Lower socioeconomic status (SES) children in the U.S. are now the primary target of elevated lead (Pb) exposure. Low SES is already a risk factor for disease and behavioral dysfunctions, including learning disorders in children, an effect believed due to greater environmental stress in low SES populations and associated prolonged cortisol elevation. Even higher SES populations experience chronic life stress. Pb and stress both affect brain mesocorticolimbic (MES) systems and produce similar behavioral deficits. An obvious question is whether Pb and stress interact, and, if so, how does it change our understanding of mechanisms of Pb neurotoxicity and associated human health risks? Our current studies demonstrate Pb/ stress interactions from preweaning or postweaning Pb and permanently elevated corticosterone levels in offspring after maternal Pb alone. This application examines the hypothesis that Pb and stress interact by altering corticosterone which then modulates MES function and associated behavioral and neurochemical effects of Pb. Using preweaning or continuous Pb with maternal stress or maternal plus offspring stress, the proposed experiments will examine how Pb exposure level, stress and gender influence the expression and nature of Pb-stress interactions for behavioral function using 2 baselines with demonstrated Pb sensitivity and mediated by MES systems (Fixed Interval, repeated learning). Time course profiles of associated changes in neurochemical function, corticosterone binding and plasma corticosterone will be related to behavior. Corticosteroid antagonists and maternal adrenalectomy wjll be used to provide a mechanistic understanding of corticosterone's role in Pb or Pb+stress effects. Brain Pb alterations as a potential mechanism will also be evaluated. Pb+stress interactions pose questions about our current understanding of mechanisms of Pb neurotoxicity and of the adequacy of current risk assessment. If Pb alters corticosterone and stress responsiveness, it could also modulate susceptibility to disease and dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
7R01ES012712-04
Application #
7555974
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-09-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$459,851
Indirect Cost
Name
University of Rochester
Department
Dentistry
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Beier, Eric E; Holz, Jonathan D; Sheu, Tzong-Jen et al. (2016) Elevated Lifetime Lead Exposure Impedes Osteoclast Activity and Produces an Increase in Bone Mass in Adolescent Mice. Toxicol Sci 149:277-88
Beier, Eric E; Sheu, Tzong-Jen; Dang, Deborah et al. (2015) Heavy Metal Ion Regulation of Gene Expression: MECHANISMS BY WHICH LEAD INHIBITS OSTEOBLASTIC BONE-FORMING ACTIVITY THROUGH MODULATION OF THE Wnt/?-CATENIN SIGNALING PATHWAY. J Biol Chem 290:18216-26
Beier, Eric E; Sheu, Tzong-Jen; Buckley, Taylor et al. (2014) Inhibition of beta-catenin signaling by Pb leads to incomplete fracture healing. J Orthop Res 32:1397-405
Weston, Hiromi I; Weston, Douglas D; Allen, Joshua L et al. (2014) Sex-dependent impacts of low-level lead exposure and prenatal stress on impulsive choice behavior and associated biochemical and neurochemical manifestations. Neurotoxicology 44:169-83
Cory-Slechta, Deborah A; Weston, Douglas; Liu, Sue et al. (2013) Brain hemispheric differences in the neurochemical effects of lead, prenatal stress, and the combination and their amelioration by behavioral experience. Toxicol Sci 132:419-30
Beier, Eric E; Maher, Jason R; Sheu, Tzong-Jen et al. (2013) Heavy metal lead exposure, osteoporotic-like phenotype in an animal model, and depression of Wnt signaling. Environ Health Perspect 121:97-104
Cory-Slechta, Deborah A; Merchant-Borna, Kian; Allen, Joshua L et al. (2013) Variations in the nature of behavioral experience can differentially alter the consequences of developmental exposures to lead, prenatal stress, and the combination. Toxicol Sci 131:194-205
Cory-Slechta, D A; Virgolini, M B; Liu, S et al. (2012) Enhanced stimulus sequence-dependent repeated learning in male offspring after prenatal stress alone or in conjunction with lead exposure. Neurotoxicology 33:1188-202
Rossi-George, A; Virgolini, M B; Weston, D et al. (2011) Interactions of lifetime lead exposure and stress: behavioral, neurochemical and HPA axis effects. Neurotoxicology 32:83-99
Cory-Slechta, D A; Virgolini, M B; Rossi-George, A et al. (2009) Experimental manipulations blunt time-induced changes in brain monoamine levels and completely reverse stress, but not Pb+/-stress-related modifications to these trajectories. Behav Brain Res 205:76-87

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