title: Developmental lead effects on behavior and brain gene expression in male and female BALB/cAnNTac mice.
abstract: Lead (Pb) was one of the first poisons identified, and the developing nervous system is particularly vulnerable to its toxic effects. Relatively low, subclinical doses, of Pb that produce no overt signs of encephalopathy can affect cognitive, emotional, and motor functions. In the present study, the effects of developmental Pb-exposure on behavioral performance and gene expression in BALB/cAnNTac mice were evaluated. Pups were exposed to Pb from gestational-day (gd) 8 to postnatal-day (pnd) 21 and later evaluated in exploratory behavior, rotarod, Morris water maze, and resident-intruder assays as adults. Pb-exposure caused significant alterations in exploratory behavior and water maze performance during the probe trial, but rotarod performance was not affected. Pb-exposed males displayed violent behavior towards their cage mates, but not to a stranger in the resident-intruder assay. Gene expression analysis at pnd21 by microarray and qRT-PCR was performed to provide a molecular link to the behavior changes that were observed. Pb strongly up-regulated gene expression within the signaling pathways of mitogen activated protein kinases (MAPKs), extra-cellular matrix (ECM) receptor, focal adhesion, and vascular endothelial growth-factor (VEGF), but Pb down-regulated gene expression within the pathways for glycan structures-biosynthesis 1, purine metabolism, and N-glycan biosynthesis. Pb increased transcription of genes for major histocompatibility (MHC) proteins, the chemokine Ccl28, chemokine receptors, IL-7, IL7R, and proteases. The qRT-PCR analysis indicated an increase of gene expression in the whole brain for caspase 1 and NOS2. Analysis of IL-1β, caspase 1, NOS2, Trail, IL-18 and IL-33 gene expression of brain regions indicated that Pb perturbed the inter-regional expression pattern of pro-inflammatory genes. Brain region protein concentrations for IL-10, an anti-inflammatory cytokine, showed a significant decrease only within the cortex region. Results indicate that Pb differentially affects the behavior of male and female mice in that females did less exploration and the males were selectively more aggressive. Gene expression data pointed to evidence of neuroinflammation in the brain of both female and male mice. Pb had more of an effect in the males on expression of vomeronasal receptor genes associated with odor detection and social behavior.
authors.affiliation: New York State Department of Health, Wadsworth Center, Albany, NY 12208, USA. kjolly@wadsworth.org
authors.forename: Jane
authors.initials: J
authors.lastname: Kasten-Jolly
authors.forename: Nina
authors.initials: N
authors.lastname: Pabello
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Bolivar
authors.forename: David A
authors.initials: DA
authors.lastname: Lawrence
mesh_terms: D000367:Age Factors; D000374:Aggression / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007854:Lead / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000235:genetics; D045442:Rotarod Performance Test; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D042442:Vascular Endothelial Growth Factors; C052131:extracellular matrix receptor; D007854:Lead