Inhibited immune responses have been observed following occupational, inadvertent, or therapeutic exposure to xenobiotics. Further, aberrant immune responses (e.g., hypersensitivity, autoimmunity) appear to be increasing in humans, a phenomenon which may be related to environmental chemical exposure. New research initiatives are determining that such exposures, often previously considered to be innocuous, may in fact be contributing to impaired human immune health. The present proposal considers immunotoxicity resulting from combined dermal exposure to a common pyrethroid insecticide (permethrin) and to cis-urcanic acid (cUCA, an isomerization product of trans-UCA and sunlight). Preliminary data have been generated showing both systemic and regional immunotoxicity from low-level topical permethrin (formerly not considered an immunotoxicant). It has previously been demonstrated that cUCA also inhibits skin and immune responses. The proposed studies will estimate the risk of immunotoxicity from combined topical permethrin and intradermal cUCA exposure, using National Toxicology Program-approved testing procedures in C57B1/6 inbred mice. These immunotoxicants will also be co-administered at levels determined to inhibit immune responses in mice, to investigate cytokine-dependent mechanisms by which cUCA and/or permethrin may cause suppression of immunity. Further, in that: 1) cUCA has been shown to inhibit antigen presentation by macrophages, 2) new data suggest the epidermal antien presenting cell (APC, Langerhans cell [LC]) may be a target of cUCA, and 3) permethrin was shown by us to inhibit skin contact hypersensitivity responses, the effect of single and combined exposure to these agents on antigen presentation by LC will be examined as a mechanism related to immunotoxicity. Providing new data to assist the estimation of risk from the combined immunotoxicant exposure (cUCA and topical insecticide) in children is a primary goal of the proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES009642-01
Application #
2729059
Study Section
Special Emphasis Panel (ZES1-DPB-A (R))
Project Start
1998-08-15
Project End
2001-07-31
Budget Start
1998-08-15
Budget End
1999-07-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
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Sharova, L V; Sharov, A A; Sura, P et al. (2003) Maternal immune stimulation reduces both placental morphologic damage and down-regulated placental growth-factor and cell cycle gene expression caused by urethane: are these events related to reduced teratogenesis? Int Immunopharmacol 3:945-55
Prater, M Renee; Gogal Jr, Robert M; De Fabo, Edward C et al. (2003) Immunotoxic effects of cis-urocanic acid exposure in C57BL/6N and C3H/HeN mice. Photochem Photobiol 77:383-9
Prater, M R; Blaylock, B L; Holladay, S D (2003) Molecular mechanisms of cis-urocanic acid and permethrin-induced alterations in cutaneous immunity. Photodermatol Photoimmunol Photomed 19:287-94
Prater, M R; Gogal Jr, R M; Blaylock, B L et al. (2003) Cis-urocanic acid increases immunotoxicity and lethality of dermally administered permethrin in C57BL/6N mice. Int J Toxicol 22:35-42
Prater, M R; Gogal Jr, R M; Blaylock, B L et al. (2002) Single-dose topical exposure to the pyrethroid insecticide, permethrin in C57BL/6N mice: effects on thymus and spleen. Food Chem Toxicol 40:1863-73
Punareewattana, K; Smith, B J; Blaylock, B L et al. (2001) Topical permethrin exposure inhibits antibody production and macrophage function in C57Bl/6N mice. Food Chem Toxicol 39:133-9
Holladay, S D; Sharova, L; Smith, B J et al. (2000) Nonspecific stimulation of the maternal immune system. I. Effects On teratogen-induced fetal malformations. Teratology 62:413-9
Sharova, L; Sura, P; Smith, B J et al. (2000) Nonspecific stimulation of the maternal immune system. II. Effects on gene expression in the fetus. Teratology 62:420-8