Targeting oligodendrocytes in developmental neurotoxicity: A systematic literature review

Mechanistic developmental neurotoxicity (DNT) research has focused predominantly on neuronal endpoints, while effects on oligodendrocytes and myelination remain less characterized. This systematic review aimed to identify mechanisms linking developmental chemical exposure to oligodendrocyte-lineage injury, impaired myelination, and associated neurodevelopmental outcomes. Eligible evidence included developmental in vitro models and in vivo exposures extending from parental preconception exposure with offspring outcomes through embryonic/fetal, neonatal, juvenile, and adolescent development. In rodents, direct exposure had to begin by postnatal day 60, and in fish and amphibians before sexual maturity; adult-only exposures without offspring developmental outcomes were excluded. PubMed, Web of Science, and Scopus were searched using an iterative strategy supported by LitSearchR, and study quality was evaluated using a modified SciRAP approach. Of 2,880 records retrieved, 1,096 remained after deduplication, 156 underwent full-text review, and 77 met the inclusion criteria for mechanistic synthesis. Disruption of oligodendrocyte-lineage development and myelination emerged as the primary outcome, associated with four recurrent mechanistic domains: hormonal and signaling dysregulation; oxidative stress, mitochondrial dysfunction, apoptosis, and cytotoxicity; astrocyte and microglia activation; and neuronal and synaptic dysfunction. Across studies, toxicant exposure impaired oligodendrocyte differentiation, maturation, and survival, with reduced or abnormal myelination and altered MBP, MAG, and CNPase. These effects were associated with thyroid-hormone and BDNF-TrkB dysregulation, oxidative-mitochondrial injury, inflammatory responses, and neuronal/synaptic alterations linked to behavioral and cognitive outcomes. These findings support oligodendrocyte and myelin endpoints as mechanistically informative components of future DNT testing and chemical risk assessment.