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Updated: Aug 8, 2026
Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation
Published on: June 17, 2015
Stress-induced premature senescence as alternative toxicological method for testing the long-term effects of
O Toussaint1, P Dumont, J F Dierick
1University of Namur (FUNDP), Unit of Cellular Biochemistry, Rue de Bruxelles, 61, B-5000 Namur, Belgium. olivier.toussaint@fundp.ac.be
Abstract:
No alternative in vitro method exists for detecting the potential long-term genotoxic effects of molecules at subcytotoxic concentrations, in terms of days and weeks after exposure(s) to the molecule tested. A theoretical model of cellular senescence led to the concept that subcytotoxic stresses under any molecules at subcytotoxic doses, such as molecules under development in the pharmaceutical, cosmetics and food industry, might lead human fibroblasts into a state closely related to in vitro senescence. This concept was then experimentally confirmed in vitro: many biomarkers of replicative senescence of human fibroblasts were found 72 h after their exposure to various kinds of stressors used at non-cytotoxic concentrations. This phenomenon has been termed stress-induced premature senescence (SIPS). Moreover, proteomics studies have revealed that, besides their effects on the appearance of the biomarkers of senescence, sublethal stresses under a variety of stressors also lead to long-term specific changes in the expression level of proteins which are stress-specific. These changes have been coined the molecular scars of stress. The proteins corresponding to these molecular scars may be identified using the latest developments in mass spectrometry. This model of stress-induced premature senescence may be applied to the toxicological sciences when testing for the potential irreversible long-term effects of molecules on the cell fate.
Insights
A new in vitro method detects long-term genotoxic effects of molecules at non-cytotoxic doses. This stress-induced premature senescence (SIPS) model reveals molecular scars, offering insights into cellular fate.
Area of Science:
- Toxicology
- Cell Biology
- Biochemistry
Background:
- Current in vitro methods cannot detect long-term genotoxic effects of molecules at subcytotoxic concentrations.
- Subcytotoxic stress may induce a state resembling senescence in human fibroblasts.
Purpose of the Study:
- To investigate the phenomenon of stress-induced premature senescence (SIPS) in human fibroblasts.
- To identify long-term molecular changes, or 'molecular scars,' resulting from subcytotoxic stress.
Main Methods:
- Exposing human fibroblasts to various stressors at non-cytotoxic concentrations.
- Analyzing biomarkers of replicative senescence 72 hours post-exposure.
- Employing proteomics and mass spectrometry to identify stress-specific protein expression changes.
Main Results:
- Confirmed that subcytotoxic stress induces biomarkers of premature senescence in human fibroblasts.
- Identified stress-specific, long-term alterations in protein expression levels ('molecular scars').
- Demonstrated the potential for these molecular scars to be identified via mass spectrometry.
Conclusions:
- The stress-induced premature senescence (SIPS) model provides a novel in vitro method for assessing long-term molecular effects.
- This approach is applicable to toxicological sciences for evaluating irreversible effects of molecules on cell fate.
- The identification of 'molecular scars' offers a new avenue for understanding cellular responses to stress.
