Figure 4.

Proposed framework of metal exposure and the development of ALS. In ALS, metal dyshomeostasis may be influenced by genetic mutations (SOD1, TDP‐43, C9orf72, genetic modifiers) (orange circle) and/or exposure to environmental toxicants (blue circles) during the prenatal and childhood periods (susceptible period). Alterations in biological pathways and epigenetic mechanisms associated with ALS pathology in addition to exposure to other environmental factors (purple circle) in early adulthood (latency period) and aging may be pathological triggers or mediators of ALS onset and progression later in life.