Development of fumonisin-induced hepatotoxicity and pulmonary edema in orally dosed swine: morphological and biochemical alterations.
The fumonisin (FB) mycotoxins induce liver injury in all species but induce fatal pulmonary edema (PE) only in pigs. They inhibit ceramide synthase in the sphingolipid biosynthetic pathway. To study the pathogenesis of PE, we examined the early events in the development of FB-induced PE and hepatotoxicity in pigs. Pigs were fed FB-contaminated culture material at 20 mg fumonsin B1 (FB1)/kg body weight/day. Groups of 4 pigs were to be euthanatized on 0, 1, 2, 3, 4, or 5 days after initial exposure to FB or when PE developed. Pigs developed PE beginning on day 3; none survived beyond day 4. Progressive elevations in hepatic parameters, including serum enzymes, bile acids, total bilirubin, and histologic changes, began on day 2. Early histologic changes in the lung (day 2) consisted of perivascular edema followed by interlobular and peribronchial edema. Ultrastructurally, alveolar endothelial cells contained unique accumulations of membranous material in the cytocavitary network beginning on day 2. Marked elevations in sphinganine, sphingosine, and their ratio began on day 1 for all tissues whether affected morphologically (lung, liver) or not (kidney, pancreas). The membranous material in endothelial cells may be accumulations of sphingoid bases with damage to the cytocavitary network. Thus, FB induces early elevations in sphingolipids and hepatic injury, followed by alveolar endothelial damage, which may be the critical event in the pathogenesis of PE in pigs.
Gumprecht
L A
LA
Department of Veterinary Pathobiology, University of Illinois, Urbana 61802, USA.
Beasley
V R
VR
Weigel
R M
RM
Parker
H M
HM
Tumbleson
M E
ME
Bacon
C W
CW
Meredith
F I
FI
Haschek
W M
WM
D000818:Animals; D001774:Blood Chemical Analysis; D002264:Carboxylic Acids / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D004730:Endothelium, Vascular / Q000187:drug effects / Q000648:ultrastructure; D037341:Fumonisins; D007124:Immunoenzyme Techniques / Q000379:methods; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D009183:Mycotoxins / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013552:Swine; D013553:Swine Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
D002264:Carboxylic Acids; D037341:Fumonisins; D009183:Mycotoxins; C056933:fumonisin B1; D013110:Sphingosine; C005682:safingol