Prenatal Methylmercury Exposure and Genetic Predisposition to Cognitive Deficit at Age 8 Years

Background: Cognitive consequences at school age associated with prenatal methylmercury (MeHg) exposure may need to take into account nutritional and sociodemographic cofactors as well as relevant genetic polymorphisms. Methods: A subsample (n = 1,311) of the Avon Longitudinal Study of Parents and Children (Bristol, UK) was selected, and mercury (Hg) concentrations were measured in freeze-dried umbilical cord tissue as a measure of MeHg exposure. A total of 1135 children had available data on 247 single-nucleotide polymorphisms (SNPs) within relevant genes, as well as the Wechsler Intelligence Scale for Children Intelligence Quotient (IQ) scores at age 8 years. Multivariate regression models were used to assess the associations between MeHg exposure and IQ and to determine possible gene–environment interactions. Results: Hg concentrations indicated low background exposures (mean = 26 ng/g, standard deviation = 13). Log10-transformed Hg was positively associated with IQ, which attenuated after adjustment for nutritional and sociodemographic cofactors. In stratified analyses, a reverse association was found in higher social class families (for performance IQ, P value for interaction = 0.0013) among whom there was a wider range of MeHg exposure. Among 40 SNPs showing nominally significant main effects, MeHg interactions were detected for rs662 (paraoxonase 1) and rs1042838 (progesterone receptor) (P < 0.05) and for rs3811647 (transferrin) and rs2049046 (brain-derived neurotrophic factor) (P < 0.10). Conclusions: In this population with a low level of MeHg exposure, there were only equivocal associations between MeHg exposure and adverse neuropsychological outcomes. Heterogeneities in several relevant genes suggest possible genetic predisposition to MeHg neurotoxicity in a substantial proportion of the population. Future studies need to address this possibility.

[1]  D. Lawlor,et al.  Cohort Profile: The ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children , 2012, International journal of epidemiology.

[2]  D. Lawlor,et al.  Cohort Profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort , 2012, International journal of epidemiology.

[3]  Nicholas J Timpson,et al.  Genome-wide association study of three-dimensional facial morphology identifies a variant in PAX3 associated with nasion position. , 2012, American journal of human genetics.

[4]  Robert Plomin,et al.  Socioeconomic Status (SES) and Children's Intelligence (IQ): In a UK-Representative Sample SES Moderates the Environmental, Not Genetic, Effect on IQ , 2012, PloS one.

[5]  J. Tobias,et al.  Insights into the programming of bone development from the Avon Longitudinal Study of Parents and Children (ALSPAC). , 2011, The American journal of clinical nutrition.

[6]  P. Robson,et al.  Corrigendum to " Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study" [NeuroToxicology 29(5) (2008) 776-782] , 2011 .

[7]  V. Boiteau,et al.  Relation between Methylmercury Exposure and Plasma Paraoxonase Activity in Inuit Adults from Nunavik , 2011, Environmental health perspectives.

[8]  Toshiko Tanaka,et al.  Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels. , 2011, Human molecular genetics.

[9]  P. Robson,et al.  A longitudinal analysis of prenatal exposure to methylmercury and fatty acids in the Seychelles. , 2011, Neurotoxicology and teratology.

[10]  Pauline Emmett,et al.  Are dietary patterns in childhood associated with IQ at 8 years of age? A population-based cohort study , 2011, Journal of Epidemiology & Community Health.

[11]  M. Vrijheid,et al.  Socioeconomic status and exposure to multiple environmental pollutants during pregnancy: evidence for environmental inequity? , 2010, Journal of Epidemiology & Community Health.

[12]  E. Castrén,et al.  Effects of maternal smoking and exposure to methylmercury on brain-derived neurotrophic factor concentrations in umbilical cord serum. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[13]  M. Hengstschläger,et al.  The relevance of the individual genetic background for the toxicokinetics of two significant neurodevelopmental toxicants: mercury and lead. , 2010, Mutation research.

[14]  D. Mendonça,et al.  BDNF and CGRP interaction: Implications in migraine susceptibility , 2010, Cephalalgia : an international journal of headache.

[15]  M. Kogevinas,et al.  Maternal fish and other seafood intakes during pregnancy and child neurodevelopment at age 4 years , 2009, Public Health Nutrition.

