PMID- 22609695 OWN - NLM STAT- MEDLINE DCOM- 20130321 LR - 20211021 IS - 1872-9711 (Electronic) IS - 0161-813X (Print) IS - 0161-813X (Linking) VI - 33 IP - 5 DP - 2012 Oct TI - Developmental lead effects on behavior and brain gene expression in male and female BALB/cAnNTac mice. PG - 1005-20 LID - S0161-813X(12)00093-9 [pii] LID - 10.1016/j.neuro.2012.04.017 [doi] AB - 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-1beta, 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. CI - Copyright (c) 2012 Elsevier Inc. All rights reserved. FAU - Kasten-Jolly, Jane AU - Kasten-Jolly J AD - New York State Department of Health, Wadsworth Center, Albany, NY 12208, USA. kjolly@wadsworth.org FAU - Pabello, Nina AU - Pabello N FAU - Bolivar, Valerie J AU - Bolivar VJ FAU - Lawrence, David A AU - Lawrence DA LA - eng GR - R01 ES011135/ES/NIEHS NIH HHS/United States GR - R21 ES013857/ES/NIEHS NIH HHS/United States GR - ES013857/ES/NIEHS NIH HHS/United States GR - ES011135/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20120516 PL - Netherlands TA - Neurotoxicology JT - Neurotoxicology JID - 7905589 RN - 0 (Cytokines) RN - 0 (Nerve Tissue Proteins) RN - 0 (Receptors, Cell Surface) RN - 0 (Vascular Endothelial Growth Factors) RN - 0 (extracellular matrix receptor) RN - 2P299V784P (Lead) SB - IM MH - Age Factors MH - Aggression/drug effects MH - Animals MH - Animals, Newborn MH - Behavior, Animal/*drug effects MH - *Brain/embryology/growth & development/metabolism MH - Cytokines/genetics/metabolism MH - Embryo, Mammalian MH - Exploratory Behavior/drug effects MH - Female MH - Focal Adhesions/genetics/metabolism MH - Gene Expression Profiling MH - Gene Expression Regulation, Developmental/*drug effects MH - Lead/*toxicity MH - Male MH - Maze Learning/drug effects MH - Mice MH - Mice, Inbred BALB C MH - Motor Activity/drug effects MH - Nerve Tissue Proteins/genetics/metabolism MH - Oligonucleotide Array Sequence Analysis MH - Pregnancy MH - *Prenatal Exposure Delayed Effects/chemically induced/pathology/physiopathology MH - Receptors, Cell Surface/genetics MH - Rotarod Performance Test MH - *Sex Characteristics MH - Signal Transduction/drug effects/genetics MH - Vascular Endothelial Growth Factors/genetics/metabolism PMC - PMC3463649 MID - NIHMS379079 COIS- Conflict of Interest Statement The authors declare that there are no conflicts of interest. EDAT- 2012/05/23 06:00 MHDA- 2013/03/22 06:00 PMCR- 2013/10/01 CRDT- 2012/05/22 06:00 PHST- 2011/09/20 00:00 [received] PHST- 2012/02/02 00:00 [revised] PHST- 2012/04/17 00:00 [accepted] PHST- 2012/05/22 06:00 [entrez] PHST- 2012/05/23 06:00 [pubmed] PHST- 2013/03/22 06:00 [medline] PHST- 2013/10/01 00:00 [pmc-release] AID - S0161-813X(12)00093-9 [pii] AID - 10.1016/j.neuro.2012.04.017 [doi] PST - ppublish SO - Neurotoxicology. 2012 Oct;33(5):1005-20. doi: 10.1016/j.neuro.2012.04.017. Epub 2012 May 16.