Dear Colleagues,

The rising incidence of neurodegenerative diseases and neurodevelopmental disorders is associated with an increasing social and financial global burden. The cause of neurodegenerative and neurodevelopmental disease is generally difficult to pinpoint, and they are largely due to a combination of genetic and environmental factors. Exposures to neurotoxicants, such as pesticides and heavy metals, are known to negatively impact the human CNS and have been implicated in the pathogenesis of CNS disease. Common molecular mechanisms of neurotoxicity, including oxidative stress, mitochondrial dysfunction and the alteration of protein homeostasis, are regulated via intracellular signaling transduction. Neurotoxicant-induced changes in signaling pathways may interfere with neural circuitry, the CNS immune system and/or blood–brain barrier function, eventually leading to neurological disorders. A considerable challenge to understanding the mechanistic basis of neurotoxicity is the lack of known molecular targets and/or the mechanism by which environmental toxicants affects these targets. Thus, there is an urgent need to investigate mechanistically relevant signaling pathways associated with the ever-growing number and levels of neurotoxicants in our environment. Therefore, we invite our colleagues in the field of neurotoxicology to submit either primary research findings or a review to this Special Issue, entitled “Molecular Signaling Pathways Associated With Neurotoxicity”.

Dr. Pan Chen
Prof. Dr. Daiana Silva Ávila
Dr. M. Diana Neely
Guest Editors

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• neurotoxicity
• signal transduction
• heavy metals
• environmental toxicants
• neurodegeneration

Title: p38- and ERK-MAPK signalling modulate developmental neurotoxicity of nickel and vanadium in the Caenorhabditis elegans model
Authors: Omamuyovwi M. Ijomone; Ann-Kathrin Weishaupt; Vivien Michaelis; Julia Bornhorst
Affiliation: Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
Abstract: Nickel (Ni) and vanadium (V) are characteristic heavy metal constituents of many crude oil blends in Sub-Saharan Africa, and we have previously demonstrated their neurotoxic impact. However, molecular mechanisms driving Ni and V neurotoxicity are still being elucidated. The p38- and ERKs-MAPK pathways, which are mostly known for their involvement in human immune and inflammatory signalling, have been shown to influence an array of neurodevelopmental processes. In the present study, we attempt to elucidate the role of p38- and ERK-MAPK in neurotoxicity after early life exposures to Ni and V using the Caenorhabditis elegans model. Synchronized larvae stage-1 (L1) worms were treated with varying concentrations of Ni and V singly or in combination for 1 hour. Our results show Ni induces lethality in C. elegans even at very low concentrations, while much higher V concentrations are required to induce lethality. Furthermore, we identified that loss-of-function of pmk-1 and pmk-3 which are both homologous to human p38-α (MAPK14) are differentially affected by Ni and V exposures. Also, all exposure scenarios triggered significant developmental delays in both wild-type and mutant strains. We also see increased mitochondrial-derived reactive oxygen species following Ni and V exposures in wild-type worms with differential responses in the mutant strains. Additionally, we observed alterations in dopamine and serotonin levels after metal exposures, particularly in the pmk-1 strain. Overall, our results suggest the p38- and ERK-MAPK signalling pathways may modulate Ni and V neurodevelopmental toxicity potentially affecting mitochondrial health, metal bioavailability and neurotransmitter levels.