FIGURE 5.

Mechanisms driving PFAS-induced neurotoxicity include direct mechanisms, such as disruption of calcium (Ca²⁺) homeostasis. PFAS-associated Ca²⁺ overload in neurons appears to be driven by Ca²⁺ influx from the extracellular space, through L-type voltage-gated Ca²⁺ channel (L-VGCC), and intracellular Ca²⁺storage organelles (mitochondria and endoplasmic reticulum), via inositol 1,4,5-triphosphate receptors (IP3R) and ryanodine receptors (RyR). Superfluous Ca²⁺ can disrupt neuronal signaling, induce oxidative stress leading to neuronal cell death, and disrupt Ca²⁺ dependent second messenger signaling cascades (CaM: calmodulin, CaN: calcineurin) that regulate diverse neuronal cell processes, including growth, reorganization, and the production and release of neurotransmitters.