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. 2014 Sep;141(1):29-43.
doi: 10.1093/toxsci/kfu101. Epub 2014 Jun 9.

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

Jay S Schneider  1 , Keyur Talsania  2 , William Mettil  2 , David W Anderson  2
Affiliations

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

Jay S Schneider et al. Toxicol Sci. 2014 Sep.

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.

Keywords: development; hippocampus; lead; mRNA; strain differences.

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Figures

FIG. 1.
FIG. 1.
Blood and brain lead (Pb) levels in male and female Long Evans, Fischer 344 and Sprague Dawley rats. Rats received Pb exposure over different developmental periods (perinatal or postnatal) and received different levels of exposure (0 ppm = control animals/no Pb exposure; 250 or 750 ppm Pb acetate incorporated into chow). Blood and brain (cerebellum) samples were taken for analysis at time of euthanasia (postnatal day 55). *p < 0.05; **p < 0.01; ****p < 0.0001.
FIG. 2.
FIG. 2.
Differential gene expression in response to lead exposure in three strains of rats. Distributions of differentially expressed transcripts in Long Evans, Fischer 344, and Sprague Dawley rats across the experimental factors considered in the statistical analysis. The circles for sex and lead/exposure indicate transcripts significantly affected by these factors independently. Lead/exposure is a combined factor of lead dose and exposure period. (Lead/exposure): sex indicates the interaction effect between these factors. The numbers of transcripts that show statistically significant differential expression due to one or more factors are indicated in the Venn diagram.
FIG. 3.
FIG. 3.
Dose- and exposure period-dependent differential gene expression in male Long Evans, Fischer 344, and Sprague Dawley rats. Heat map visualization of transcript profiles show differential expression in perinatal and postnatal conditions both within and across strains. The vertical bars adjacent to the heat maps indicate the genes that show significant changes for each of the two lead dose levels studied. Up- and downregulated gene expression is represented by red and green, respectively in the heat maps. Fold-change calibration bar (−1 to 1) appears at the bottom of the figure.
FIG. 4.
FIG. 4.
Dose- and exposure period-dependent differential gene expression in female Long Evans, Fischer 344, and Sprague Dawley rats. Heat map visualization of transcript profiles show differential expression in perinatal and postnatal conditions both within and across strains. The vertical bars adjacent to the heat maps indicate the genes that show significant changes for each of the two lead dose levels studied. Up- and downregulated gene expression is represented by red and green, respectively in the heat maps. Fold-change calibration bar (−1 to 1) appears at the bottom of the figure.
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References

    1. Advisory Committee on Childhood Lead Poisoning Prevention. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. 2012. Available at: http://www.cdc.gov/nceh/lead/ACCLPP/Final_Document_030712.pdf. Accessed May 19, 2014.
    1. Anderson D. W., Mettil W., Kidd S. K., Schneider J. S. Effects of developmental lead exposure on associative learning and memory are modified by sex, developmental window of exposure and level of exposure. The Toxicologist. 2012b;126:131. (Abstract)
    1. Anderson D. W., Pothakos K., Schneider J. S. Sex and rearing condition modify the effects of perinatal lead exposure on learning and memory. Neurotoxicology. 2012a;33:985–995. - PMC - PubMed
    1. Bellinger D., Rappaport L. Developmental assessment and interventions. In: Harvey B., editor. Managing Elevated Blood Lead Levels Among Young Children: Recommendations from the Advisory Committee on Childhood Lead Poisoning Prevention. US Department of Health and Human Services, PHS; 2002. pp. 77–95.
    1. Centers for Disease Control (US) Preventing lead poisoning in young children: A statement by the Centers for Disease Control. Atlanta: CDC; 1991. Available at: http://www.cdc.gov/nceh/lead/Publications/books/plpyc/contents.htm. Accessed May 19, 2014.

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