Welcome to the DeWitt Lab
Our environmental toxicology research program explores the relationships between biological organisms and their responses to emerging chemical contaminants. The lab’s focus is on developmental toxicology, utilizing tools from immunotoxicology and neurotoxicology to ascertain and evaluate the responses of individual organisms to toxicant exposures. A variety of compounds affect immune, nervous, and reproductive function if exposure occurs during development; therefore, our goal is to understand upstream events that might influence the function of more than one system. These types of studies will help us to understand how toxicants exert developmental effects on biological organisms. Our main research interests are:
1) Exploring effects of environmental toxicants on immune function in adult organisms exposed during development. Evaluating immune function allows us to ask “is the immune system doing what it is asked?” We use a variety of functional tests to assess adaptive and innate immunity; such tests are reliable predictors of immunotoxicity and allow us to begin the process of backtracking to modes or mechanism of action at the cellular, molecular, and genetic levels that lead to change in function.
2) Exploring the developmental relationships between the immune system and the nervous system. Specifically, we are interested in how exposure to developmental immunotoxicants leads to changes in nervous system function that may occur via common mechanisms of action. Developmental immunotoxicity (DIT) occurs when the developing immune system experiences an adverse outcome after exposure to a toxicant or other stressor. Exposure to developmental immunotoxicants has been suggested in several neurological disorders, including autism and autism spectrum disorder, chronic fatigue syndrome, and mental retardation, and possibly plays a role in disease susceptibility in aging populations. We are especially interested in regulatory T cells (Tregs) and how toxicant effects on Tregs may lead to damage from autoreactivity.
Our recent work has centered on immune system effects of perfluorooctanoic acid (PFOA), a fluorinated compound with myriad industrial and commercial applications that is of regulatory concern to the U.S. Environmental Protection Agency (EPA). Our data indicate that T-dependent antibody responses are suppressed in adults exposed to PFOA for only 15 days. We are currently exploring differences in host phenotype, corticosterone production, and the role of the peroxisome proliferator activated receptor alpha (PPARα) as potential mechanisms of this suppression. We are also evaluating immune responses in offspring developmentally exposed to PFOA as several studies suggest that PFOA is a developmental toxicant.
In addition to understanding the immunotoxicity of PFOA, we are developing models for evaluating neurological responses after exposure to developmental immunotoxicants. We are currently exploring developmental immunopathogenesis in the etiology of autism and autism spectrum disorders (ASDs). Immune dysfunction is a common immunological finding among autistic patients, which suggests a role for the immune system in the development of these diseases. My lab is particularly interested in understanding the relationships among developmental exposure to environmental agents, regulatory T cells (Tregs), autoreactive T cells, and neurological damage. Our basic hypothesis is that an autistic phenotype occurs after developmental exposure to an environmental agent disrupts the Treg population and results in dysregulation of autoreactive T cells. We believe that autoreactive T cells lead to neuronal damage and suspect that mast cells alter the permeability of the blood-brain barrier to allow infiltration of autoreactive T cells into the brain (we are working with Dr. Jared Brown to develop a mast cell project).
Selected publications:
Papers
DeWitt JC, Copeland CB, and Luebke RW. 2009. Suppression of humoral immunity by perfluorooctanoic acid is independent of elevated serum corticosterone concentration in mice. Toxicological Sciences. 109:106-12.
Peden-Adams MM, Stuckey JE, Gaworecki K, Berger-Ritchie J, Bryant K, Jodice PG, Scott TR, Boone S, McGuinn WD, DeWitt JC, Keil DE. 2009. Developmental toxicity in white leghorn chickens following in ovo exposure to perfluorooctane sulfonate (PFOS). Reproductive Toxicology. 27:307-18.
Whalen MM, DeWitt JC, Luebke RW. 2008. Serum supplementation modulates the effects of dibutyltin on human natural killer cell function. Toxicological Sciences, 104:312-319.
DeWitt JC, Copeland CB, Strynar MJ, and Luebke RW. 2008. Perflurooctanoic acid-induced immunomodulation in adult C57BL/6J or C57BL/6 female mice. Environmental Health Perspectives. 116:644-650.
