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 hepatoto xicity in pigs. Pigs were fed FB-contaminated culture material at 20 mg fum onsin B-1 (FB1)/kg body weight/day. Groups of 4 pigs were to be euthanatize d on 0, 1, 2, 3, 4, or 5 days after initial exposure to FB or when PE devel oped. Pigs developed PE beginning on day 3; none survived beyond day 4. Pro gressive elevations in hepatic parameters, including serum enzymes, bile ac ids, total bilirubin, and histologic changes, began on day 2. Early histolo gic changes in the lung (day 2) consisted of perivascular edema followed by interlobular and peribronchial edema. Ultrastructurally, alveolar endothel ial cells contained unique accumulations of membranous material in the cyto cavitary network beginning on day 2. Marked elevations in sphinganine, sphi ngosine, and their ratio began on day 1 for all tissues whether affected mo rphologically (lung, liver) or not (kidney, pancreas). The membranous mater ial in endothelial cells may be accumulations of sphingoid bases with damag e to the cytocavitary network. Thus, FB induces early elevations in sphingo lipids and hepatic injury, followed by alveolar endothelial damage, which m ay be the critical event in the pathogenesis of PE in pigs.