Modulation of selected cell signaling genes in mouse liver by fumonisin B1.
Fumonisin B1 (FB1) is a naturally occurring mycotoxin produced primarily by Fusarium verticillioides and related fungi, common contaminants of corn throughout the world. FB1 is a carcinogen and causative agent of several lethal animal diseases, including equine leukoencephalomalacia and porcine pulmonary edema. Liver is the primary target organ in mice. In vivo and vitro, cells exposed to FB1 undergo a mixture of necrotic and apoptotic cell death. Our previous studies showed gender differences in hepatotoxicity caused after 5 day FB1 treatment. Gene alterations in cytokine network and apoptosis signaling molecules were also observed after an acute single dose of FB1. To further investigate the gene alterations after a subchronic FB1 exposure and its correlation to observed gender differences, male and female BALB/c mice (five per group) were injected subcutaneously with either saline or 2.25 mg/kg per day of FB1 for 5 days. FB1 caused increased expression of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-10, IL-12 p40, IL-18 and interferon gamma (IFNgamma) in male liver, with a similar increase in females except for IL-1beta and IL-18. Control females showed higher basal levels of IL-1alpha, IL-1Ra, IL-10, IL-12 p40 and IFNgamma compared with males. Expression of TNF receptor 55 and TNF receptor associated death domain (TRADD) was increased, with no changes in Fas signaling molecules, Fas, Fas ligand (FasL), Fas associated death domain (FADD) and Fas-associated protein factor (FAF). Expression of oncogenic transcription factors, c-Myc, B-Myc, Max and Mad, and apoptotic genes, namely Bcl-2, Bax and Bad, was increased after FB1 treatment. FB1 caused an activation of cytokine network in liver, particularly the TNFalpha signaling pathway, suggesting its involvement in hepatotoxic mechanisms. Induction of IL-1Ra and oncogenes is a likely mechanism for the cancer promoting properties of FB1, through a mechanism involving apoptotic necrosis, oncotic necrosis and consequent regeneration.
Bhandari
Neetesh
N
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
Raghubir P
Sharma
D000818:Animals; D002264:Carboxylic Acids / Q000633:toxicity*; D016207:Cytokines / Q000235:genetics; D005260:Female; D037341:Fumonisins; D005670:Fusarium; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009183:Mycotoxins / Q000633:toxicity*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D003313:Zea mays / Q000382:microbiology
D002264:Carboxylic Acids; D016207:Cytokines; D037341:Fumonisins; D009183:Mycotoxins; C056933:fumonisin B1; D012313:RNA