? ? The overall goal is to demonstrate a link between mercury (Hg) exposure and elevated risks of autoimmune disease. In this project, the investigators will test two hypotheses in translational research linking basic research in an animal model of autoimmune disease and a pilot epidemiological study in a Hg-exposed human population in Amazonian Brazil. The hypotheses are that: 1) exposure of mice (adults and fetuses) to Hg, at low dose, can result in changes in the innate immune response to infection such that ultimately post-infection autoimmune disease is exacerbated in terms of severity and prevalence and 2) exposure of humans to Hg, at low dose, can result in changes in the immune system that are measurable and indicative of elevated risk of autoimmune dysfunction. Autoimmune diseases are among the most devastating chronic diseases in the US, affecting nearly 50 million people. While autoimmune diseases are generally recognized to involve both heritable and acquired risk factors, relatively little is known about the latter risks for human disease aside from exposure to infectious agents, such as viruses and bacteria. These infectious agents are believed to trigger the development of autoimmune diseases, but the expression and severity of disease may be a reflection of pre-existing genetic susceptibility. This project will assess programming changes that occur during the innate immune response to infection following exposure (either at adulthood or during fetal development) to Hg, with an overall effect on the progression of Coxsackie virus-induced autoimmune heart disease in mice and apply the biomarkers mined from the studies in animals to a Hg-exposed human population in Amazonian Brazil. ? ? Specific Aim 1: To test the hypothesis that adult (murine) exposure to Hg induces changes in the innate immune response to Coxsackie virus infection, which result in exacerbation of subsequent autoimmune heart disease. ? ? Specific Aim 2: To test the hypothesis that fetal (murine) exposure to Hg induces changes in the immune system that are long lasting and that these early events affect the innate immune response to Coxsackie virus infection and the subsequent development of autoimmune heart disease in adulthood. ? ? Specific Aim 3: To test the hypothesis that human exposure to Hg induces changes in the immune system that are measurable and indicative of elevated risk of autoimmune dysfunction. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Career Transition Award (K99)
Project #
1K99ES015426-01
Application #
7224405
Study Section
Special Emphasis Panel (ZES1-LKB-C (K9))
Program Officer
Shreffler, Carol K
Project Start
2006-12-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
1
Fiscal Year
2007
Total Cost
$90,585
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Penta, Kayla L; Fairweather, DeLisa; Shirley, Devon L et al. (2015) Low-dose mercury heightens early innate response to coxsackievirus infection in female mice. Inflamm Res 64:31-40
Motts, Jonathan A; Shirley, Devon L; Silbergeld, Ellen K et al. (2014) Novel biomarkers of mercury-induced autoimmune dysfunction: a cross-sectional study in Amazonian Brazil. Environ Res 132:12-8
Nyland, Jennifer F; Fairweather, DeLisa; Shirley, Devon L et al. (2012) Low-dose inorganic mercury increases severity and frequency of chronic coxsackievirus-induced autoimmune myocarditis in mice. Toxicol Sci 125:134-43
Nyland, Jennifer F; Wang, Susie B; Shirley, Devon L et al. (2011) Fetal and maternal immune responses to methylmercury exposure: a cross-sectional study. Environ Res 111:584-9
Nyland, Jennifer F; Fillion, Myriam; Barbosa Jr, Fernando et al. (2011) Biomarkers of methylmercury exposure immunotoxicity among fish consumers in Amazonian Brazil. Environ Health Perspect 119:1733-8
Gardner, Renee M; Nyland, Jennifer F; Silbergeld, Ellen K (2010) Differential immunotoxic effects of inorganic and organic mercury species in vitro. Toxicol Lett 198:182-90
Gardner, Renee M; Nyland, Jennifer F; Silva, Ines A et al. (2010) Mercury exposure, serum antinuclear/antinucleolar antibodies, and serum cytokine levels in mining populations in Amazonian Brazil: a cross-sectional study. Environ Res 110:345-54
Nyland, Jennifer F; Bai, Jennifer J K; Katz, Howard E et al. (2009) In vitro interactions between splenocytes and dansylamide dye-embedded nanoparticles detected by flow cytometry. Nanomedicine 5:298-304
Nyland, J F; Silbergeld, E K (2009) A nanobiological approach to nanotoxicology. Hum Exp Toxicol 28:393-400