In this population, with substantial PCB exposure, an association was not observed between maternal, cord, or infant serum PCB concentration and total serum concentration of IgG, IgA, IgM, or IgE determined at 6-months-of-age. These results are discussed below in terms of existing epidemiologic studies, and potential alternative hypotheses that could explain our null findings.
At least three previous cohort studies have examined the association between maternal/perinatal PCB exposures and immunoglobulin concentrations during infancy and childhood. In one study, data published from a different cohort of mother-infant pairs from the Slovak Republic showed increased cord IgE concentrations with increasing levels of placental PCB-118, but no association with any other dioxin-like or non-dioxin-like congener was observed (Reichrtova et al., 1999). While these data may indicate specificity for dioxin-like PCBs, the PCB-118-IgE association may have been attenuated (or non-existent) had adjustment for potential confounders occurred. In another study, mother-infant pairs from the Faroe Islands were followed from birth to 7 years-of-age when total serum IgE was assessed (Grandjean et al., 2010
). Despite the considerable serum PCB concentrations in this population, no association was observed between maternal PCB exposures and total IgE in the child. A prospective cohort study by Dewailly et al. (2000)
also measured IgG, IgA, and IgM concentrations in infants at 3-, 7-. and 12-months-of-age and found no association between these parameters and prenatal PCB exposure. Similarly, in the current study, no association was observed between PCB concentrations measured in maternal, cord, or infant serum and immunoglobulin concentrations at 6-months-of-age; furthermore, this study did not reveal any evidence of congener-specific associations that might indicate, for example, Ah receptor-mediated immunotoxicity (Hogaboam et al., 2008
). These (essentially) null findings from cohort studies contrast with results from three cross-sectional analyses that observed some association between PCB and immunoglobulin concentrations. In one study of Flemish adolescents, Van Den Heuvel et al. (2002)
observed inverse associations between total IgG and non-dioxin-like PCB congeners 138, 153, and 180. In a German study, a positive association between PCB concentrations and IgM levels in 7–8-year-old children was noted (Karmaus et al., 2005
). In addition to assessing PCB exposure during pregnancy, the Faroe Islands cohort determined PCB concentrations in children at 5 and 7 years-of-age; unlike prenatal exposure, increasing PCB concentrations at 5 and 7 years (sum of non-dioxin-like PCB congeners 138, 153, and 180) were associated with higher total IgE at 7 years-of-age (Grandjean et al., 2010
One candidate explanation for the divergent findings across studies, at least in terms of in utero
exposure, may be attributable to the degree of PCB exposure in each population, though this possibility appears to be an unlikely explanation. Among those studies discussed above, prenatal PCB concentrations in the Faroe Islands cohort were greatest, followed by concentrations in the current and former Slovak populations, and the Northern Quebec study (Longnecker et al., 2003
) - all of which showed essentially null results with regard to in utero
exposure and total immunoglobulin concentrations. In addition, approximately 95% of mothers breastfed their child at least 1 month in our study, and 41% of mothers reported breastfeeding their child at 6-months-of-age, suggesting that peak PCB exposures were occurring during lactation in our sample (i.e., at 6-months-of-age). However, we observed no association between these 6-month infant PCB concentrations and immunoglobulin measures.
Another possible explanation of our null findings, and of the discrepant results between the cohorts and cross-sectional studies described above, is that circulating IgG and IgA concentrations measured during infancy are highly variable, especially compared to measures taken during toddlerhood and adulthood (Stiehm and Fudenberg, 1966
). Variability in IgG concentrations at 6-months-of-age may be the result of (i) still present, but declining maternal IgG and (ii) rapidly increasing IgG production by the infant. Thus, even if PCB concentrations were a cause of altered immunoglobulin concentrations at 6-months-of-age, variability in total immunoglobulin measures may limit power and thus detection of associations with PCBs (or other environmental toxicants). Such a hypothesis is consistent with the results of the studies discussed here; those which assessed immunoglobulin concentrations later in childhood and into adolescence (van den Heuvel et al., 2002
; Karmaus et al., 2005
; Grandjean et al., 2010
) observed associations with PCB concentrations while those studies which assessed immunoglobulin concentrations during infancy (Dewailly et al., 2000
; and the current study), did not observe associations between PCB measures and immunoglobulin concentrations.
While larger variability in total immunoglobulin concentrations is a measurement issue which concerns statistical power, a slightly different but related issue in using total immunoglobulin concentrations as a measure of potential immunotoxicity concerns lack of specificity. For instance, a measure of “total” immunoglobulin concentration includes all antibodies in an extremely large (> 108) antibody repertoire. Therefore, if maternal and early life exposure to a toxicant causes subtle perturbation in the functional capacity of the immune system, a measure of total serum immunoglobulins may “miss” detection of immunotoxicity.
The present study has some additional limitations. First, immunoglobulin concentrations beyond 6-months-of-age were not assessed. Doing so, and in the context of a longitudinal model, would have increased power to detect associations, and as noted above, immunoglobulin concentrations measured later in life would be less variable. Second, statistical power was reduced for analyses that included 6-month infant PCB concentrations as the exposure of interest, owing to a smaller number of samples analyzed for PCB concentrations at that time-point. Further, besides PCB-118, other dioxin-like congeners that may be associated with altered immunoglobulin concentrations were not measured, as they exhibit stronger Ah receptor activity.
Strengths of the current study include the ability to analyze both pre and postnatal measures of PCB exposure, which may be particularly relevant in this population where, 41% of mothers are breastfeeding at 6 months, and PCB concentrations in the infant are likely greatest at this age. Compared to some previous studies, the current investigation also collected extensive medical and demographic data longitudinally, which allowed adjustment for factors such as prenatal or postnatal exposure to maternal smoking and breastfeeding duration. Adjustment for these factors should have reduced bias in the estimates of association. Further, PCB exposures varied widely in this study compared to most contemporary populations (Longnecker et al., 2003
), thereby increasing power to detect an association with immunoglobulin concentrations.
Immunoglobulin concentrations may be valuable markers of later morbidity, and as such, the goal of the current study was to determine whether in utero and early postnatal PCB concentrations are associated with altered immunoglobulin concentrations. The current findings suggest that in utero and early postnatal PCB exposures are not associated with immunoglobulin concentrations in infants at 6-months-of-age, despite the fact that maternal PCB concentrations in our study were substantial, and several-fold higher than contemporary concentrations in the United States. Our results need to be interpreted with caution, however, since total immunoglobulin concentrations during infancy are highly variable, and a true association may have been obscured by the “noise” inherent in this outcome. Future studies of environmental exposures may be more successful in detecting associations in children during later childhood when immunoglobulin measures are less variable, and nearer to adult concentrations.