A strong body of evidence suggests that, in addition to postnatal exposure, maternal or cord blood lead levels are associated with poorer cognitive outcomes (28
). Our study demonstrates that cord BLLs are associated with global measures of child development at 24 months of age, independently of the exposures that occurred in the postnatal period. This relationship was not apparent at 48 months of age, possibly because with longer postnatal exposure the influence of prenatal BLL on brain structure and the development of cognitive competencies becomes less influential. In fact, BLL measured at 48 months of age was statistically associated with lower GCI and memory scores of the McCarthy Scales administered at 48 months of age. Although cord BLLs were higher in our sample than in other groups [0.44–6.90 μg/dL in Polish newborns (31
) and 0.2–9.7 μg/dL in Innuit newborns (28
)], our findings are consistent with those reports.
Second, we investigated the interaction between BLLs and two gene polymorphisms. We found that although the TT genotype of the DRD2 was positively associated with MDI and memory scores, it did not modify the association between cord BLL (or BLL measured postnatally) and child development. The DAT1 was not associated with child development in lead exposed children and did not modify the relationship between lead exposure and neurocognitive measures used in this study. The majority of other studies that examined the effects of lead exposure on children’s development have not investigated potential effect modification due to genetic variability.
Lead exposure in children has been associated with dopamine-related cognition including executive functioning (2
) and behavior problems including ADHD (32
). Lead affects several aspects of dopamine neurotransmission, in a dose-related and brain region-specific manner (5
). The effects include changes in dopamine metabolism, release, and reuptake by DAT (5
). There is evidence of increased D2 receptor sensitivity after postnatal (4
) and prenatal (6
) lead exposure. In addition, moderately elevated BLLs (~15μg/dL) are associated with synaptic dopamine overflow in the nucleus accumbens (7
Dopaminergic neurotransmission is also affected by gene polymorphisms. The majority, 80.8%, of children in this study had the 10-repeat VNTR of the DAT1
. Approximately 20% of the sample had at least 9-repeat VNTRs. This is consistent with previous work, which shows that the 10-repeat VNTR allele occurs frequently in various populations (33
). The 10-repeat VNTR of the DAT1
is associated with increased DAT expression (13
) and availability (14
), whereas the Taq 1A
polymorphism has been associated with reduced D2 receptor density (15
). The functional implications of this are still unclear for populations exposed to toxicants that affect dopamine signaling. We did not observe statistical interactions between children’s BLLs and dopamine gene polymorphisms and cannot speculate on the potential mechanisms that would drive the combined effects of lead exposure and dopamine gene polymorphisms on neural functioning or child development. In another study of school children, those with variant DRD2 Taq 1A
genotype experienced a stronger deficit in IQ scores for each unit increase in BLLs measured concurrently to the IQ test than children with wild type genotype (24
), although the lead × DRD2 interaction term was not statistically significant.
Our study failed to document significant lead × DRD2 interactions but Roy et al suggest that reduced D2 receptor density is associated with worse outcomes in lead-exposed children (24
). Because we did not observe effect modification by dopamine genes either with prenatal or postnatal exposure, the possibility of the differential findings between our study and that of Roy et al being due to differences in the timing of exposure is not likely. Rather, differences between these two studies could be due to differences in the severity of lead exposure (BLL [mean±SD]: 11.5±5.3 μg/dL among Indian children and 8.1±4.4 μg/dL in our study). In addition, the developmental measures employed to assess preschool children in our study are thought to correlate poorly with the types of cognitive and IQ assessments used in school-age children by Roy et al (24
). It is possible that the two studies are assessing different cognitive domains, particularly because many functions contributing to IQ, such as attention, follow a developmental trajectory and mature during the school years. Finally, our measures may not be sensitive to lead-induced damage to the prefrontal cortex, which subserves the executive functions we hypothesized could link the dopaminergic system and lead exposure to IQ deficits.
Our study had some limitations. First, the analysis was based on a modest sample size. It is possible we did not have the appropriate statistical power to detect interactions between prenatal lead exposure and dopamine gene polymorphisms. However, in another examination of gene-environment interactions in this cohort, Cantonwine et al found effect modification between HFE
gene polymorphism and cord BLL on birth weight (34
). In a sample of 174 children, interactions were also found between child’s DRD4
polymorphism, BLL and executive function (3
). These studies suggest that with the sample sizes used here, gene-environment interactions are detectable. Our limited sample size was due to participant attrition. Because we found no significant differences in demographic characteristics between study participants and those excluded from analysis, we believe the findings accurately represent the relationship between lead exposure and measures of child development in the target population. The exclusion of children reflects the difficulty of prospectively following a large cohort of participants who have multiple assessments and visits over time, and does not appear to reflect a systematic bias (). Nevertheless, a larger sample size would likely clarify the effects of the DRD2
polymorphism on the developmental measures, where children with the TT
genotype performed better on the MDI but not the PDI at 24 months and better on the memory sub-scale but not on GCI at 48 months. We also had limited ability to account for children’s home environment, an important determinant of child development. Some factors that influence the home environment include maternal IQ and marital status, physical characteristics and crowding in the house. We accounted for these and other potentially influential factors in our analysis.
In summary, an index of prenatal lead exposure was adversely associated with global measures of child development at 24 but not 48 months of age, independently of the influence of postnatal lead exposure. We also found independent positive associations between DRD2 polymorphisms and global measures of child development. However, we found no evidence of gene-environment interactions where dopamine gene polymorphisms modify the effect of lead exposure, either measured pre or postnatally, on neurocognitive outcomes in young children. In light of contrasting results in other populations, further studies of this kind are warranted.