Fetal exposure of man and mice to mercury (Hg) induces long-term behavioral and neuronal dysfunctions, but the mechanistic involvement of neuroendocrine immune network activities, e.g.,hypothalamo-pituitary- adrenal (HPA) axis, centrally located immune cells (microglia and mast cells), and autoantibodies to central nervous system (CNS) antigens, have not been adequately addressed. In addition, based on their genetic differences, certain mouse strains develop Hg-induced immunopathologies (autoimmune disease), which are posited to include autoantibody-induced neuroinflammation, leading to neuronal damage and dysfunction. Hg induces enhancement of type-2 immunity, which includes heightened levels of Th2 cytokines IL-4, IL-5 and IL-6 as well as IgE and elevated release of factors from mast cells, eosinophils and basophils. Some mouse strains (e.g., BALB/c mice) develop immune complexes which can localize in certain organs eliciting inflammation whereas mice with the H-2s haplotype (e.g., A.SW mice) develop autoantibodies that bind to select antigens directly initiating targeted damage. We hypothesize that based on the genetics and environmental exposures, some strains have CNS inflammation due to antibodies inducing activation of microgia and mast cells, which leads to behavioral aberrance and neuropathological outcomes that occur in adults following developmental exposures to Hg. The sequence of events that culminate in adult neuroimmune-induced pathologies are posited to be: i) altered neuroendocrine regulation, which enhances type-2 immunity; ii) increased autoimmune responses to CNS antigens; iii)modulation of immune cell (microglia and mast cells) distribution and function in the brain; and iv) elevated neuroinflammation which disrupts neuronal functions. We will first demonstrate that Hg enhances generation of autoantibodies to CNS antigens, dependent on haplotype, and then identify the autoantigens.
Aim 2 will investigate the specific brain regions with autoantibodies and the phenotype of the cells present.
Aim 3 will evaluate whether autoantibodies in the absence of Hg can cause similar neuroinflammation in Hg-susceptible (H-2s and Th2-prone strains) and Hg-non-susceptible strains. We suggest that certain environmental agents can initiate heightened immunity to self-antigens, including brain antigens, based on the genetics of the host. We will compare the ability of inorganic and organic Hg to initiate the described consequences.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES013857-02
Application #
7514651
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
2006-12-01
Project End
2010-11-30
Budget Start
2007-12-01
Budget End
2010-11-30
Support Year
2
Fiscal Year
2008
Total Cost
$163,197
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204
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Zhang, Yubin; Bolivar, Valerie J; Lawrence, David A (2012) Developmental exposure to mercury chloride does not impair social behavior of C57BL/6 ýý BTBR F(1) mice. J Immunotoxicol 9:401-10
Kasten-Jolly, Jane; Pabello, Nina; Bolivar, Valerie J et al. (2012) Developmental lead effects on behavior and brain gene expression in male and female BALB/cAnNTac mice. Neurotoxicology 33:1005-20
Kasten-Jolly, Jane; Heo, Yong; Lawrence, David A (2011) Central nervous system cytokine gene expression: modulation by lead. J Biochem Mol Toxicol 25:41-54
Zhang, Yubin; Gao, Donghong; Bolivar, Valerie J et al. (2011) Induction of autoimmunity to brain antigens by developmental mercury exposure. Toxicol Sci 119:270-80
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Gao, Donghong; Mondal, Tapan K; Lawrence, David A (2007) Lead effects on development and function of bone marrow-derived dendritic cells promote Th2 immune responses. Toxicol Appl Pharmacol 222:69-79