Date of Award:

5-1-1988

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Biology

Department name when degree awarded

Toxicology

Committee Chair(s)

R.P. Sharma

Committee

R.P. Sharma

Committee

Roger A. Coulombe

Committee

LeGrande Ellis

Abstract

The macrocyclic trichothecenes are a unique group of toxins which have some antileukemic properties. In the first study, verrucarin A and roridin A were examined. Both mycotoxins were administered intraperitoneally at an equitoxic dose of 0.35 mg/kg to CD-1 mice. Lymphocyte proliferation was studied on days 2, 4, and 7 after animals were dosed with verrucarin A. After day 2, no differences in 3HThymidine (3H-TdR) incorporation were observed using concanavalin A (Con A), phytohaemagglutinin (PHA), pokeweed mitogen (PWM), or lipopolysaccharide (LPS). On day 4, DNA synthesis induced by Con A, PHA, and PWM increased significantly. On day 7, PHA stimulation increased (P ≤ 0.01) above controls while Con A, PWM, and LPS responses were not significantly different. In contrast, roridin A decreased PHA stimulation only on day 7 (P ≤ 0.05). In the second study the mycotoxins roritoxin B, myrotoxin B, roridin A, verrucarin A, 16-hydroxyverrucarin A, verrucarin J, baccharinoid B12, roridin D, roridin E, baccharinoid B4, and baccharinoid B5 were investigated. An equitoxic dose was administered i.p. at half the LD50. Organ weights, WBC, RBC, differentials, blastogenesis of splenic lymphocytes in response to Con A, LPS, PHA and PWM, and mixed lymphocyte reaction (MLR) were studied on day 4 after administration. Organ weights showed significant responses to the baccharinoids with a decrease in spleen weight in B12- and an increased liver weight in B4- and B5-treated animals. Myrotoxin B-, roridin A-, verrucarin J-, and roridin E-treated animals had statistically different total WBC counts. Myrotoxin B induced a decrease in RBC. Roritoxin Band baccharinoid B5 increased Con A stimulation. Roridin A and baccharinoid B12 increased LPS stimulation and baccharinoid B5 decreased the LPS response. Stimulation with PHA was significantly increased by roridin A and baccharinoid B5. Response to PWM was not altered significantly by any mycotoxin. The baccharinoids B12 and B4 caused significant increases in the MLR. Anti-SRBC antibodies were significantly decreased in the roridin D- and E- and baccharinoid B5-treated animals. Total IgG titers were significantly depressed in baccharinoid B5-treated animals. In the third study lymphocytes were cultured with each of the mycotoxins for 48 hr to assess their lethality. Results indicated that maximum lethality occurred at concentrations ranging from 10-6 to 10-4 M. The no-effect levels for these mycotoxins ranged from 10-12 to 10-7 M. Mitogenic stimulation demonstrated that culturing with various concentrations of selected mycotoxins inhibited blastogenesis, resulting in an IC50 concentration two-to-five orders of magnitude lower than the LC50s of each mycotoxin.

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