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A cohort study of developmental polychlorinated biphenyl (PCB) exposure in relation to post-vaccination antibody response at 6-months of age

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A cohort study of developmental polychlorinated biphenyl (PCB) exposure in relation to post-vaccination antibody response at 6-months of age
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  A cohort study of developmental polychlorinated biphenyl (PCB) exposurein relation to post-vaccination antibody response at 6-months of age Todd A. Jusko a,b, n , Anneclaire J. De Roos b,c , Stephen M. Schwartz b,c , B. Paige Lawrence d ,Lubica Palkovicova e , Tomas Nemessanyi f  , Beata Drobna g , Anna Fabisikova g , Anton Kocan g ,Dean Sonneborn h , Eva Jahnova f  , Terrance J. Kavanagh i , Tomas Trnovec g , Irva Hertz-Picciotto h a Epidemiology Branch, National Institute of Environmental Health Sciences, PO Box 12233, MD A3-05, 111 T.W. Alexander Dr, Rall Bldg 101, Rm A361,Research Triangle Park, NC 27709-2233, USA b Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA c Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA d Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA e Department of Environmental Medicine, Slovak Medical University, Bratislava, Slovak Republic  f  Department of Immunology and Immunotoxicology, Slovak Medical University, Bratislava, Slovak Republic  g Department of Toxic Organic Pollutants, Slovak Medical University, Bratislava, Slovak Republic  h Department of Public Health Sciences, University of California, Davis, CA, USA i Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA a r t i c l e i n f o  Article history: Received 20 October 2009Received in revised form4 February 2010Accepted 22 February 2010 Keywords: B-cellDirected acyclic graphSlovakiaRomaEpidemiologyBiomarkerInfant a b s t r a c t Background:  Extensive experimental data in animals indicate that exposure to polychlorinatedbiphenyls (PCBs) during pregnancy leads to changes in offspring immune function during the postnatalperiod. Whether developmental PCB exposure influences immunologic development in humans hasreceived little study. Methods:  The study population was 384 mother–infant pairs recruited from two districts of easternSlovakia for whom prospectively collected maternal, cord, and 6-month infant blood specimens wereavailable. Several PCB congeners were measured in maternal, cord, and 6-month infant sera by high-resolution gas chromatography with electron capture detection. Concentrations of IgG-specific anti-haemophilus influenzae type b, tetanus toxoid, and diphtheria toxoid were assayed in 6-month infantsera using ELISA methods. Multiple linear regression was used to estimate the relation betweenmaternal, cord, and 6-month infant PCB concentrations and the antibody concentrations evaluated at6-months of age. Results:  Overall, there was little evidence of an association between infant antibody concentrations andPCB measures during the pre- and early postnatal period. In addition, our results did not showspecificity in terms of associations limited to a particular developmental period (e.g. pre- vs. postnatal),a particular antibody, or a particular PCB congener. Conclusions:  At the PCB concentrations measured in this cohort, which are high relative to most humanpopulations today, we did not detect an association between maternal or early postnatal PCB exposureand specific antibody responses at 6-months of age.Published by Elsevier Inc. 1. Introduction Polychlorinated biphenyls (PCBs) are ubiquitous compoundsthat were produced as complex mixtures for a variety of applications which included dielectric fluids for capacitors andtransformers, and as additives to paint, adhesives, sealants, andcarbonless copy paper (ATSDR, 2000). PCBs are chemically stableand lipophilic and as a result, are not easily degraded ormetabolized, and their concentrations thereby tend to bioaccu-mulate up the food chain. Despite a general decline in PCB levelsin human tissues worldwide (Fangstrom et al., 2005), there is stillconcern about their potential health effects, particularly amongpopulations exposed through environmental contamination (Han-sen et al., 2003; Kocan et al., 2001; Park et al., 2007) or thosepopulations whose diet includes consumption of PCB contami-nated seafood (Fangstrom et al., 2005; Dallaire et al., 2004).Much of the concern over the potential