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Genetic diversity influences the response of the brain to developmental lead exposure.

ABSTRACT: Although extrinsic factors, such as nutritional status, and some intrinsic genetic factors may modify susceptibility to developmental lead (Pb) poisoning, no studies have specifically examined the influence of genetic background on outcomes from Pb exposure. In this study, we used gene microarray profiling to identify Pb-responsive genes in rats of different genetic backgrounds, including inbred (Fischer 344 (F344)) and outbred (Long Evans (LE), Sprague Dawley (SD)) strains, to investigate the role that genetic variation may play in influencing outcomes from developmental Pb exposure. Male and female animals received either perinatal (gestation through lactation) or postnatal (birth through weaning) exposure to Pb in food (0, 250, or 750 ppm). RNA was extracted from the hippocampus at day 55 and hybridized to Affymetrix Rat Gene 1.0 ST Arrays. There were significant strain-specific effects of Pb on the hippocampal transcriptome with 978 transcripts differentially expressed in LE rats across all experimental groups, 269 transcripts differentially expressed in F344 rats, and only 179 transcripts differentially expressed in SD rats. These results were not due to strain-related differences in brain accumulation of Pb. Further, no genes were consistently differentially regulated in all experimental conditions. There was no set of "Pb toxicity" genes that are a molecular signature for Pb neurotoxicity that transcended sex, exposure condition, and strain. These results demonstrate the influence that strain and genetic background play in modifying the brain's response to developmental Pb exposure and may have relevance for better understanding the molecular underpinnings of the lack of a neurobehavioral signature in childhood Pb poisoning.

SUBMITTER: Schneider JS

PROVIDER: S-EPMC4271117 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Genetic diversity influences the response of the brain to developmental lead exposure.

Schneider Jay S JS Talsania Keyur K Mettil William W Anderson David W DW

Toxicological sciences : an official journal of the Society of Toxicology 20140609 1

Although extrinsic factors, such as nutritional status, and some intrinsic genetic factors may modify susceptibility to developmental lead (Pb) poisoning, no studies have specifically examined the influence of genetic background on outcomes from Pb exposure. In this study, we used gene microarray profiling to identify Pb-responsive genes in rats of different genetic backgrounds, including inbred (Fischer 344 (F344)) and outbred (Long Evans (LE), Sprague Dawley (SD)) strains, to investigate the r ...[more]

PMID: 24913800

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Project description:ImportanceAlthough the effects of lead (Pb) exposure on neurocognition in children have been confirmed, the individual associations of prenatal Pb exposure and its interaction with genetic factors on cognitive developmental delay (CDD) in children remain unclear.ObjectiveTo investigate the association of prenatal Pb exposure and its interaction with genetic factors with CDD risk.Design, setting, and participantsWomen in Wuhan, China, who had an expected delivery date between March 2014 and December 2017, were recruited for this prospective cohort study. Children were assessed for cognitive development at approximately 2 years of age (March 2016 to December 2019). Maternal venous blood, cord blood, and venous blood from children were collected in a longitudinal follow-up. Data analysis was performed from March 2022 to February 2023.ExposurePrenatal Pb exposure, and genetic risk for cognitive ability evaluated by polygenic risk score constructed with 58 genetic variations.Main outcomes and measuresCognitive developmental delay of children aged approximately 2 years was assessed using the Chinese revision of the Bayley Scale of Infant Development. A series of multivariable logistic regressions was estimated to determine associations between prenatal Pb exposure and CDD among children with various genetic backgrounds, adjusting for confounding variables.ResultsThis analysis included 2361 eligible mother-child pairs (1240 boys [52.5%] and 1121 girls [47.5%]; mean [SD] ages of mothers and children, 28.9 [3.6] years and 24.8 [1.0] months, respectively), with 292 children (12.4%) having CDD. Higher maternal Pb levels were significantly associated with increased risk of CDD (highest vs lowest tertile: odds ratio, 1.55; 95% CI, 1.13-2.13), adjusting for demographic confounders. The association of CDD with maternal Pb levels was more evident among children with higher genetic risk (highest vs lowest tertile: odds ratio, 2.59; 95% CI, 1.48-4.55), adjusting for demographic confounders.Conclusions and relevanceIn this cohort study, prenatal Pb exposure was associated with an increased risk of CDD in children, especially in those with a high genetic risk. These findings suggest that prenatal Pb exposure and genetic background may jointly contribute to an increased risk of CDD for children and indicate the possibility for an integrated strategy to assess CDD risk and improve children's cognitive ability.

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Genetic diversity influences the response of the brain to developmental lead exposure.

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Genetic diversity influences the response of the brain to developmental lead exposure.

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