[16]  Antonio F. Hernández,et al.  Interaction between human serum esterases and environmental metal compounds. , 2009, Neurotoxicology.

[17]  M. Sakaue,et al.  Acceleration of methylmercury-induced cell death of rat cerebellar neurons by brain-derived neurotrophic factor in vitro , 2009, Brain Research.

[18]  Leena Peltonen,et al.  Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. , 2009, American journal of human genetics.

[19]  P. Robson,et al.  Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study. , 2008, Neurotoxicology.

[20]  P. Grandjean,et al.  Negative Confounding in the Evaluation of Toxicity: The Case of Methylmercury in Fish and Seafood , 2008, Critical reviews in toxicology.

[21]  Robert L. Jones,et al.  Fish consumption in pregnancy, cord blood mercury level and cognitive and psychomotor development of infants followed over the first three years of life: Krakow epidemiologic study. , 2007, Environment international.

[22]  S. Nelson,et al.  Association of progesterone receptor with migraine-associated vertigo , 2007, Neurogenetics.

[23]  I. Deary,et al.  A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition , 2007, BMC Genetics.

[24]  N. Saunders,et al.  Developmental neurotoxicity of industrial chemicals , 2007, The Lancet.

[25]  John M. Davis,et al.  Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study , 2007, The Lancet.

[26]  Esben Budtz-Jørgensen,et al.  Separation of Risks and Benefits of Seafood Intake , 2006, Environmental health perspectives.

[27]  E. Budtz-Jørgensen,et al.  Selenium as a potential protective factor against mercury developmental neurotoxicity. , 2006, Environmental research.

[28]  K. Kleinman,et al.  Maternal Fish Consumption, Hair Mercury, and Infant Cognition in a U.S. Cohort , 2005, Environmental health perspectives.

[29]  E. Budtz-Jørgensen,et al.  Umbilical Cord Mercury Concentration as Biomarker of Prenatal Exposure to Methylmercury , 2005, Environmental health perspectives.

[30]  M. Longnecker,et al.  Fish Intake During Pregnancy and Early Cognitive Development of Offspring , 2004, Epidemiology.

[31]  Roberta F. White,et al.  Consequences of exposure measurement error for confounder identification in environmental epidemiology , 2003, Statistics in medicine.

[32]  J. Chatton,et al.  Brain-Derived Neurotrophic Factor Stimulates Energy Metabolism in Developing Cortical Neurons , 2003, The Journal of Neuroscience.

[33]  M. Karayiorgou,et al.  Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. , 2003, American journal of human genetics.

[34]  前田 健康,et al.  BDNF(brain-derived neurotrophic factor)の機械受容器における役割 , 2002 .

[35]  E. Budtz-Jørgensen,et al.  Maternal seafood diet, methylmercury exposure, and neonatal neurologic function. , 2000, The Journal of pediatrics.

[36]  Abraham Silvers,et al.  Influence of Prenatal Mercury Exposure Upon Scholastic and Psychological Test Performance: Benchmark Analysis of a New Zealand Cohort , 1998, Risk analysis : an official publication of the Society for Risk Analysis.

[37]  Roberta F. White,et al.  Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. , 1997, Neurotoxicology and teratology.

[38]  G. Smith,et al.  Bias due to measurement imprecision , 1992, The Lancet.

[39]  P. Grandjean,et al.  Methylmercury and brain development: imprecision and underestimation of developmental neurotoxicity in humans. , 2011, The Mount Sinai journal of medicine, New York.

[40]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[41]  D. Stein,et al.  Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. , 2009, Progress in brain research.

[42]  R. Yokel.  Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. , 2006, Journal of Alzheimer's disease : JAD.

[43]  P. Stewart,et al.  Cognitive development in preschool children prenatally exposed to PCBs and MeHg. , 2003, Neurotoxicology and teratology.

[44]  M. Pembrey,et al.  ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology. , 2001, Paediatric and perinatal epidemiology.

[45]  A. Phillips,et al.  Bias in relative odds estimation owing to imprecise measurement of correlated exposures. , 1992, Statistics in medicine.

[46]  H. Tsuchiya,et al.  Placental transfer of heavy metals in normal pregnant Japanese women. , 1984, Archives of environmental health.