Date of Award:

5-1988

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Animal, Dairy, and Veterinary Sciences

Department name when degree awarded

Toxicology

Committee Chair(s)

R. P. Sharma

Committee

R. P. Sharma

Abstract

T-2 toxin (T-2), produced by the genus Fusarium, is a cytotoxic trichothecene mycotoxin, a feed contaminant, and has been shown to be immunomodulatory. It is suspected that T-2-associated immunomodulation is mediated partly through the hypothalamic-pituitary-adrenal axis. The presence of endotoxin, a bacterial product capable of activating the hypothalamic-pituitary-adrenal axis as well as the levels of several hormones, also associated with activation of the hypothalamic-pituitary-adrenal axis, were determined in both vehicle- and toxin-treated animals. Endotoxemia was evident twenty-four hours after a single oral exposure to T-2. Blood levels of adrenocorticotropic hormone and corticosterone, parameters of the stress response, also increased twenty-four hours after T-2 exposure. Hypothalamic norepinephrine and serum corticosterone levels increased in a dose-related manner after two weeks of T-2 exposure. An increased corticosteroid level was associated with thymic involution leading potentially to decreased T-dependent antibody response, a known effect of T-2. The effects of exposure to T-2 on the development of both T-dependent and T-independent antibody response were determined in nonoperated, sham-operated and adrenalectomized mice. T-2 decreased the antibody response to a T-dependent antigen and increased a T-independent response. The effects of T-2 were partially nullified by adrenalectomy. These results provide a further confirmation of the postulate that the hypothalamic-pituitary-adrenal axis plays an important role in T-2 toxin-immunomodulation. In vitro studies were undertaken to investigate the direct effects of T-2 on various populations of lymphatic cells. Exposure to T-2 after twenty-four hours caused an increase in the uptake of 3H-thymidine by mouse splenic cells. Pokeweed mitogen stimulation also increased in this system; the response to lipopolysaccharide increased to a lesser extent. However, T-cell responses to phytohaemagglutinin and concanavalin A (Con A) decreased. Thymic cells were also sensitive to T-2. The possibility of pharmacological activity of T-2 with thymocytes was investigated. Both specific and nonspecific cell associations were observed. The association of T-2 with thymocytes was altered in the presence of dexamethasone, a synthetic corticosteroid. T-2 was shown to have both indirect as well as direct activities on the immune system. Endocrine dysfunction resulting from chronic stress and possible pharmacologic activity of T-2 provide the impetus for further investigations.

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