health effectsof PCBs stems from their structural similarity to 2,3,7, ARTICLE IN PRESS Contents lists available at ScienceDirectjournal homepage: www.elsevier.com/locate/envres Environmental Research 0013-9351/$-see front matter Published by Elsevier Inc.doi:10.1016/j.envres.2010.02.010 n Corresponding author at: Epidemiology Branch, National Institute of Environ-mental Health Sciences, PO Box 12233, MD A3-05, 111 T.W. Alexander Dr, RallBldg 101, Rm A361, Research Triangle Park, NC 27709-2233, USA. Fax:+1 919 541 2511. E-mail address:  juskota@niehs.nih.gov (T.A. Jusko).Environmental Research 110 (2010) 388–395  ARTICLE IN PRESS 8-tetrachloro-dibenzodioxin (TCDD) — which demonstrates strongimmunotoxic effects in experimental studies. Dioxin-like PCBs, orthose with a planar or co-planar configuration, appear to affectthe immune system by binding the aryl hydrocarbon (Ah)receptor (Safe, 1994; Silkworth et al., 1984; Tryphonas andFeeley, 2001). Less is known about the potential immunotoxiceffects of non-dioxin-like PCBs, or the so called ‘‘non-coplanar’’PCBs. Since these compounds do not bind as strongly (if at all) tothe Ah receptor, it is thought that they are significantly lessimmunotoxic. However, recent experimental work by Lyche et al.(2006) demonstrated that neonatal immunity to several environ-mental microbes was reduced in goat kids following in uteroexposure to PCB-153, a non-coplanar PCB.T-cell dependent functional measures of immunity, such asvaccination response, serve as valuable biomarkers to assesspotential developmental immunotoxicity (Dietert and Holsapple,2007; Luster et al., 2005). Indeed, some epidemiologic evidencesuggests that both dioxin-like and non-dioxin-like PCBs affectresponses to vaccinations in infants and children. For instance, ina cohort of Dutch infants environmentally exposed to PCBs,antibody levels to measles, mumps, and rubella were assessedwhen children were 18 and 42 months of age and someassociations between elevated maternal and cord PCBs anddecreased antibody levels at 42 months were noted (Weisglas-Kuperus et al., 1995, 2000). Other evidence comes from twocohorts of children followed in the Faroe Islands, which examinedpre- and postnatal PCB exposures in relation to diphtheria andtetanus vaccine responses (Heilmann et al., 2006). In this study,the authors noted lower concentrations of diphtheria and tetanusantibodies in relation to higher pre- and postnatal PCB exposures,even after adjusting for several potential confounding factors.To our knowledge, the relation between antibody response and in utero  and early postnatal PCB exposures in humans has onlybeen examined in these two populations.To better understand the role of PCBs on children’s develop-ment, we initiated a cohort study in 2002 enrolling mother–infantpairs from two districts in eastern Slovakia: Michalovce, a districthome to a chemical manufacturing facility that produced PCBsfrom 1959 to 1984 and resulted in significant environmentalcontamination; and Svidnik, an area approximately 70 km to thenorthwest with significantly less contamination. Exposure to PCBsin this population appears to occur, at least in part, throughconsumption of fats from locally produced sources (Sonnebornet al., 2008). In a previous analysis of mother–infant pairs fromthese districts, higher maternal PCB concentrations were asso-ciated with smaller thymus size in newborn infants (Park et al.,2008), suggesting that infant immune development might bealtered by in utero exposure to PCBs at concentrations presentin this population. The current paper reports on pre- andpostnatal PCB concentrations in relation to functional measuresof immunity (post-vaccination antibody response) among6-month-old infants in this eastern Slovak population. 2. Methods  2.1. Sample selection, specimen collection, and follow-up Women were approached to participate in our study between 2002 and 2004 atthe time they came to the local hospital in either Michalovce or Svidnik to delivertheir child, and since each district has only one hospital, the vast majority of womendelivering during this period delivered at these two hospitals. There, research nursesexplained the details of the study, and answered any questions the mother mighthave about the study procedures. The mother was then presented with a consentform, which further described the details of the study and was asked to read it over.After having the opportunity to ask questions, she