University of Belgrade
Department of Ecology
Immunotoxicology as a discipline originated due to recognition of environmental chemicals and therapeutic drugs potential to alter immune function and increase sensitivity to infections and cancers. Owing to its complexity, the immune system represents a sensitive target for a variety of environmental influences such as xenobiotics, which might change immune function per se, and/or alter host sensitivity to diseases. The aim of our investigations is to examine immunomodulatory effects of selected xenobiotics, namely heavy metal cadmium, as one of the most important environmental pollutants, and widely used anticoagulant warfarin. In order to assess immunotoxicity of cadmium and warfarin, tiered approach composed of a series of assays is used. Using TIER 1 approach, direct effects of selected xenobiotics are evaluated based on changes in cellular and molecular mechanisms of immunity in laboratory rats (exposed to nonlethal doses of these agents) in the context of exposure duration and physiological factor such as host genetic variability. Namely, the effect of acute or prolonged administration of agents (in a way that corresponds to the natural way of xenobiotic entry in the organism) was measured using two inbred rat strains (AO and DA) known to mount qualitatively and/or quantitatively different immune responses to chemical and biological insults. Beside traditional tissues used for immunotoxicological investigations like blood and spleen, effects of xenobiotics on specialized tissues such as gut, skin and lungs (and associated lymph nodes), that are important for maintaining host immune homeostasis, were analyzed as well. TIER 2 approach is applied in order to assess the significance of affected immune activity induced by xenobiotics for host sensitivity/resistance to additional environmental stimulus, as in vivo correlate to disease susceptibility. Changes in the dynamic of development, intensity of innate and specific cellular immune response and resolution of pulmonary infection with opportunistic fungus Aspergillus fumigatus are used for assessment of immunomodulatory cadmium potential to the lungs. Effects of metal/therapeutic drug on skin immune reactivity are estimated based on changes in the hapten-specific immune responses in a model of contact hypersensitivity to dinitrochlorobenzene. Data showed that both cadmium and warfarin affected immune activity/reactivity of examined tissues, which could have its significance for adverse health effects. Generally, these studies are in correlation with modern epidemiological studies which highlight importance of link between exposure to environmental factors and inflammatory/immune mediated diseases.
Mirkov I, Popov Aleksandrov A, Demenesku J, Ninkov M, Mileusnic D, Zolotarevski L, Subota V, Kataranovski D, Kataranovski M. Intestinal toxicity of oral warfarin intake in rats. Food Chem Toxicol. 2016;94:11–8.
Ninkov M, Popov Aleksandrov A, Mirkov I, Demenesku J, Mileusnic D, Jovanovic Stojanov S, Golic N, Tolinacki M, Zolotarevski L, Kataranovski D, Brceski I, Kataranovski M. Strain differences in toxicity of oral cadmium intake in rats. Food Chem Toxicol. 2016;96:11–23.
Demenesku J, Popov Aleksandrov A, Mirkov I, Ninkov M, Zolotarevski L, Kataranovski D, Brceski I, Kataranovski M. Strain differences of cadmium-induced toxicity in rats: Insight from spleen and lung immune responses. Toxicol Lett. 2016;256:33–43.
Subota V, Mirkov I, Demenesku J, Popov Aleksandrov A., Ninkov M., Mileusnic D., Kataranovski D., Kataranovski M. Transdermal toxicity of topically applied anticoagulant rodenticide warfarin in rats. Environ Toxicol Pharmacol. 2016;41:232–40.
Mirkov I., Popov Aleksandrov A., Ninkov M., Mileusnic D., Demenesku J., Zolotarevski L., Subota V., Stefik D., Kataranovski D., Kataranovski M. Strain differences in intestinal toxicity of warfarin in rats. Environ Toxicol Pharmacol. 2016;48:175–82.
Popov Aleksandrov A., Mirkov I., Zolotarevski L., Ninkov M., Mileusnic D., Kataranovski D., Kataranovski M. Oral warfarin intake affects skin inflammatory cytokine responses in rats. Environ Toxicol Pharmacol. 2017;54: 93–98.
Popov Aleksandrov A., Mirkov I., Ninkov M., Mileusnic D., Demenesku J., Subota V., Kataranovski D., Kataranovski M. Effects of warfarin on biological processes other than haemostasis: A review. Food Chem Toxicol. 2018;13:19–32.
Tucovic D., Popov Aleksandrov A., Mirkov I., Ninkov M., Kulas J., Zolotarevski L., Vukojevic V., Mutic J., Tatalovic N., Kataranovski M. Oral cadmium exposure affects skin immune reactivity in rats. Ecotoxicol Environ Safe. 2018;164:12–20.
Kulas J., Mirkov I., Tucovic D., Zolotarevski L., Glamoclija J., Veljović K., Tolinački M., Golić N., Kataranovski M. Pulmonary Aspergillus fumigatus Infection in Rats Affects Gastrointestinal Homeostasis. Immunobiology 2019;224:116–23.
Kulas J., Ninkov M., Tucovic D., Popov Aleksandrov A., Ukropina M., Cakic Milosevic M., Mutic J., Kataranovski M., Mirkov I. Subchronic oral cadmium exposure exerts both stimulatory and suppressive effects on pulmonary inflammatory/immune reactivity in rats. Biomed. Environ. Sci., 2019;doi: 10.3967/bes2019.043.