Molecular epidemiological studies with the aim to establish dose-response relationship have failed to demonstrate direct-association of acute exposures (exposure to a chemicals once in lifetime, such as methyl isocyanate exposure in Bhopal) per se with chromosomal anomalies. Results of in-vitro examinations and animal studies grossly differ from human bio-monitoring investigations. What could be the specific reasons ? Does that mean cytogenetic studies in exposed cohorts might result in false positives ?
Dear Prof. Pradyumna Mishra,
Yes. Not always does the acute exposures would lead to cytogenetic aberrations. Acute exposures are usually single incidents of relatively short
duration--a minute to a few days. Acute exposures most oftenly lead to cytotoxic response depending on the magnitude and dosage of exposure. Results of acute in vitro and in vivo animal experimentation studies are confined to defined /artificial environmental scenarios and portray probable model system which are not conclusive. Cytogenetic alterations are resultants of the long term accumulation of induced mutations in cell population at the G0 phase of their growth cycle. Stable (balanced translocations, paracentric inversions) and unstable (acentric fragments and rings) chromosomal aberration types can be found after exposure to chemical. Stable aberrations are the manifestations of over a period of time that in turn increase the possibility of genomic instability. There are several factors that influence the toxicity of exposure during human biomonitoring studies such as heredity; immunology; nutrition; hormones; age; sex; health status; pre-existing diseases. Hence, these parameters become important for cytogenetic analysis in exposed cohorts . Whatever the positives results in acute exposure, if any, might be attributed to low level non-viable (unstable) aberrations that do not completely explain clastogenicity of chemical.
Regards
Raghuram
One of possible answers may be that cells' gross damage leading to their death due to a strong cytotoxic action is an alternative to cytogenetic events, be it on gene or cromosomal level. We saw some evidence of it even in a subchronic experiment on rats exposed to nanoCuO (see in my ResGate profile Contributions the article by Privalova et al "Subchronic Toxicity of Copper Oxide Nanoparticles and Its Attenuation with the Help of a Combination of Bioprotectors"
published in the International Journal of Molecular Sciences "Bioactive nanoparticles 2014" which can be found on line too)
Thank you Dr. Boris Katsnelson for providing us your insightful views.
Regards - Pradyumna
Possibly the cells when subjected to a high dose produces cell death, ie cytotoxic activity (gene or chromosome)
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