was asked to sign the consentform if she agreed to participate. All forms of communication were in Slovak. Theprotocolexcluded: (1) mothers withmorethanfourpreviousbirths, (2) mothers lessthan18yearsofage,(3)motherswhohadresidedfewerthan5yearsintheirdistrict,and (4) mothers with a major illness during pregnancy. Following birth, we alsoexcludedmotherswhoseinfantshadsevere birthdefects. Intotal, 1134womenwereenrolled (811 in Michalovce and 323 in Svidnik). The study protocol was approvedby Institutional Review Boards at the University of Washington, the University of California at Davis, and the Slovak Medical University.Once a woman provided written consent, a note was made in her medicalchart to have maternal and cord blood specimens collected. Two 9-ml vacutainertubes were used to collect the serum for PCB and lipid determination. Aftercollection, these tubes were refrigerated between 5 and 10  1 C, and within 2 hof collection, transferred to the hospital’s Department of Biochemistry forfurther processing. There, samples were allowed to clot, then centrifuged at3000 rpm for 15 min to isolate serum. For the determination of PCBs, approxi-mately 3 ml of the serum was pipetted into an 8 ml glass tube, and approximately0.2 ml of serum was transferred to a 1.5 ml microcentrifuge tube for lipiddetermination. After the serum samples were aliquoted, samples were frozen at  20  1 C for future analyses.Following delivery, cord blood was also collected for PCB and lipid analysis.The infant was held at the level of the introitus or mother’s abdomen to prevent asignificant shift of the infant’s blood volume. As soon as possible after suctioning,the cord was clamped and cut to 5 cm from the infant’s abdomen. After the infantwas dried and stabilized and the umbilical base appeared normal, an umbilicalclamp was secured to the cord 1–2 cm distal to the abdominal wall, and any excesslength was cut. Blood from the cord was collected into vacutainers for furtherprocessing, and after centrifugation serum was aliquoted in a manner similar tothat of the maternal specimens.When the child was 5 months of age, each mother was sent reminders andrequests to schedule an appointment for the 6-month follow-up. The 6-monthvisit took place at the respective hospital in the Department of Pediatrics. Duringthe visit, approximately 9 ml of blood was collected for PCB, lipid, and immuneassays at 6 months, and samples were processed in a manner similar to thematernal and cord blood. For immune assays, approximately 500 m l of the serumwas aliquoted into each microcentrifuge tube (2 tubes total), and stored frozen at  20  1 C. At 6 months of age, 971 mother–infant pairs were still participating in thestudy (86%).  2.2. PCB measurement  From the maternal, cord, and 6-month infant serum samples, we determinedthe wet-weight concentrations (in ng/ml) of 15 PCB congeners [InternationalUnion of Pure and Applied Chemistry (IUPAC) numbers 28, 52, 101, 105, 114, 118,123 +149 , 138 +163 , 153, 156 +171 , 157, 167, 170, 180, and 189]. PCB concentrationswere determined at the Department of Toxic Organic Pollutants at the SlovakMedical University in Bratislava. This laboratory serves as the National ReferenceLaboratory for Dioxins and Related Compounds for the Slovak Republic, andregularly participates in interlaboratory comparison tests, such as the Inter-comparison Programme (German External Quality Assessment Scheme) andthe Interlaboratory Quality Assessment coordinated by the World HealthOrganization. The procedure for determination of PCB concentrations involvedextraction, cleanup, and quantitation by high-resolution gas chromatography withelectron capture detection (GC-ECD), as described below (Conka et al., 2005; Kocanet al., 1994).First, samples were extracted on a solid-phase extraction column, using PCB-174 as an extraction standard. Samples were then extracted from the dry columnwith n-hexane — DCM (1:1, v/v), and concentrated under a nitrogen stream.Samples were then purified on a florisil–H 2 SO 4 /silica gel column. After washingthe column, analytes were eluted with hexane. The eluate was concentrated byvacuum rotary evaporation. PCB-103 was added as an injection standard, and analiquot was injected and analyzed on a chromatography system (HP 5890;Hewlett-Packard, Palo Alto, CA, USA) equipped with a Ni-63 electron capturedetector using a 60-m DB-5 capillary column (J&W Scientific, Folsom, MA, USA).Quantification was based on