p38- and ERK-MAPK Signalling Modulate Developmental Neurotoxicity of Nickel and Vanadium in the Caenorhabditis elegans Model

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 h. 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), is 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. In conclusion, both Ni and V induce lethality, developmental delays, and mitochondrial-derived ROS in worms, with V requiring a much higher concentration. Further, the 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.