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The genetic toxicology of cadmium and cadmium/mutagen mixtures

The genetic toxicology of cadmium and cadmium/mutagen mixtures
The genetic toxicology of cadmium and cadmium/mutagen mixtures

Cultured muntjac cells have been used to investigate the genetic toxicology of Cd(II) ions and the influence of the cation on the genotoxicity of five other mutagens (ethyl methane sulfonate. mitomycin C, acridine orange, Hoechst 33258 and nickel (II) ions). 

Cd(II) ions could only induce chromosomal aberrations in cells treated for short periods followed by long recovery periods. Sister chromatid exchanges (SCEs) were not induced by the cation, possibly due to the removal of SCE-inducing lesions by excision repair. In treated cells, most intracellular cadmium was located in the cytosol bound to a low molecular weight molecule. This molecule was not metallothionein but might be glutathione.

In general 3, co-treatment or pretreatment of cells with Cd(II) ions tended to decrease the chromosomal effects of alkylating agents and increase those of other compounds. Experimental evidence suggesting an involvement of the following in these interactions has been produced: (i) inhibition of excision repair by Cd(II) ions leading to increased chromosomal effects of non-covalent DNA-binding agents. (ii) a CD(II)-inducible repair system reducing the effects of alkylating agents on SCE, (iii) increased cytosolic free Cd(II) ions enhancing chromosomal aberration formation.

In general, co-treatment or pretreatment of cells with Cd(II) ions tended to decrease the chromosomal effects of alkylating agents and increase those of other compounds. Experimental evidence suggests an involvement of the following in these interactions has been produced: (i) inhibition of excision repair by Cd(II) ions leading to increased chromosomal effects of non-covalent DNA-binding agents, (ii) a Cd(II)-inducible repair system reducing the effects of alkylating agents on SCE, (iii) increased cytosolic free Cd(II) ions enhancing chromosomal aberration formation.

The effects of the five mutagens on a cadmium resistant strain of muntjac cells, able to grow in 5μM cadmium acetate, were also investigated. The increased resistance of these cells may involve lipid production and/or increased Cd binding to a cytosolic glutathione-like molecule. Each of the mutagens induced fewer SCEs in resistant cells than in normal cells. However, due to the higher baseline SCE frequency in resistant cells, mutagen treated cells had higher absolute SCE frequencies than similarly treated normal cells. The reduction in sensitivity may involve the conjugation of mutagens with the cytosolic glutathione-like molecule so protecting the nucleus from damage.

These findings imply that exposure to cadmium might alter the susceptibility of humans to chemically induced cancers. Whether susceptibility would be increased or decreased being dependent upon the carcinogen considered and the nature of cadmium exposure.

University of Southampton
Bouffler, Simon David
6ef2382e-c2fc-4360-ab91-3665ccd06b25
Bouffler, Simon David
6ef2382e-c2fc-4360-ab91-3665ccd06b25
Bell, L.G.E.
9494f61c-f97d-4eca-931c-57ac550be5ad

Bouffler, Simon David (1985) The genetic toxicology of cadmium and cadmium/mutagen mixtures. University of Southampton, Doctoral Thesis, 213pp.

Record type: Thesis (Doctoral)

Abstract

Cultured muntjac cells have been used to investigate the genetic toxicology of Cd(II) ions and the influence of the cation on the genotoxicity of five other mutagens (ethyl methane sulfonate. mitomycin C, acridine orange, Hoechst 33258 and nickel (II) ions). 

Cd(II) ions could only induce chromosomal aberrations in cells treated for short periods followed by long recovery periods. Sister chromatid exchanges (SCEs) were not induced by the cation, possibly due to the removal of SCE-inducing lesions by excision repair. In treated cells, most intracellular cadmium was located in the cytosol bound to a low molecular weight molecule. This molecule was not metallothionein but might be glutathione.

In general 3, co-treatment or pretreatment of cells with Cd(II) ions tended to decrease the chromosomal effects of alkylating agents and increase those of other compounds. Experimental evidence suggesting an involvement of the following in these interactions has been produced: (i) inhibition of excision repair by Cd(II) ions leading to increased chromosomal effects of non-covalent DNA-binding agents. (ii) a CD(II)-inducible repair system reducing the effects of alkylating agents on SCE, (iii) increased cytosolic free Cd(II) ions enhancing chromosomal aberration formation.

In general, co-treatment or pretreatment of cells with Cd(II) ions tended to decrease the chromosomal effects of alkylating agents and increase those of other compounds. Experimental evidence suggests an involvement of the following in these interactions has been produced: (i) inhibition of excision repair by Cd(II) ions leading to increased chromosomal effects of non-covalent DNA-binding agents, (ii) a Cd(II)-inducible repair system reducing the effects of alkylating agents on SCE, (iii) increased cytosolic free Cd(II) ions enhancing chromosomal aberration formation.

The effects of the five mutagens on a cadmium resistant strain of muntjac cells, able to grow in 5μM cadmium acetate, were also investigated. The increased resistance of these cells may involve lipid production and/or increased Cd binding to a cytosolic glutathione-like molecule. Each of the mutagens induced fewer SCEs in resistant cells than in normal cells. However, due to the higher baseline SCE frequency in resistant cells, mutagen treated cells had higher absolute SCE frequencies than similarly treated normal cells. The reduction in sensitivity may involve the conjugation of mutagens with the cytosolic glutathione-like molecule so protecting the nucleus from damage.

These findings imply that exposure to cadmium might alter the susceptibility of humans to chemically induced cancers. Whether susceptibility would be increased or decreased being dependent upon the carcinogen considered and the nature of cadmium exposure.

Text
Bouffler 1984 Thesis - Version of Record
Available under License University of Southampton Thesis Licence.
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Published date: 1985

Identifiers

Local EPrints ID: 459679
URI: http://eprints.soton.ac.uk/id/eprint/459679
PURE UUID: 0fc8c7f8-0bbd-4023-a5c5-b4d044b56936

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Date deposited: 04 Jul 2022 17:16
Last modified: 16 Mar 2024 18:32

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Contributors

Author: Simon David Bouffler
Thesis advisor: L.G.E. Bell

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