the calibration curve generated by authentic PCBstandard solutions at five different concentration levels. Quality control activitiesconsisted of analyses of samples in batches of 10 run simultaneously with a blanksample and in-house reference material (spiked porcine serum). To check the dailyresponse of the detector prior to batch sample analysis, response for a particularcongener in a standard solution had to be in the range of 90–110%, or additionalquality control procedures were initiated. We calculated the limit of detection(LOD) for each analyte using the ratio of background to noise (multiplied by three)and the peak height of the analyte in standard solution.  2.3. Lipid measurement  We estimated total serum lipid (TL) concentrations in maternal, cord, andinfant serum samples using the enzymatic summation method proposed by Akinset al. (1989). We measured serum total cholesterol (TC) and triglyceride (TG)concentrations at the Department of Clinical Biochemistry of TOP-MED GeneralHospital Bratislava using a DuPont Automatic Clinical Analyzer III (DuPont, Jonesboro, AR, USA), and cholesterol oxidase without cholesterol esterase was T.A. Jusko et al. / Environmental Research 110 (2010) 388–395  389  ARTICLE IN PRESS used to detect free cholesterol (FC). The method by Takayama et al. (1977) wasused to determine serum choline-containing phospholipids (PL). Total serum lipidswere calculated using the formula:TL  ¼ 1 : 677 ð TC  FC Þþ FC þ TG þ PL   2.4. Post-vaccination antibody response During the first 6-months of life, Slovak infants receive several mandatoryprimary vaccinations which include haemophilus influenzae type b (HIB), tetanustoxoid (TT), and diphtheria toxoid (DT). The first dose for all three primaryvaccinations is given concurrently at 3–4 months of age. A second dose is given atapproximately 5–6 months of age, and the final dose of the primary series is givenbetween 11 and 12 months of age. To determine the antibody response to thesevaccinations at 6 months of age, we performed immunologic assays on a subset of the 971 infants still enrolled in the study at 6 months. Based on estimates of thepartial correlation between antibody concentrations and PCBs from previousstudies (Weisglas-Kuperus et al., 1995, 2000; Heilmann et al., 2006), we selected 40% of the 6-month infant samples for analysis ( n ¼ 384) to ensure adequate powerto examine hypotheses related to post-vaccination antibody response and PCBconcentrations. To select the subset of 384 infants, we randomly sampled mother–infant pairs within strata defined by total maternal PCB concentrations: (1) lessthan the 75th percentile; (2) between the 75th and 85th percentile; (3) betweenthe 85th and 95th percentiles; and (4) greater than the 95th percentile. Withinthese 4 strata, we randomly sampled approximately 25%, 75%, 75%, and 90% of subjects, respectively, to arrive at our targeted sample size. We sampled subjectsbased on maternal PCB concentrations (rather than cord or infant PCB concentra-tions) because the potential health effects of in utero PCB exposure was one of themain hypotheses of the study. This stratified random sampling maximizedstatistical power by oversampling mother–infant pairs with higher total maternalPCB concentrations. At the analysis stage, we adjusted for this design by applyingnormalized weights in all regression models (described below).ELISA analyses were conducted at the Department of Immunology andImmunotoxiocology at the Slovak Medical University. Commercial ELISA kitswere purchased from The Binding Site (Birmingham, UK) to quantify anti-tetanustoxoid (Kit # MK010), anti-diphtheria toxoid (Kit # MK014), and anti-haemophilusinfluenzae type b (Kit # MK016) antibodies. Each ELISA assayed anti-IgG levelsspecific to each antigen, since the IgG isotype (1) makes up approximately 75% of the immunoglobulin isotypes in blood ( Janeway, 2005), and (2) has been theoutcome examined in other studies (Weisglas-Kuperus et al., 1995, 2000;Heilmann et al., 2006) of PCB exposure and antibody response.  