Toxic and genotoxic effects of oral administration of furan in mouse liver.
In this study, the effects induced in mouse liver by repeated oral exposure to furan were investigated. To this aim, the compound was given for 28 days by daily gavage to male B6C3F1 mice at 2, 4, 8 and 15 mg/kg body weight (b.w.)/day. Twenty-four hours after last administration, animals were sacrificed, liver was excised and the following parameters were evaluated: histological alterations, apoptosis, cell proliferation, polyploidy, overall DNA methylation, gene expression and DNA damage by the immunofluorescence detection of foci of phosphorylated histone H2AX (gamma-H2AX) and by alkaline comet assays, using both standard and modified protocols for the detection of DNA cross links. Liver DNA damage by comet assays was also evaluated in mice receiving furan as a single acute oral dose (15, 100 or 250 mg/kg b.w.). Microscopic analysis of liver sections indicated that repeated oral administration of furan was moderately toxic, producing mild histological alterations with necrotic figures, apoptosis and limited regenerative cell proliferation. The flow cytometric analysis of DNA content in single-cell suspensions of liver cells showed a statistically significant increase in polyploid (8N) cells at the highest dose. No treatment-related changes in overall DNA methylation, gamma-H2AX foci, DNA strand breaks and cross links were observed at the end of the 4-week exposure period. However, several genes involved in DNA damage response, beyond stress and liver toxicity, were over-expressed in mice treated with the highest furan dose (15 mg/kg b.w./day). Acute administration of furan induced evident liver toxicity at the highest dose (250 mg/kg b.w.), which was associated with a significant increase of DNA damage in the alkaline comet assay and with a distinct decrease in gamma-ray-induced DNA migration. Overall, the results obtained suggest that the contribution of genotoxicity to the mechanism of furan carcinogenicity in mouse liver should not be dismissed.
Cordelli
Eugenia
E
Section of Toxicology and Biomedical Sciences, ENEA CR Casaccia, Research Center Casaccia, Via Anguillarese 301, 00123-Rome, Italy.
Leopardi
Paola
P
Villani
Paola
P
Marcon
Francesca
F
Macrì
Caterina
C
Caiola
Stefania
S
Siniscalchi
Ester
E
Conti
Luigi
L
Eleuteri
Patrizia
P
Malchiodi-Albedi
Fiorella
F
Crebelli
Riccardo
R
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005663:Furans / Q000008:administration & dosage* / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009929:Organ Size / Q000187:drug effects; D016019:Survival Analysis
D005663:Furans; D001973:Bromodeoxyuridine; D016650:Fluorescein-5-isothiocyanate; C039281:furan