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Neurotoxicity: Challenges and Chemistry

A recent Virtual Special Issue in ACS Chemical Neuroscience and Chemical Research in Toxicology focuses on cross-disciplinary strategies to address the many challenges embedded in the field of neurotoxicity.

Read the Virtual Special Issue Online

Defining Neurotoxicity: An Ongoing Challenge

Our bodies are continuously exposed to toxic chemicals—both natural and synthetic—that can negatively impact many physiological functions.1 Neurotoxicity can result from exposure to classic contaminants such as heavy metals and pesticides, as well as less understood compounds including food additives, packaging, personal care products, industrial solvents, and even medicine coatings. Exposure has increased to the point where all children are now born pre-polluted with hundreds of synthetic chemicals in their bodies. Many of these substances still need to be identified, let alone evaluated for potential neurotoxicity.1  

Given the multitude of contaminants affecting the nervous system and the complexity of possible measurements, it has been challenging for toxicologists to fully define what neurotoxicity really means.1 Although there is growing consensus that exposure to such chemicals is significantly hazardous to our health, we still lack a clear understanding of the relationships between certain environmental drivers and the ways in which they manifest in the nervous system.

A Virtual Special Issue in ACS Chemical Neuroscience and Chemical Research in Toxicology includes 15 recent papers demonstrating novel approaches and cross-disciplinary collaborations that may aid in advancing understanding and addressing challenges in the field.

Plant-Based Problems (and Protection)

Acrylamide (ACR) is a neurotoxicant produced by the high-temperature frying and baking of plant-based foods and found in carbohydrate-rich items such as fried potatoes, chocolate, cereals, and bread. One study examines the effects of repeated low-dose exposure to ACR with evidence of disrupted PERK signaling, shedding light on a possible mechanism for impaired memory and cognitive deficits.2 This work is significant because many chemicals such as ACR are known to be toxic at high doses, but understanding how the brain is vulnerable to low-dose exposure is broadly informative.

Other plant compounds seem to be more protective – including fustin, a phytogenic flavonol with the potential to protect against cognitive impairment following low-dose exposure to streptozotocin, a neurotoxicant that is also potently diabetogenic.3

Is Your Medicine Doing More Harm Than Good?

Food ingestion is not the only route of entry for toxins. Some commonly used medicines can have adverse effects on the central nervous system—for example, Cefepime, a common antibiotic used to treat a variety of infections, has been linked to side effects including reduced consciousness, confusion, and various anxiety-like behaviors.1,4

Another study reports that current antiseizure medications are effective in only 60%–70%  of patients, and development of new treatments has been limited by various—and potentially life-threatening—side effects.5 The researchers found, however, that new benzo[d]isoxazole derivatives display anticonvulsant activity by selectively blocking voltage-gated sodium channel NaV1.1, which provides good alternatives for antiseizure drugs in the future.5

The Dangers of Pesticide Exposure

Chronic pesticide exposure might result in oxidative stress, inflammatory reactions, and mitochondrial dysfunction.6 Exposure to the herbicide paraquat not only compromises lung, liver, and kidney function but has also been associated with cancer.7 However, new research suggests citric acid-sourced carbon quantum dots (Cit-CQDs) as a potentially viable biobased nanomaterial, made using environmentally friendly methods, for intervention in neurodegenerative disorders.8

Advances in Neurotoxicity Testing

One key challenge in the field remains the ability to test for neurotoxicity. Acute neurotoxicity that results in death or severe impairment is easily measured in the laboratory or clinical setting, but subtle effects resulting from exposure during a sensitive development period—or from chronic or cumulative exposure—are far more difficult to assess.1

One study shows how zebrafish represent an economical alternative to rodents for developmental neurotoxicity testing.9 Other new research suggests toxicity can be measured using fluorescent false neurotransmitters, allowing visualization of vesicular packaging at baseline levels, and following pharmacological and toxicological manipulations.10

The Special Issue also includes the first in vivo evidence to support the role of dopaminergic toxins in Parkinson’s disease (PD) using Caenorhabditis elegans models. The results suggest that some neurotoxins known to cause PD-related symptoms may be part of a broader group of chemicals that, if commonly present in laboratory or industrial settings, could have a detrimental impact on public health and safety.11

Paving the Way for Progress and Prevention

Ensuring that chemicals in use are as nontoxic as possible is essential for the long-term wellbeing of future generations and our planet. Ultimately, researchers agree there is an essential need for greater cross-disciplinary collaboration between neuroscientists, toxicologists, and chemists to advance the field.

Visit the Full Virtual Special Issue

References

  1. Sombers, L. A., and Patisaul, H. B. Virtual Issue: Neurotoxicology (Editorial). ACS Chem. Neurosci. 2022, 13, 15, 2238–2239.
  2. Yan, D. et al. Subchronic Acrylamide Exposure Activates PERK-eIF2α Signaling Pathway and Induces Synaptic Impairment in Rat Hippocampus. ACS Chem. Neurosci. 2022, 13, 9, 1370–1381
  3. Afzal, M. et al. Fustin Inhibits Oxidative Free Radicals and Inflammatory Cytokines in Cerebral Cortex and Hippocampus and Protects Cognitive Impairment in Streptozotocin-Induced Diabetic Rats. ACS Chem. Neurosci. 2021, 12, 24, 4587–4597
  4. Liu, X. et al. Lipidomics Reveals Dysregulated Glycerophospholipid Metabolism in the Corpus Striatum of Mice Treated with Cefepime. ACS Chem. Neurosci. 2021, 12, 23, 4449–4464
  5. Huang, X. et al. Design, Synthesis, and Evaluation of Novel Benzo[d]isoxazole Derivatives as Anticonvulsants by Selectively Blocking the Voltage-Gated Sodium Channel NaV1.1. ACS Chem. Neurosci. 2022, 13, 6, 834–845
  6. Yan, Q. et al. High-Resolution Metabolomic Assessment of Pesticide Exposure in Central Valley, California. Chem. Res. Toxicol. 2021, 34, 5, 1337–1347
  7. Henriquez, G. et al. Citric Acid-Derived Carbon Quantum Dots Attenuate Paraquat-Induced Neuronal Compromise In Vitro and In Vivo. ACS Chem. Neurosci. 2022, 13, 16, 2399–2409
  8. Dong, H. et al. Characterization of Developmental Neurobehavioral Toxicity in a Zebrafish MPTP-Induced Model: A Novel Mechanism Involving Anemia. ACS Chem. Neurosci. 2022, 13, 13, 1877–1890
  9. Black, C.A. et al. Assessing Vesicular Monoamine Transport and Toxicity Using Fluorescent False Neurotransmitters. Chem. Res. Toxicol. 2021, 34, 5, 1256–1264
  10. Murphy, D. et al. Caenorhabditis elegans Model Studies Show MPP+ Is a Simple Member of a Large Group of Related Potent Dopaminergic Toxins. Chem. Res. Toxicol. 2021, 34, 5, 1275–1285

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