538 AJVR, Vol 63, No. 4, April 2002 F umonisins are a group of mycotoxins primarily pro- duced by the fungus Fusarium verticillioides (for- merly F moniliforme), 1 of the most prevalent fungi associated with corn intended for consumption by humans and domestic animals. 1 Since their identifica- tion in 1988, 2 these toxic fungal metabolites have been implicated in outbreaks of leukoencephalomalacia in horses 3 and pulmonary edema in pigs 4,5 and also have been linked epidemiologically with esophageal cancer in humans. 6 Leukoencephalomalacia has been experi- mentally reproduced in horses by administering fumonisin B 1 orally 7 and intravenously. 8,9 Horses are considered to be the most susceptible species to fumonisin mycotoxicosis, yet little is known about the mechanism of toxicity in this species. Fumonisins inhibit sphingosine-N-acyltransferase and sphinganine-N-acyltransferase, 10 enzymes that are key components in the pathway for de novo sphin- golipid biosynthesis. Fumonisin-induced enzyme inhi- bition results in increased concentrations of free sphin- ganine and sphingosine in the serum and tissues of horses. 11,12 It is currently believed that altered sphin- golipid biosynthesis is responsible for the clinical signs of fumonisin toxicosis. We have reported 13-17 that inges- tion of fumonisin-containing culture material or IV administration of fumonisin B 1 causes decreases in heart rate, cardiac output, cardiac contractility, mean arterial pressure, oxygen tension in arterial and mixed- venous blood, and systemic oxygen delivery as well as increases in mean pulmonary artery pressure, pul- monary artery wedge pressure, oxygen consumption, and oxygen extraction ratio in pigs. Our findings indi- cate that fumonisin-induced pulmonary edema in pigs is attributable to acute left-sided heart failure, which was probably mediated by sphingosine inhibition of the myocardial and L-type calcium channel. Accordingly, we hypothesized that cardiovascular dys- function would also be evident in horses with leukoen- cephalomalacia. The objective of the study reported here was to examine the cardiovascular effects of fumonisin B 1 administration in horses to determine whether there was an association among development of neurologic signs of toxicosis, increased serum and myocardial concentrations of sphingosine, and decreased cardiovascular function. Materials and Methods Animals—Eleven healthy horses of various breeds that were between 6 and 24 months old and weighed between 252 and 367 kg were obtained from local sources. On arrival at our facility, horses were orally administered a broad-spec- trum anthelmintic (ivermectin a ) and vaccinated IM with tetanus toxoid. b Horses were housed separately in stalls Received Jul 17, 2001. Accepted Oct 31, 2001. From the Departments of Veterinary Clinical Medicine (Smith, Constable, Foreman), Pathobiology (Waggoner, Haschek), and Biosciences (Tumbleson), University of Illinois, Urbana, IL 61802; and the Food and Drug Administration, 200 C Street SW, Washington, DC 20204 (Eppley). Supported by the USDA-Cooperative State Research, Education, and Extension Services (grant No. 928-39453). This report represents a portion of the dissertation submitted by the senior author in par- tial fulfillment of the requirements of the PhD degree. The authors thank Mike Haus for technical assistance. Address correspondence to Dr. Smith. Cardiovascular changes associated with intravenous administration of fumonisin B 1 in horses Geoffrey W. Smith, DVM, MS; Peter D. Constable, BVSc, PhD; Jonathan H. Foreman, DVM, MS; Robert M. Eppley, PhD; Amy L. Waggoner, BS; Mike E. Tumbleson, PhD; Wanda M. Haschek, BVSc, PhD Objective—To determine whether cardiovascular dysfunction is evident in horses with leukoencephalo- malacia experimentally induced by administration of fumonisin B 1 . Animals—11 healthy horses of various breeds (body weight, 252 to 367 kg). Procedure—Horses were randomly assigned to 3 groups and administered fumonisin B 1 daily. Horses received IV injections of 0 (control horses; n = 4), 0.01 (3), or 0.20 mg (4) of fumonisin B 1 /kg for 7 to 28 days. Horses were examined daily for evidence of neurologic disease. When neurologic signs consistent with leukoencephalomalacia were evident, horses were anesthetized, and catheters were inserted for evaluation of the cardiovascular system. After recovery from anes- thesia, hemodynamic measurements were obtained. Results—Fumonisin-treated horses with clinical signs of neurologic disease had evidence of cardio- vascular dysfunction manifested as decreases in heart rate, cardiac output, right ventricular contractili- ty (assessed by measuring the maximal rate of change of right ventricular pressure), coccygeal artery pulse pressure, and pH and base excess in venous blood as well as increases in systemic vascular resis- tance, compared with values for control horses. Fumonisin-treated horses with and without clinical signs of neurologic disease also had higher serum and right ventricular sphinganine and sphingosine concentrations than control horses. Conclusions and Clinical Relevance—An association was detected among fumonisin-induced neurologic disease, increased serum and myocardial sphinganine and sphingosine concentrations, and decreased cardio- vascular function in horses. Fumonisin-induced decreases in cardiovascular function may contribute to the pathophysiologic development of leukoencephalo- malacia in horses. (Am J Vet Res 2002;63:538–545).