2.5. Data collection At birth, mothers completed a questionnaire that included sociodemographicinformation, questions related to maternal health and medication use, familyliving environment, past pregnancies, and tobacco use. From the infant’s medicalrecord, we abstracted child’s birth weight and gestational age, the latter based onlast menstrual period reported in the medical records and the judgment made bythe woman’s physician. We also estimated a standardized measure of birth weight,which was expressed as a  Z  -score standardized for sex, parity, and gestational agebased on all births in Slovakia in 2004. To collect information on the dates of anyvaccinations during the first 6 months after birth, we abstracted data from 6-month pediatric medical records. At the child’s 6-month visit, mothers completedanother questionnaire to update information, with specific collection of questionsabout the home environment of the child, breastfeeding, illnesses the child had,and smoking habits of persons in the household. Data from this questionnairewere used to estimate the duration of breastfeeding up to age 6 months.  2.6. Statistical analyses 2.6.1. Selection of PCBs In maternal, cord, and 6-month serum samples, we selected six, four, and fourcongeners, respectively, to evaluate in relation to antibody response. This decisionwas based on having  o 20% of samples below the limit of detection (LOD) for thecongener. In maternal samples, these were PCB congeners 118, 138 +163 , 153,156 +171 , 170, and 180. In both cord and 6-month infant samples, these were PCBcongeners 138 +163 , 153, 170, and 180. When an individual value was  o LOD, weassigned the value as the LOD divided by the square root of 2 (Lubin et al., 2004).For maternal, cord, and 6-month PCB concentrations, the corresponding ‘‘sum’’variable is the sum of these six, four, and four congeners, respectively.  2.6.2. Selection of potential confounding variables To select potential confounding variables for our regression models, weemployed directed acyclic graphs (DAGs) (Greenland et al., 1999; Hernan et al.,2002). This method provides a graphical approach to causal modeling whichallows one to identify a minimally sufficient set of adjustment variables that willadequately reduce confounding while avoiding adjustment for inappropriatevariables, which may actually induce confounding. To do this, two separate DAGs[one for perinatal (maternal/cord) and one for postnatal exposure] were created.We did not consider separate DAGs for individual PCB congeners or antibodies aswe regarded the causal structure of these models to be similar. Thus, we selectedtwo different sets of confounders for our models. These were: (1) ethnicity (Romavs. other), maternal smoking before or during pregnancy (yes/no), and maternalage at child’s birth (years) for maternal and cord PCB models; and (2) sex, ethnicity(Roma vs. other), maternal smoking at 6 months (yes/no), maternal age at child’sbirth (years), and infant age at the time of 6-month blood draw (days) for 6-monthinfant PCB models. In secondary analyses, we also adjusted for: child’s age (days)(maternal and cord PCB models), number of vaccine doses received (1 vs. 2), timesince most recent vaccination (days), infant sex (maternal and cord PCB models),and  Z  -score birth weight, in addition to those variables already in our primarymodels formed by the DAG. Variables for our secondary models were selectedfrom other potential confounders reported in the literature (Heilmann et al., 2006)and from variables noted in our DAGs to be predictors of the outcome, but whichdid not necessarily meet the criteria of a confounder, i.e., were not associated withPCB concentrations.  2.6.3. Multivariate methods To estimate associations between PCB concentrations and post-vaccinationantibody response, we fit linear regression models using the SURVEYREGprocedure in SAS (version 9.1; SAS Institute, Inc., Cary, NC, USA). This procedurewas chosen because the 384, 6-month-old children in whom we measuredantibody concentrations were not selected by simple random sampling from thefull cohort at 6 months. Specifically, the SURVEYREG procedure allows for (1) theapplication of weights to the regression model (which are inversely proportionalto the sampling probabilities of each stratum), and (2) valid measures of variancebased on the stratified sampling design, which is necessary given the potentiallygreater homogeneity within our sampling strata. When weights are applied to theregression analysis, the results are as if the sample of 384 children was drawncompletely at random from the 971 children participating at the 6-month follow-up. Thus, any potential bias created by the stratified sampling procedure isremoved.To reduce the potential influence of outlying values, exposure was the naturallog transformation of the wet-weight concentration [in ng/ml (ppb)] of PCBs. Inaddition, all antibody response measures were transformed by the natural log toensure homogeneity in error term variance. We excluded a small proportion of infants who did not receive (or for whom no report was found in their medicalrecord) at least one vaccination of HIB, TT, or DT, or who were more than 7 monthsof age at the time of the 6-month blood draw. Results from multivariate analysesare expressed as the percent change in antibody concentration for a change in PCBconcentration across the interquartile range, i.e. the 25th to the 75th percentile. 