title: 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.
abstract: Delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter haplotype 2*2 (hPEPT2*2) through different pathways can increase brain levels of delta-aminolevulinic acid and are associated with higher blood lead burden in young children. Past child and adult findings regarding ALAD2 and neurobehavior have been inconsistent, and the possible association of hPEPT2*2 and neurobehavior has not yet been examined. Mean blood lead level (BLL), genotype, and neurobehavioral function (fine motor dexterity, working memory, visual attention and short-term memory) were assessed in 206 males and 215 females ages 5.1-11.8years. Ninety-six percent of children had BLLs<5.0μg/dl. After adjusting for covariates (sex, age and mother's level of education) and sibling exclusion (N=252), generalized linear mixed model analyses showed opposite effects for the ALAD2 and hPEPT2*2 genetic variants. Significant effects for ALAD2 were observed only as interactions with BLL and the results suggested that ALAD2 was neuroprotective. As BLL increased, ALAD2 was associated with enhanced visual attention and enhanced working memory (fewer commission errors). Independent of BLL, hPEPT2*2 predicted poorer motor dexterity and poorer working memory (more commission errors). BLL alone predicted poorer working memory from increased omission errors. The findings provided further substantiation that (independent of the genetic variants examined) lowest-level lead exposure disrupted early neurobehavioral function, and suggested that common genetic variants alter the neurotoxic potential of low-level lead. ALAD2 and hPEPT2*2 may be valuable markers of risk, and indicate novel mechanisms of lead-induced neurotoxicity. Longitudinal studies are needed to examine long-term influences of these genetic variants on neurobehavior.
authors.affiliation: College of Health Sciences, Department of Public Health Sciences, University of Texas, El Paso, TX, United States; Border Biomedical Research Center, Toxicology Core, University of Texas, El Paso, TX, United States; Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, United States. Electronic address: casobin@utep.edu.
authors.forename: Christina
authors.initials: C
authors.lastname: Sobin
authors.affiliation: Border Biomedical Research Center, Toxicology Core, University of Texas, El Paso, TX, United States; Department of Psychology, University of Texas, El Paso, TX, United States.
authors.forename: Mayra Gisel
authors.initials: MG
authors.lastname: Flores-Montoya
authors.affiliation: Department of Psychology, University of Texas, El Paso, TX, United States.
authors.forename: Marisela
authors.initials: M
authors.lastname: Gutierrez
authors.affiliation: New Mexico State University, Las Cruces, NM, United States.
authors.forename: Natali
authors.initials: N
authors.lastname: Parisi
authors.affiliation: New Mexico State University, Las Cruces, NM, United States.
authors.forename: Tanner
authors.initials: T
authors.lastname: Schaub
mesh_terms: D001288:Attention / Q000187:drug effects / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D002658:Developmental Disabilities / Q000139:chemically induced* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007854:Lead / Q000097:blood / Q000633:toxicity*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000623:Porphobilinogen Synthase / Q000235:genetics*; D027981:Symporters / Q000235:genetics*
chemical_list: D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D007854:Lead; D000623:Porphobilinogen Synthase
keywords: ALAD; Child lead exposure; Delta-aminolevulinic acid dehydratase; Neurobehavior; Proton-coupled oligopeptide transporter; hPEPT2