DeWitt JC, Copeland CB, and Luebke RW. 2008. An organotin mixture found in polyvinyl chloride (PVC) pipe is not immunotoxic to adult Sprague-Dawley rats. Journal of Toxicology and Environmental Health Part A. 71:276-282.
DeWitt JC, Copeland CB, and Luebke RW. 2007. Immune function in Sprague-Dawley rats exposed to dimethyltin dichloride in drinking water during development or adulthood. Toxicology. 232:303-310.
Lim J, DeWitt JC, Sanders RA, Watkins JB III, and Henshel DS. 2007. Suppression of endogenous anti-oxidant enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin-Induced oxidative stress in chicken liver during development. Archives of Environmental Contamination and Toxicology. 52:590-595.
DeWitt JC, Copeland CB, and Luebke RW. 2006. Developmental exposure to 1.0 or 2.5 mg/kg of dibutyltin dichloride does not impair immune function in Sprague-Dawley rats. Journal of Immunotoxicology. 3:245-252.
DeWitt JC, Millsap DS, Yeager RL, Heise SS, Sparks DW, and Henshel, DS. 2006. External heart deformities in passerine birds exposed to environmental mixtures of polychlorinated biphenyls during development. Environmental Toxicology and Chemistry. 25(2):541-551.
DeWitt JC, Copeland CB, and Luebke RW. 2005. Immune responses in sprague-dawley rats exposed to dibutyltin dichloride in drinking water as adults. Journal of Immunotoxicology. 2:151-160.
DeWitt JC, Meyer EB, and Henshel DS. 2005. Environmental toxicity studies using chickens as surrogates for wildlife: Effects of vehicle volume. Archives of Environmental Contamination and Toxicology. 48:260-269.
DeWitt JC, Meyer EB, Watkins JB, and Henshel DS. 2005. Environmental toxicity studies using chickens as surrogates for wildlife: Effects of day of injection. Archives of Environmental Contamination and Toxicology. 48:270-277.
Stanton B, DeWitt J, Henshel D, Watkins S, and Lasley B. 2003. Fatty acid metabolism in neonatal chickens (Gallus domesticus) treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3’,4,4’,5-pentachlorobiphenyl (PCB-126) in ovo. Comparative Biochemistry and Physiology C - Pharmacology and Toxicology, 136:73-84.
Henshel DS, Martin JW and DeWitt JC. 1997. Brain asymmetry as a potential biomarker for developmental TCDD intoxication: A dose-response study. Environmental Health Perspectives. 105:2-11.
Henshel DS, Martin JW, Norstrom RJ, Elliot J, Cheng KM and DeWitt JC. 1997. Morphometric brain abnormalities in double-crested cormorant chicks exposed to polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls. Journal of Great Lakes Research. 23:11-26.
Book Chapters and Reviews
DeWitt JC, Shnyra A, Badr MZ, Loveless SE, Hoban D, Frame SR, Cunard R, Anderson SE, Meade BJ, Peden-Adams MM, Luebke RW, and Luster MI. 2009. Immunotoxicity of perfluorooctanoic acid and perfluorooctane sulfonate and the role of peroxisome proliferator activated receptor alpha. Critical Reviews in Toxicology 39:76-94.
Dietert, R.R. and DeWitt, J. 2009. Developmenntal immunotoxicity (DIT): the why, where and how of DIT Testing. In Dietert. R.R. (ed.) /Immunotoxicity Testing/. Humana Press, Inc., Totowa, NJ, in press.
Luebke RW, Beamer CA, Bowman C, DeWitt J, Gowdy K, Johnson VJ, Shepherd DM, and Germolec DR. Immunotoxicology. In: General and Applied Toxicology, 3rd Edition (MB Silva, Ed.), John Wiley & Sons, West Sussex, UK, in press.
Luebke RW and DeWitt JC. Aging and the Immune System. In: Comprehensive Toxicology, 2nd Edition (Ed.), Elsevier Limited, Oxford, UK, in press.
Henshel DS, DeWitt JC, and Troutman, A. Using chicken embryos for teratology studies. In: Current Protocols in Toxicology (M.D. Maines, L.G. Costa, E. Hodgson, D.J. Reed, and I.G. Sipes, Eds.), Supplement 14, pp. 13.4.1-13.4.19. 2002.