3. Results  3.1. Study subjects Table 1 presents descriptive data for the subset of 384 mother–infant pairs selected for immunologic assessment and the 971mother–infant pairs participating at the 6-month follow-up. In the384 mother–infant pairs, slightly more male infants were in thestudy sample, and approximately 45% of women were nulliparous.Thirty-seven percent of women reported breastfeeding their childthrough the first 6 months of life, whereas only 4% of womenreported no breastfeeding. Approximately 1 in 5 infants was of Romani ethnicity, and 74% of mothers were between 20 and 30years of age at their child’s birth. Additionally, 38% of womenreported smoking before or during pregnancy, and at the 6-monthfollow-up, 24% of mothers reported smoking. Overall,characteristics for the 384 women and infants we selected weresimilar to those still participating in the overall cohort at 6 months.  3.2. PCB concentrations Descriptive data for maternal, cord, and 6-month PCBconcentrations are presented in Table 2 on a wet-weight basis(ng/ml), and to facilitate comparisons with other studies, on a per-lipid basis (ng/g lipid). In the selected subset of 384 mother–infant pairs, cord, and 6-month-infant PCB measurements wereavailable for 376, and 246 infants, respectively. Compared to thenon-dioxin-like PCBs (PCB congners 138 +163 , 153, 170, and 180) T.A. Jusko et al. / Environmental Research 110 (2010) 388–395 390  ARTICLE IN PRESS which were detected in nearly all maternal samples, the mono-ortho-substituted dioxin-like congeners PCB-118 and PCB-156 +171 were below the limit of detection in 12% and 2.6% of samples, respectively. PCB-153, the congener with the highestconcentration in our population, had a median concentration of 153, 122, and 138 ng/g lipid in maternal, cord, and 6-monthsamples, respectively.As expected (natural log), PCB concentrations were stronglyassociated both within sampling periods (i.e. maternal, cord, and6-month) and across sampling periods. In maternal samples, PCBcongeners 138 and 153 were strongly associated ( r  ¼ 0.99,  p o 0.0001) as were PCB congeners 170 and 180 ( r  ¼ 0.99,  p o 0.0001); a similarly strong association was noted for thesecongeners in cord and 6-month infant samples. Maternal PCB-118showed the weakest association with other maternal congenersand total maternal PCBs — although not insignificant — with corre-lation coefficients between 0.72 and 0.79 (  p o 0.0001). Examiningthe associations between PCB concentrations across samplingperiods, total maternal PCBs were associated with total cord PCBs( r  ¼ 0.91,  p o 0.0001), but associations of total maternal PCBs with6-month total PCB concentrations were more moderate ( r  ¼ 0.51,  p o 0.0001), and similarly of total cord with total 6-month PCBconcentrations ( r  ¼ 0.50,  p o 0.0001).  3.3. Post-vaccination antibody concentrations Of the 384 infants selected for immunologic analysis, 350(91%) had blood specimens collected before 7 months of age; of these, 334 received the first dose each for HIB, TT, and DT prior tothe 6-month blood draw for this study, and are included in ouranalysis. For 14 infants, the date of the first vaccination was laterthan the 6-month blood draw, and for 2 infants, the date of thefirst vaccination was not known, or the infant was not immu-nized. The first two doses of all three vaccines were completed for284 children (85%); 63 children were given the second dose afterblood was drawn at age 6 months, and for 3 children either thedate of secondary vaccination was missing or the child was notimmunized. In those 284 infants who received two doses of vaccine, protective levels of anti-haemophilus influenza type b( Z 1 m g/ml), anti-tetanus toxoid ( Z 0.1 IU/ml), and anti-diphther-ia toxoid ( Z 0.1 IU/ml) were reached in 79%, 98%, and 88% of children, respectively. Post-vaccination antibody concentrationswere moderately correlated across specific vaccines both ininfants who received 1 dose of each vaccination ( r  HIB andTT ¼ 0.65;  r  HIB and DT ¼ 0.43;  r  TT and DT ¼ 0.58,  p o 0.01 for all) andin infants who received 2 doses of each vaccination ( r  HIB andTT ¼ 0.55;  r  HIB and DT ¼ 0.35;  r  TT and DT ¼ 0.43,  p o 0.0001 for all).  