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Characterization of mouse cell lines resistant to nickel(II) ions
1Institute of Environmental Medicine, New York University Medical Center, New York 10016.
Abstract:
BALB/c-3T3 cells have been isolated that are resistant to NiCl2. The degree of resistance is directly dependent upon the NiCl2 exposure concentration and ranges from 6- to 11-fold. Resistance to NiCl2 does not appear to be due to alterations in cellular uptake, since the entry of Ni(II) into wild-type or resistant cells was similar. Resistance does not appear to be due to alterations in metallothionein expression. Resistant cells have a high incidence of heterochromatic abnormalities involving fusions at the centromeres as determined by C-banding and in situ hybridization utilizing a cloned mouse satellite DNA probe. Cells retain nickel resistance for many generations in the absence or presence of NiCl2 selection; however, with time in the absence of NiCl2, the level of resistance decreases. This loss of resistance is associated with a decreased number of centromeric fusions. These results indicate that nickel resistance is involved with changes in heterochromatin and suggest that this effect of nickel on heterochromatin may be important as an early step in nickel carcinogenesis.
Insights
Nickel exposure creates resistant cells with centromeric abnormalities. This nickel resistance is linked to heterochromatin changes, potentially an early step in nickel carcinogenesis.
Area of Science:
- Cell Biology
- Toxicology
- Carcinogenesis
Background:
- Nickel chloride (NiCl2) is a known toxicant.
- Understanding cellular resistance mechanisms is crucial for toxicology and cancer research.
Purpose of the Study:
- To investigate the mechanisms of nickel resistance in BALB/c-3T3 cells.
- To explore the relationship between nickel resistance, cellular uptake, metallothionein expression, and chromosomal abnormalities.
- To assess the potential role of nickel-induced heterochromatin changes in nickel carcinogenesis.
Main Methods:
- Isolation and characterization of NiCl2-resistant BALB/c-3T3 cell lines.
- Measurement of Ni(II) cellular uptake in wild-type and resistant cells.
- Analysis of metallothionein expression.
- Cytogenetic analysis including C-banding and in situ hybridization to detect heterochromatic abnormalities.
- Long-term culture to assess stability of resistance and associated chromosomal changes.
Main Results:
- NiCl2-resistant cell lines were established with 6- to 11-fold resistance.
- Resistance was not attributed to altered Ni(II) cellular uptake or metallothionein expression.
- Resistant cells exhibited a high incidence of centromeric heterochromatic abnormalities.
- Nickel resistance was stable over generations but decreased over time without selection, correlating with reduced centromeric fusions.
Conclusions:
- Nickel resistance in BALB/c-3T3 cells is associated with significant heterochromatic abnormalities, particularly centromeric fusions.
- These findings suggest that nickel-induced alterations in heterochromatin may play a role in the early stages of nickel-induced carcinogenesis.