title: 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.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 jay.schneider@jefferson.edu.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Schneider
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Keyur
authors.initials: K
authors.lastname: Talsania
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: William
authors.initials: W
authors.lastname: Mettil
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: David W
authors.initials: DW
authors.lastname: Anderson
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D007774:Lactation; D007854:Lead / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D038081:Organogenesis / Q000187:drug effects* / Q000235:genetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000235:genetics*; D011916:Rats, Inbred F344; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012727:Sex Characteristics; D013045:Species Specificity; D059467:Transcriptome
chemical_list: D004785:Environmental Pollutants; D007854:Lead
keywords: development; hippocampus; lead; mRNA; strain differences