3.4. Adjusted associations between PCBs and post-vaccinationantibody concentrations Overall, there was no strong evidence for an associationbetween pre- or postnatal PCB levels and antibody concentrationsmeasured at 6 months of age, and confidence intervals were wide(Table 3). Furthermore, the results lacked any consistent patternthat would indicate specificity of an association for a particularwindow of exposure, congener, or a particular antibody.We also fit models for maternal, cord, and infant 6-month PCBswhere we adjusted for child’s age at the time of blood draw(maternal and cord PCB models), number of vaccine dosesreceived, time since most recent vaccination, infant sex (maternaland cord PCB models), and  Z  -score birth weight, in addition to thevariables in our primary model. Overall, our results did notchange appreciably with the addition of these variables, and nonoteworthy associations were observed after the additionalcovariates were included into the model. 4. Discussion We observed little evidence of an association betweenmeasures of PCB exposure during the prenatal and early postnatalperiod and post-vaccination antibody concentrations measured at6 months of age. These null findings were consistent across thevarious sampling periods of PCB concentration (maternal, cord,and 6-month infant), and our results showed no consistentpattern with regard to a particular congener or the variousantibodies assayed.Much of the experimental work concerning the potentialeffects of TCDD and PCBs on the immune system has shown thesecompounds to be immunosuppressive, both  in vivo  and  in vitro (though there are notable exceptions (Vorderstrasse et al., 2003)).For TCDD, these findings include thymic atrophy and suppressionof B-cell responsiveness (Kerkvliet, 2002; Lawrence and Kerkvliet,2006), and most relevant, decreases in antibody response inrelation to gestational exposure to TCDD (Vorderstrasse et al.,2004). Existing epidemiologic evidence also supports the poten-tial immunosuppressive effects of PCBs. For instance, in the samecohort of Slovak infants, Park et al. (2008) found lower thymicindices among newborns with higher total maternal PCB  Table 1 Characteristics of infants and mothers in subset selected for immunologic analysis,and those in the full cohort followed to 6 months.Characteristic Immunology subset( n ¼ 384)Full cohort at 6months ( n ¼ 971) N   % a N   % a Infant sexMale 197 51.3 495 51.0Female 187 48.7 476 49.0Birth weight (grams) o 2500 21 5.5 43 4.42500–3499 213 55.5 550 56.6 Z 3500 150 39.1 378 38.9Gestation length (weeks) o 37 14 3.7 32 3.337–41 359 93.5 910 93.7 Z 42 11 2.9 29 3.0Parity0 173 45.1 401 41.31 117 30.5 322 33.22–4 83 24.2 246 25.3Missing 1 0.3 2 0.2Breastfeeding duration(months)0 17 4.4 33 3.41– o 6 196 51.0 457 47.16 141 36.7 402 41.4Missing 30 7.8 79 8.1Ethnicity of childRomani 69 18.0 189 19.5Slovak/Eastern European 315 82.0 782 80.5Maternal age at child’s birth(years)18– o 20 26 6.8 83 8.620–30 285 74.2 716 73.7 4 30 73 19.0 172 17.7Maternal smoking before orduring pregnancyYes 146 38.0 345 35.5No 238 62.0 626 64.5Maternal smoking at 6-monthfollow-upYes 93 24.2 213 21.9No 280 72.9 722 74.4Missing 11 2.9 36 3.7 a Percents may not sum to 100 because of rounding. T.A. Jusko et al. / Environmental Research 110 (2010) 388–395  391  ARTICLE IN PRESS concentrations. In a study of Dutch infants environmentallyexposed to PCBs, 207 infants were followed longitudinally withimmunologic assessments of antibody levels to measles, mumps,and rubella at 18 and 42 months of age (Weisglas-Kuperus et al.,2000, 1995, 2004). At age 18 months, these authors found noassociation between pre- or postnatal PCB exposure and any of the antibody levels. However at 42 months, antibody levels tomumps were inversely associated with total maternal PCBconcentrations ( r  ¼ 0.17), and antibody levels to rubella wereinversely associated with cord total PCB concentrations( r  ¼ 0.19). A recent study from the Faroe Islands also examinedpre- and postnatal PCB exposures in relation to antibody levels  Table 2 Weighted a PCB concentrations in maternal, cord, and 