollege of Physicians and Surgeons, New York, NY; ethe National Center for Envi-ronmental Health, Centers for Disease Control and Prevention, Atlanta, Ga; andfthe Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics,Columbia University, College of Physician and Surgeons, New York, NY. E-mail:rmw5@columbia.edu.This study was supported by the National Institute of Environmental HealthSciences (NIEHS) (grant nos. R01ES014393, RC2ES018784, R01ES13163, andR01ES08977 and NIEHS/EPA P01 ES09600/RD 83214101 and P30ES009089);the John and Wendy Neu Family Foundation; the Blanchette Hooker RockefellerFund; the New York Community Trust; and the Millstream Fund. The findings ex-pressed in this article are the opinions of the authors and do not necessarily reflectthe official position of the Centers for Disease Control and Prevention.Disclosure of potential conflict of interest: This study was funded by the National Insti-tutes of Health (NIH) (R01ES014393, RC2ES018784, R01ES13163, R01ES08977,P01 ES09600, and P30ES009089) and the Environmental Protection Agency (RD83214101). L. Hoepner’s institution has received grants from the National Instituteof Environmental Health Sciences (NIEHS) (R01ES014393, RC2ES018784,R01ES13163, R01ES08977, P01ES09600, R01ES013543, and R01ES014400) andthe Environmental Protection Agency (RD83450901); she has received consultancyfees from Transcendent International. R. L. Miller and her institution have receivedfunding from the National Institute of Environmental Health Sciences(R01ES014393, RC2ES018784, R01ES13163, R01ES08977, and P01ES09600) andthe Environmental Protection Agency (RD83214101). M. S. Perzanowski hasreceived or has grants pending from the National Institute of Environmental HealthSciences (R014400), the Centers for Disease Control and Prevention (CDC-TP-13001), and the Department of Housing and Urban Development (NYHHU003,NYHHU0021); and has received support for travel and other meeting-related ex-penses from ThermoFisher. R. M. Whyatt has received funding from National Insti-tute of Environmental Health Sciences (R01ES021482, R01ES013543,R01ES014393, RC2ES018784) and the Environmental Protection Agency(RD83214101). K. M. Donohue has received support from the National Institute ofEnvironmental Health Sciences (RC2ES0187894), the National Heart, Lung andBlood Institute (HHSN268200625233C, N01HC95161), and the ALPHA Foundation(CU110766). F. P. Perera and her institution have received funding from the NationalJ ALLERGY CLIN IMMUNOLVOLUME nnn, NUMBER nnLETTER TO THE EDITOR 3Institute of Environmental Health Sciences (P01ES09600, P30ES009089), the Envi-ronmental Protection Agency (RD83214101), the John and Wendy Neu Family Foun-dation, the Blanchette Hooker Rockefeller Fund, the New York Community Trust,and the Millstream Fund. A. Just received support the National Institute of Environ-mental Health (R01ES014393, T32ES007069, K99ES023450). A. G. Rundle is amember of the board of EHE International. The rest of the authors declare thatthey have no relevant conflicts of interest.REFERENCES1. Donohue KM, Miller RL, Perzanowski MS, Just AC, Hoepner LA, Arunajadai S,et al. Prenatal and postnatal bisphenol A exposure and asthma development amonginner-city children. J Allergy Clin Immunol 2013;131:736-42.2. Whyatt RM, Perzanowski MS, Just AC, Rundle AG, Donohue KM, Calafat AM,et al. Asthma in inner-city children at 5-11 years of age and prenatal exposureto phthalates: the Columbia Center for Children’s Environmental Health. EnvironHealth Perspect. Sept 17, 2014 [E-pub ahead of print].3. Perera F, Viswanathan S, Whyatt R, Tang D, Miller RL, Rauh V. Children’s envi-ronmental health research–highlights from the Columbia Center for Children’sEnvironmental Health. Ann N Y Acad Sci 2006;1076:15-28.4. Kato K, Silva MJ, Needham LL, Calafat AM. Determination of 16 phthalate metab-olites in urine using automated sample preparation and on-line preconcentration/high-performance liquid chromatography/tandem mass spectrometry. Anal Chem2005;77:2985-91.5. Ye X, Kuklenyik Z, Needham LL, Calafat AM. Automated on-linecolumn-switching HPLC-MS/MS method with peak focusing for the deter-mination of nine environmental phenols in urine. Anal Chem 2005;77:5407-13.6. Hauser R, Meeker JD, Park S, Silva MJ, Calafat AM. Temporal variability ofurinary phthalate metabolite levels in men of reproductive age. Environ HealthPerspect 2004;112:1734-40.7. Zou GA. modified Poisson regression approach to prospective studies with binarydata. Am J Epidemiol 2004;159:702-6.http://dx.doi.org/10.1016/j.jaci.2014.07.027METHODSEighteen- to 35-year-old women who self-identified as African Americanor Dominican were enrolled through prenatal clinics at Harlem Hospital andNew York Presbyterian Hospital. Women were excluded if they reportedactive smoking or use of other tobacco products or illicit drugs; had diabetes,hypertension, or knownHIV; had their first prenatal visit after the 20thweek ofgestation; or had resided in the study area for less than 1 year beforepregnancy. Family history of asthma was not a required inclusion