Researching chemicals that may cause damage to the nervous system is very challenging—of the 1,000 known toxic chemicals, only a dozen have been found to be toxic, but many unknowns exist. While mammal models remain the primary selection of research labs looking at the effects of metals and certain organic molecules on the brain—especially the developing brain—C. elegans may often be a better choice.
Of the 1,000 metals, pesticides and other organic compounds and molecules known to be toxic to animals, around 200 are harmful to adult brains, and only a dozen of those in turn are known as toxic during nervous system development. These developmental toxins include arsenic, lead, methylmercury, manganese, fluoride, ethanol, toluene, tetrachloroethylene, organophosphate pesticides, and DDT. The small number of known developmental neurotoxins should not bring any sense of relief—many more could be toxic, but most harmful effects only appear years after exposure, making identification both in humans and in rodent models much slower and daunting for researchers.
Other disorders, like attention deficit hyperactivity disorder (ADHD) or autism, have complex causes which could include exposure to environmental factors like chemicals or other toxins. Genetic factors only explain 30-40% of these disorders, but research attempts to link environmental factors to neurological developmental problems have been beset by inconsistency of results, heterogeneity, inadequate documentation of exposure and a lack of precision in tracking trends over time (such as from childhood to adulthood).
Mammal models in this field are popular and their results well-documented, but time to results is much longer and experiments using them have driven up research costs. C. elegans is uniquely suited to help speed up characterization of such developmental neurotoxins, as its nervous system is structurally and functionally similar to mammals, including humans.
A transparent, free-living, fast-reproducing nematode, C. elegans has many advantages over mammalian models. The worms are no more than a millimeter long with a diameter of about 80 µm, requiring minimal cell culture setup. As pointed out in our blog post “Worms, Flies or Fish?” the worm grows on agar medium and can live by feeding on E. coli, making laboratory growth very easy and cost efficient. Its short life cycle of 3.5 days and prolific reproduction (140 eggs per adult daily) make studying development and generational changes much easier. Its genome was one of the first sequenced, and the worms express homologues to about 80 percent of human genes. Reporter gene fusions (like GFP) are easy to assemble, and the worm’s transparency make it simple to observe physiological changes. And most important for neurotoxicology, its nervous system is structurally and functionally similar to mammals, including humans.
The biochemistry of the worm’s nervous system shares a great deal with mammalian systems (including humans), as well. C. elegans has ion channels, receptors, transporters and synapses that are similar to mammals, and uses glutamate, GABA, dopamine, serotonin and acetylcholine (but not epinephrine) as neurotransmitters.
Every known chemical known to trigger a toxic reaction has now been tested in C. elegans on some level. Neurotoxicology studies have made advances for several chemicals using C. elegans.
High-throughput toxicology screening systems are available for C. elegans, determining effects on locomotion or development. The NemaMetrix ScreenChip system provides lower throughput but greater experimental power to investigate underlying mechanisms, especially for neurotoxins. A direct, electrical readout of a worm’s physiological health provides a real-time measurement of toxic effects. ScreenChip toxicology studies have evaluated the effects of copper, cadmium, and the organophosphate pesticide dichlorvos on C. elegans.
For at least 10 years, C. elegans has been increasingly used as a new, convenient animal model for toxicology, particularly neurological toxicology during development. The model is creating new insights in not only how certain toxins can influence nervous system function, but also is more effective at mapping how these changes can occur over time. The tiny roundworm could finally determine how certain disorders and toxic reactions can have long-term effects, as well as rule out chemicals that may not ultimately have any effect.
- Hunt, P.R. (2017) The C. elegans model in toxicity testing. J. Appl. Toxicol. https://www.ncbi.nlm.nih.gov/pubmed/27443595
- Leung, M., et al. (2008) Caenorhabditis elegans: an emerging model in biomedical and environmental toxicology. https://www.ncbi.nlm.nih.gov/pubmed/18566021
- Lewis, J.A. et al. (2013) Alterations in gene expression in Caenorhabditis elegans associated with organophosphate pesticide intoxication and recovery. BMC Genomics. https://www.ncbi.nlm.nih.gov/pubmed/23631360
- Ruszkiewicz, J.A. et al. (2018) C. elegans as a model in developmental neurotoxicology Tox. Appl. Pharm. https://www.ncbi.nlm.nih.gov/pubmed/29550512
- Terron, A. and Bennekou, S.H. (2018) Towards a regulatory use of alternative developmental neurotoxicity testing. Tox. Appl. Pharm. https://www.ncbi.nlm.nih.gov/pubmed/29454059
- Tejeda-Benitz, L. and Olivero-Verbel, J. (2016) Caenorhabditis elegans, a biological model for research in toxicology. Rev. Environ. Contamin. Toxicol. https://www.ncbi.nlm.nih.gov/pubmed/26613986