ENDOGENOUS-EXOGENOUS CHEMICALS WITH NEUROTOXIC POTENTIAL

Introduction: While certain highly reactive chemicals are neurotoxic at high environmental concentrations, low endogenous concentrations of the same substances are required for normal neurophysiological function. Methods/Results: Airborne pollutants carbon monoxide, hydrogen sulfide, nitric oxide and cyanide are each employed as endogenous gasotransmitters [1], while high concentrations are associated with various neurological disorders. The pyrrole-forming neurotoxic gamma-diketone metabolites of certain aliphatic (n-hexane) and aromatic solvents (1,2-diethylbenzene) cause axonal polyneuropathy, yet gamma-diketones are present in solvent-unexposed subjects, and their urinary pyrrole derivatives increase in diabetes mellitus, a major cause of polyneuropathy [2]. Formaldehyde, the common metabolite of two naturally occurring epi/genotoxic neurotoxins (MAM, L-BMAA) linked to a prototypical neurodegenerative disease (Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex) [3], is a neurotoxic and carcinogenic xenobiotic, but the substance is an indispensable component of one-carbon metabolism essential for biosynthetic reactions and epigenetic modulation [4]. Elevated levels of endogenous formaldehyde have been linked to Alzheimer disease [5]. Conclusions: Such considerations suggest that understanding the relationship between the endogenous functions and effects of such highly reactive chemicals may illuminate both how their endogenous mis-regulation may contribute to neurological disease and the mechanisms underlying their neurotoxic effects from exposure to high concentrations. As taught by Paracelsus (1491-1541), the “Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy.”

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994231/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291117/;
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113121/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9574754/
3. https://pubmed.ncbi.nlm.nih.gov/33190068/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804977/
5. https://onlinelibrary.wiley.com/doi/full/10.1111/jnc.12356; https://pubmed.ncbi.nlm.nih.gov/37100142/; https://pubmed.ncbi.nlm.nih.gov/25282336/