Caenorhabditis elegans as a powerful alternative model organism to promote research in genetic toxicology and biomedicine

Abstract

In view of increased life expectancy the risk for disturbed integrity of genetic information increases. This inevitably holds the implication for higher incidence of age-related diseases leading to considerable cost increase in health care systems. To develop preventive strategies it is crucial to evaluate external and internal noxae as possible threats to our DNA. Especially the interplay of DNA damage response (DDR) and DNA repair (DR) mechanisms needs further deciphering. Moreover, there is a distinct need for alternative in vivo test systems for basic research and also risk assessment in toxicology. Especially the evaluation of combinational toxicity of environmentally present genotoxins and adverse effects of clinically used DNA damaging anticancer drugs is a major challenge for modern toxicology. This review focuses on the applicability of Caenorhabditis elegans as a model organism to unravel and tackle scientific questions related to the biological consequences of genotoxin exposure and highlights methods for studying DDR and DR. In this regard large-scale in vivo screens of mixtures of chemicals and extensive parallel sequencing are highlighted as unique advantages of C. elegans. In addition, concise information regarding evolutionary conserved molecular mechanisms of the DDR and DR as well as currently available data obtained from the use of prototypical genotoxins and preferential read-outs of genotoxin testing are discussed. The use of established protocols, which are already available in the community, is encouraged to facilitate and further improve the implementation of C. elegans as a powerful genetic model system in genetic toxicology and biomedicine.

Piperazine designer drugs elicit toxicity in the alternative in vivo model Caenorhabditis elegans

“…Therefore, C. elegans provides a feasible in vivo platform for large‐scale screening tests, offers the possibility for in‐depth molecular elucidation of signaling pathways and mutation signatures through plenty of available endpoints in single whole animals up to population level and even over several generations. Additionally, most compounds can only enter C. elegans via the intestine, and the drug concentration reached inside the nematodes was comparable with what has been found in mice upon oral administration (Honnen, ). This is also observed because C. elegans has consistently shown good correlation with rodent oral LD 50 ranking (Hunt, ).…”

Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin

“…We observed that the effect of cisplatin on fertility and cell cycle arrest in the mitotic germline is similar to that produced by other DNA-damaging insults, such as ionizing or ultraviolet C radiations ( Gartner et al, 2004 ), suggesting a direct action of cisplatin on DNA that is supported by our southwestern blots for DNA adducts (1,2-GpG-intrastrand crosslinks). This cisplatin-induced DNA damage response (DDR) in the C. elegans germline has already been documented ( van Haaften et al, 2006 ; Meier et al, 2014 ; Honnen, 2017 ). In addition, however, we found that defective sperm is a major cause of the reduced C. elegans fertility observed upon cisplatin exposure at L4.…”

Genetic and cellular sensitivity ofCaenorhabditis elegansto the chemotherapeutic agent cisplatin

“…We observed that the effect of cisplatin in fertility and cell cycle arrest in the mitotic germ line is similar to that produced by other DNA-damaging insults as ionizing or ultraviolet C radiations 22 , suggesting a direct action of cisplatin on DNA that is supported by our South-Western Blots for DNA adducts (1,2-GpG-intrastrand crosslinks). This cisplatin-induced DNA damage response (DDR) in the C. elegans germ line has already been documented [38][39][40] . In addition, however, we found that defective sperm is a major cause of the reduced C. elegans fertility observed upon cisplatin exposure.…”