δ-Aminolevulinic Acid Dehydratase Single Nucleotide Polymorphism 2 and Peptide Transporter 2*2 Haplotype May Differentially Mediate Lead Exposure in Male Children

Abstract

Child low-level lead (Pb) exposure is an unresolved public health problem and an unaddressed child health disparity. Particularly in cases of low-level exposure, source removal can be impossible to accomplish, and the only practical strategy for reducing risk may be primary prevention. Genetic biomarkers of increased neurotoxic risk could help to identify small subgroups of children for early intervention. Previous studies have suggested that, by way of a distinct mechanism, δ-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and/or peptide transporter 2*2 haplotype (hPEPT2*2) increase Pb blood burden in children. Studies have not yet examined whether sex mediates the effects of genotype on blood Pb burden. Also, previous studies have not included blood iron (Fe) level in their analyses. Blood and cheek cell samples were obtained from 306 minority children, ages 5.1 to 12.9 years. 208Pb and 56Fe levels were determined with inductively coupled plasma–mass spectrometry. General linear model analyses were used to examine differences in Pb blood burden by genotype and sex while controlling for blood Fe level. The sample geometric mean Pb level was 2.75 µg/dl. Pb blood burden was differentially higher in ALAD2 heterozygous boys and hPEPT2*2 homozygous boys. These results suggest that the effect of ALAD2 and hPEPT2*2 on Pb blood burden may be sexually dimorphic. ALAD2 and hPEPT2*2 may be novel biomarkers of health and mental health risks in male children exposed to low levels of Pb.

δ-Aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter 2*2 haplotype (hPEPT2*2) differently influence neurobehavior in low-level lead exposed children

“…Similar to the gender effects observed for ALAD 2 , at lowest levels of lead exposure, males but not females homozygous for hPEPT2*2 had significantly increased BLL (4.9 µg/dL vs. 2.6 µg/dL) (Sobin et al, 2011b). (Why hPEPT2*2 may be associated with higher blood lead burden in males has not yet been determined; possible explanations are discussed in the referenced manuscript).…”

“…Detailed procedures were previously described (Sobin et al, 2011a; Sobin et al, 2011b). Aggregate blood lead level was the mean of two values obtained an average of 60 days apart for each child.…”

“…Similarly, in 229 children in China, mean BLL was higher in children with ALAD 2 (11.7 µg/dL vs. 9.7 µg/dL) (Shen et al, 2001). Associations were also observed at lowest levels of exposure in young children (Sobin et al, 2009), and when gender effects were examined differences were found (Sobin et al, 2011b). As compared to other subgroups, mean BLL was highest among males with ALAD 2 [ID: rs1800435] (3.5 µg/dL vs. 2.7 µg/dL).…”

“…Two studies thus far have examined associations between blood lead burden and hPEPT2*2 (Sobin et al, 2009; Sobin et al, 2011b). Similar to the gender effects observed for ALAD 2 , at lowest levels of lead exposure, males but not females homozygous for hPEPT2*2 had significantly increased BLL (4.9 µg/dL vs. 2.6 µg/dL) (Sobin et al, 2011b).…”

Early Life Lead Exposure Causes Gender-Specific Changes in the DNA Methylation Profile of DNA Extracted from Dried Blood Spots

“…Studies conducted with children exposed to ≤10 μg/dl of Pb from the environment, showed that blood Pb levels in boys were greater than that of girls and was exacerbated by a polymorphism in the gene encoding ALAD or PEPT2 [11]. …”