Dynamic Telomere Length Response to Neurodevelopmental Arsenic Exposure: Insights into Transcriptional Regulation and Neuronal Morphogenesis

Abstract

Developmental exposure to arsenic (As) has been linked to irreversible adverse health outcomes in offspring. However, the underlying molecular mechanisms remain a mystery. Here, maternal mice were exposed to As via drinking water. Subsequently, the hippocampi of their offspring were collected at different developmental stages to explore the dynamic changes during hippocampal maturation and the effects of As. Time-series RNA-seq analysis revealed a significant temporal correlation between As neurodevelopmental toxicity and the mRNA expression profile of the hippocampal region during critical postnatal developmental windows. Further, downregulation of genes associated with neurogenesis and telomere maintenance was observed. Notably, dynamic changes in hippocampal telomeres were observed in response to As exposure, with critically shortened telomeres inhibiting neural stem cells (NSCs) proliferation, impairing neuroblast maturation, and reducing the number and size of neurospheres. Additionally, the populations of BrdU⁺ and MAP2⁺ cells were decreased while GFAP⁺ cells were increased, indicating a decline in NSCs stemness. Furthermore, As exposure significantly impaired dendritic complexity in the hippocampus of mice, altered dendritic spine morphology, and disrupted synaptic ultrastructure, ultimately leading to cognitive impairment. These findings highlight the importance of analyzing telomere dynamics in environmental toxicology and offer insights into the neurotoxic mechanisms of maternal As on offspring development.