4.7 Article

Major changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift

Journal

ARCHIVES OF TOXICOLOGY
Volume 92, Issue 12, Pages 3487-3503

Publisher

SPRINGER HEIDELBERG
DOI: 10.1007/s00204-018-2326-5

Keywords

Human genome; Cell stability; Dopamine transporter; genome comparison; genotype-phenotype correlation

Categories

Funding

  1. Luxembourg government through the plan Technologies de la Sante
  2. National Centre of Excellence in Research on Parkinson's disease (NCER-PD) grant from the FNR
  3. Land Baden Wurttemberg
  4. German Federal Ministry of Education and Research (BMBF)
  5. EU-ToxRisk

Ask authors/readers for more resources

Genomic drift affects the functional properties of cell lines, and the reproducibility of data from in vitro studies. While chromosomal aberrations and mutations in single pivotal genes are well explored, little is known about effects of minor, possibly pleiotropic, genome changes. We addressed this question for the human dopaminergic neuronal precursor cell line LUHMES by comparing two subpopulations (SP) maintained either at the American-Type-Culture-Collection (ATCC) or by the original provider (UKN). Drastic differences in susceptibility towards the specific dopaminergic toxicant 1-methyl-4-phenylpyridinium (MPP+) were observed. Whole-genome sequencing was performed to identify underlying genetic differences. While both SP had normal chromosome structures, they displayed about 70 differences on the level of amino acid changing events. Some of these differences were confirmed biochemically, but none offered a direct explanation for the altered toxicant sensitivity pattern. As second approach, markers known to be relevant for the intended use of the cells were specifically tested. The ATCC cells rapidly down-regulated the dopamine-transporter and tyrosine-hydroxylase after differentiation, while UKN cells maintained functional levels. As the respective genes were not altered themselves, we conclude that polygenic complex upstream changes can have drastic effects on biochemical features and toxicological responses of relatively similar SP of cells.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available