criterion.Study subjects’ characteristics are presented in Table E1. The 292 subjects didnot differ significantly from the remaining 435 subjects in the Columbia Cen-ter for Children’s Environmental Health cohort by race/ethnicity, maternalprenatal marital status and education level, household income, prenatal andpostnatal tobacco smoke, or maternal history of asthma (all P values >_ .16).All participants provided written informed consent, children aged 7 yearsand older provided assent, and the institutional review boards at the ColumbiaUniversityMedical Center and the Centers for Disease Control and Preventionapproved the study.Variables assessed as potential confounders were selected on the basis ofour previous analyses of prenatal MBzP and postnatal BPA as describedearlierE1,E2 and were retained in the models if they were significant (P < .05)and/or their inclusion in the model resulted in more than 10% change in pre-dictor variables. The variables assessed as potential confounders includedmaternal age, maternal education, maternal history of asthma, race/ethnicity,household smoke exposure (from others during pregnancy because the cohortwas restricted to nonsmoking pregnant women at enrollment and from themother and/or others during childhood because some mothers began smokingafter delivery), number of previous live births, breast-feeding history, maternalprenatal BPA concentrations, child age at asthma diagnosis or classification asnonasthmatic, child sex, and child bodymass index. Maternal prenatal demor-alization (measured by using a 27-item Psychiatric Epidemiology ResearchInstrument-Demoralization ScaleE3) was also assessed because it has beenpreviously associated with wheeze among children in the cohort.E4 Prenataland postnatal urinary specific gravity concentrations were included in modelsto control for urinary dilution.We did not collect a validated history of all childviral illnesses from cohort subjects by questionnaire because we did notbelieve that we could do so reliably at the onset of the study. Therefore, wewere not able to determine whether child viral illnesses were potential con-founders. Child postnatal MBzP and MnBP concentrations were notcontrolled because they were not associated with any of the outcomes (all Pvalues >_ .4) and inclusion did not alter results over those presented here.The cohort was predominantly full-term (97% >_ 37 weeks’ gestation) andneither gestational age nor birth weight was a confounder.REFERENCESE1. Donohue KM, Miller RL, Perzanowski MS, Just AC, Hoepner LA, Arunajadai S,et al. Prenatal and postnatal bisphenol A exposure and asthma developmentamong inner-city children. J Allergy Clin Immunol 2013;131:736-42.E2. Whyatt RM, Perzanowski MS, Just AC, Rundle AG, Donohue KM, Calafat AM,et al. Asthma in inner-city children at 5-11 years of age and prenatal exposure tophthalates: the Columbia Center for Children’s Environmental Health. EnvironHealth Perspect Sept 17, 2014 [E-pub ahead of print].E3. Dohrenwend BS, Krasnoff L, Askenasy AR, Dohrenwend BP. Exemplification ofa method for scaling life events: the Peri Life Events Scale. J Health Soc Behav1978;19:205-29.E4. Reyes M, Perzanowski MS, Whyatt RM, Kelvin EA, Rundle AG, Diaz DM, et al.Relationship between maternal demoralization, wheeze, and immunoglobulin Eamong inner-city children. Ann Allergy Asthma Immunol 2011;107:42-9.e41.J ALLERGY CLIN IMMUNOLnnn 20143.e1 LETTER TO THE EDITORTABLE E1. Maternal and child characteristics (n 5 292)Maternal age (y), mean 6 SD 25.3 6 4.8Maternal asthma, n (%) 71 (24.3)Maternal ethnicity, n (%)Dominican 189 (64.7)African American 103 (35.3)Maternal education, n (%)<High school 106 (36.3)High school or general educational development 106 (36.3)>High school 80 (27.4)Maternal marital status, n (%)Never married 194 (66.4)Married* 84 (28.8)Separated, widowed, divorced 14 (4.8)Child age and sexChild age (y), mean 6 SD 8.2 6 1.9Child sex (female), n (%) 157 (53.8)Household tobacco smoke exposureOthers in the home prenatally 93 (31.8)Maternal and others early to mid-childhood 129 (44.2)Maternal MBzP (ng/mL), geometric mean (95% CI) 13.2 (11.4-15.5)Child BPA (ng/mL),§ geometric mean (95% CI) 3.9 (3.5-4.3)*Includes women living with a partner for more than 7 years.Age at asthma diagnosis for those diagnosed with current asthma and at the lastnegative screen for asthmalike symptoms for those classified as nonasthmatic.The study excluded active smoking women during pregnancy.§Mean concentrations in samples of children aged 3 to 7 years, except children (n5 10)missing respiratory questionnaire data after age 6 years for whom the mean BPAwascalculated for ages 3 to 5 years.J ALLERGY CLIN IMMUNOLVOLUME nnn, NUMBER nnLETTER TO THE EDITOR 3.e2

Prenatal phthalate and early childhood bisphenol A exposures increase asthma risk in inner-city children

http://dx.doi.org/10.1016/j.jaci.2014.07.027

Prenatal phthalate and early childhood bisphenol A exposures increase asthma risk in inner-city children

Abstract

Similar works

Full text

Available Versions

Crossref

Columbia University Academic Commons