title: Polymorphisms of pesticide-metabolizing genes in children living in intensive farming communities.
abstract: Polymorphisms in genes encoding xenobiotic-metabolizing enzymes (XME) are important parameters accounting for the wide inter-individual variability to environmental exposures. Paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and Cytochrome-P450 constitute major classes of XME involved in the detoxification of pesticide chemicals, in particular organophosphates. This study explored the allelic frequency, linkage disequilibrium and haplotype analysis of ten common polymorphic variants of seven key genes involved in organophosphate metabolism (BCHE-K, BCHE-A, PON1 Q192R, PON1 L55M, PON1 -108C/T, CYP2C19 G681A, CYP2D6 G1846A, CYP3AP1 -44G/A, GSTM1∗0 and GSTT1∗0) in a children population living near an intensive agriculture area in Spain. It was hypothesized that individuals with unfavorable combinations of gene variants will be more susceptible to adverse effects from organophosphate exposure. Genomic DNA from 496 healthy children was isolated and amplified by PCR. Hydrolysis probes were used for the detection of eight specific SNPs and two copy number variants (CNVs) by using TaqMan® Assay-based real-time PCR. Frequencies of SNPs and CNVs in the target genes were in Hardy-Weinberg equilibrium and broadly consistent with European populations. Linkage disequilibrium was found between the three PON1 genetic polymorphisms studied and between BCHE-K and BCHE-A. The adverse genotype combination (unusual BCHE variants, PON1 55MM/-108TT and null genotype for both GSTM1 and GSTT1) potentially conferring a greater genetic risk from exposure to organophosphates was observed in 0.2% of our study population. This information allows broadening our knowledge about differential susceptibility toward environmental toxicants and may be helpful for further research to understand the inter-individual toxicokinetic variability in response to organophosphate pesticides exposure.
authors: Department of Legal Medicine and Toxicology, University of Granada School of Medicine, Granada, Spain; Center GENYO (Pfizer-University of Granada-Andalusian Government Center for Genomics and Oncological Research), Granada, Spain.
authors: Antonio
authors: A
authors: Gómez-Martín
authors: Department of Legal Medicine and Toxicology, University of Granada School of Medicine, Granada, Spain. Electronic address: ajerez@ugr.es.
authors: Antonio F
authors: AF
authors: Hernández
authors: Center GENYO (Pfizer-University of Granada-Andalusian Government Center for Genomics and Oncological Research), Granada, Spain.
authors: Luis Javier
authors: LJ
authors: Martínez-González
authors: Andalusian School of Public Health (EASP), Granada, Spain; Institute of Biosanitary Research (ibs.GRANADA), University Hospitals/University of Granada, Granada, Spain.
authors: Beatriz
authors: B
authors: González-Alzaga
authors: Andalusian School of Public Health (EASP), Granada, Spain; Institute of Biosanitary Research (ibs.GRANADA), University Hospitals/University of Granada, Granada, Spain.
authors: Miguel
authors: M
authors: Rodríguez-Barranco
authors: Department of Genetics, University of Granada School of Sciences, Granada, Spain.
authors: Inmaculada
authors: I
authors: López-Flores
authors: Center for Public Health Research (CSISP-FISABIO), Valencia, Spain.
authors: Clemente
authors: C
authors: Aguilar-Garduno
authors: Andalusian School of Public Health (EASP), Granada, Spain; Institute of Biosanitary Research (ibs.GRANADA), University Hospitals/University of Granada, Granada, Spain; CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.
authors: Marina
authors: M
authors: Lacasana
mesh_terms: D000293:Adolescent; D000383:Agriculture; D043303:Aryldialkylphosphatase / Q000235:genetics; D002648:Child; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D056915:DNA Copy Number Variations / Q000187:drug effects*; D004781:Environmental Exposure / Q000009:adverse effects / Q000032:analysis; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity; D005787:Gene Frequency; D005982:Glutathione Transferase / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D010575:Pesticides / Q000493:pharmacokinetics* / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects*; D013030:Spain
chemical_list: D043303:Aryldialkylphosphatase; D051544:Cytochrome P-450 CYP3A; D004785:Environmental Pollutants; D005982:Glutathione Transferase; D010575:Pesticides; C104464:CYP3A protein, human; C413545:glutathione S-transferase T1; C468406:PON1 protein, human
keywords: CNVs; Environmental toxicants; Esterases; Genetic biomarkers; Organophosphates; SNPs; Xenobiotic-metabolizing enzymes