6-month serum samples of mother–infant pairs in the study subset ( n ¼ 384 b ).PCB measure  N  c % o LOD Wet-weight (ng/ml or ppb) Per-lipid (ng/g or ppb)Mean Min P25 P50 P75 Max Mean Min P25 P50 P75 MaxMaternal PCBPCB 118 384 12.0 0.159 0.008 0.055 0.101 0.170 7.228 15.7 0.7 6.0 10.0 17.6 509.6PCB 138 +163 384 0 1.360 0.192 0.625 0.944 1.431 39.786 135.5 19.4 64.2 95.2 148.8 2805.2PCB 153 384 0 2.085 0.343 1.023 1.533 2.237 56.132 208.8 34.6 108.4 152.6 227.5 3957.8PCB 156 +171 384 2.6 0.196 0.003 0.090 0.137 0.216 4.889 19.5 0.2 9.3 13.8 21.5 451.4PCB 170 384 0 0.820 0.117 0.388 0.573 0.922 17.212 81.8 12.3 39.9 57.4 90.2 1361.7PCB 180 384 0 1.908 0.231 0.896 1.322 2.136 40.802 191.0 24.3 92.6 133.9 211.2 2876.9Sum of 6 384 – 6.529 1.118 3.127 4.625 7.206 166.045 652.2 108.5 334.5 455.0 719.9 11707.5Cord PCBPCB 138 +163 376 0 0.288 0.026 0.128 0.202 0.323 5.494 119.1 9.5 56.6 85.6 125.5 2889.5PCB 153 376 0 0.398 0.034 0.181 0.286 0.449 6.389 164.4 13.8 79.8 121.8 184.0 3989.3PCB 170 376 0.8 0.138 0.004 0.062 0.094 0.161 2.302 56.4 1.5 25.6 39.6 62.4 1064.3PCB 180 376 0 0.342 0.042 0.160 0.236 0.395 4.869 140.9 12.2 69.1 98.3 155.0 3084.6Sum of 4 376 – 1.166 0.143 0.537 0.829 1.332 18.829 480.7 41.0 224.3 343.1 534.8 11027.86-Month PCBPCB 138 +163 246 0.4 0.956 0.004 0.137 0.496 1.094 36.878 164.2 0.8 25.1 91.4 195.1 7608.0PCB 153 246 0.8 1.363 0.004 0.211 0.779 1.602 46.562 233.1 1.0 36.8 138.1 289.8 9605.9PCB 170 246 4.9 0.457 0.001 0.059 0.229 0.487 16.839 78.1 0.1 10.2 38.8 87.4 3473.9PCB 180 246 1.6 1.127 0.002 0.136 0.509 1.299 38.062 192.2 0.4 22.7 88.2 228.6 7852.3Sum of 4 246 – 3.903 0.015 0.546 2.035 4.577 138.341 667.6 3.5 93.7 360.7 786.7 28540.1 a Sampling weights applied to reflect the PCB distributions among the 971 mother–infant pairs participating at 6 months. b Numbers for maternal, cord, and 6-month concentrations on a per-lipid basis were 380, 358, and 243 due to missing lipid values. c Note that the values in the table reflect the distributions following imputation of values below the LOD.  Table 3 Adjusted a percent change in post-vaccination antibody concentrations for an increase in wet-weight maternal, cord, and 6-month PCB concentrations across theinterquartile range.PCB Measure Haemophilus influenzae type b Tetanus toxoid Diphtheria toxoid N   % change 95% CI  p -value  N   % change 95% CI  p -value  N   % change 95% CI  p -valueMaternal PCBPCB 118 316 4.7   13.9, 27.4 0.64 329   2.2   19.3, 18.6 0.82 306 2.9   12.8, 21.4 0.73PCB 138 +163 316   5.6   22.6, 15.0 0.56 329 1.4   16.0, 22.5 0.88 306   2.3   16.0, 13.5 0.76PCB 153 316   3.0   21.0, 19.1 0.77 329 2.5   15.3, 24.1 0.80 306   1.5   15.7, 15.0 0.84PCB 156 +171 316   0.9   16.9, 18.1 0.92 329   2.9   19.3, 16.8 0.75 306   10.5   22.7, 3.6 0.14PCB 170 316   8.6   24.6, 10.8 0.36 329   4.2   21.9, 17.6 0.68 306   7.0   21.4, 10.1 0.40PCB 180 316   8.7   24.7, 10.9 0.36 329   4.9   22.7, 17.1 0.64 306   6.1   20.8, 11.3 0.47Sum of 6 316   6.8   23.4, 13.3 0.48 329   1.7   19.5, 20.1 0.87 306   4.5   18.9, 12.5 0.58Cord PCBPCB 138 +163 309   5.1   22.7, 16.6 0.62 322 4.9   14.0, 27.9 0.64 300   3.7   18.1, 13.2 0.64PCB 153 309   1.3   20.8, 23.1 0.91 322 4.9   14.7, 29.1 0.65 300   2.0   17.3, 16.1 0.82PCB 170 309   5.3   18.8, 10.5 0.49 322 1.2   14.1, 19.2 0.89 300   7.4   19.5, 6.5 0.28PCB 180 309   3.9   20.2, 15.7 0.67 322 0.7   18.0, 23.6 0.95 300   5.3   20.3, 12.5 0.53Sum of 4 309   4.3   20.9, 15.9 0.66 322 2.6   16.2, 25.6 0.81 300   4.5   19.4, 13.0 0.596-Month PCBPCB 138 +163 211   8.3   31.7, 23.0 0.56 217 6.1   18.2, 37.6 0.66 198   15.2   34.8, 10.1 0.21PCB 153 211   7.0   29.6, 22.7 0.60 217 7.7   16.1, 38.3 0.56 198   16.6   35.5, 8.0 0.17PCB 170 211   8.1   28.9, 18.9 0.52 217   0.5   21.2, 25.6 0.96 198   14.5   32.0, 7.4 0.18PCB 180 211   2.5   27.2, 30.6 0.87 217 2.8   20.6, 33.2 0.83 198   15.3   34.4, 9.5 0.20Sum of 4 211   6.4   30.0, 25.1 0.65 217 5.4   18.8, 36.9 0.69 198   16.6   35.9, 8.7 0.18 a Maternal and cord PCB analyses adjusted for: Romani ethnicity (vs. other), maternal smoking before or during pregnancy (yes/no), and maternal age at child’s birth(years). Infant PCB analyses adjusted for: sex, Romani ethnicity (vs. other), maternal smoking at 6 months (yes/no), maternal age at child’s birth (years), and infant’s age atthe time of blood draw (days). T.A. Jusko et al. / Environmental Research 110 (2010) 388–395 392
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