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Genetic and non-genetic biomarkers related to carcinogenesis in evaluating toxicological risk from Fenarimol
M Paolini1, R Mesirca, L Pozzetti
1Department of Pharmacology, Biochemical, University of Bologna, Italy.
Abstract:
A multibiomarker approach based on the study of toxicity mechanisms at both genetic and metabolic levels has been applied to Fenarimol. With regard to genotoxicity, particular attention was given to assays for chromosomal aberration and micronuclei; clastogenic potential was assessed in human peripheral blood lymphocytes in vitro, while the induction of micronuclei was studied in male CD1 mouse bone marrow polychromatic erythrocytes (PCE). Fenarimol did not induce any significant dose-related increase in micronucleated PCEs, up to 4-fold above the control level at a single dose of 75 mg/kg b.w., was observed 24 h after treatment. Using selective biochemical markers of effect Fenarimol was found to induce CYP 2B1 isoforms in liver, kidney and lung microsomes of Swiss Albino CD1 male and female mice, as shown by the significant increase in specific 2B1-probe pentoxyresorufin O-dealkylase activity. On the contrary, CYP 3A, probed by N-demethylation of aminopyrine, were only induced in the liver. Results were corroborated by means of Western immunoblotting using rabbit polyclonal antibodies anti-CYP 2B1 and 3A. Northern blotting analysis with CYP 2B1 and 3A cDNA biotinylated probes showed that the expression of such isoforms is regulated at mRNA level. Taken as a whole, these data indicate the possible (mutagenic) cotoxic/cocarcinogenic and promoting potential of this fungicide.
Insights
Fenarimol fungicide did not show genotoxicity in mouse bone marrow. However, it induced specific cytochrome P450 enzymes (CYP 2B1 and CYP 3A) in mice, suggesting potential toxic and carcinogenic effects.
Area of Science:
- Environmental toxicology
- Biomarker research
- Fungicide safety assessment
Background:
- Fenarimol is a fungicide with potential toxicological implications.
- Understanding its genotoxic and metabolic effects is crucial for risk assessment.
- Multibiomarker approaches provide comprehensive toxicity insights.
Purpose of the Study:
- To evaluate the genotoxicity of Fenarimol using chromosomal aberration and micronucleus assays.
- To investigate the metabolic effects of Fenarimol by examining cytochrome P450 (CYP) enzyme induction.
- To determine if Fenarimol's effects are regulated at the gene expression level.
Main Methods:
- In vitro assessment of clastogenic potential in human lymphocytes.
- In vivo micronucleus assay in mouse bone marrow polychromatic erythrocytes (PCE).
- Biochemical assays (pentoxyresorufin O-dealkylation, aminopyrine N-demethylation) to probe CYP activity.
- Western immunoblotting and Northern blotting to confirm protein and mRNA expression of CYP isoforms.
Main Results:
- Fenarimol did not induce significant genotoxicity or micronuclei formation in mouse bone marrow.
- Fenarimol significantly induced CYP 2B1 isoforms in liver, kidney, and lung microsomes.
- Fenarimol induced CYP 3A isoforms primarily in the liver, with regulation observed at the mRNA level.
Conclusions:
- Fenarimol lacks direct genotoxic potential in vivo.
- Fenarimol's induction of CYP enzymes suggests potential for cotoxicity, carcinogenicity, and promotion.
- Further research is warranted to fully elucidate the toxicological profile of Fenarimol.