Per- and polyfluoroalkyl substances (PFAS) are a group
of persistent
environmental pollutants that are ubiquitously found in the environment
and virtually in all living organisms, including humans. PFAS cross
the blood–brain barrier and accumulate in the brain. Thus,
PFAS are a likely risk for neurotoxicity. Studies that measured PFAS
levels in the brains of humans, polar bears, and rats have demonstrated
that some areas of the brain accumulate greater amounts of PFAS. Moreover,
in humans, there is evidence that PFAS exposure is associated with
attention-deficit/hyperactivity disorder (ADHD) in children and an
increased cause of death from Parkinson’s disease and Alzheimer’s
disease in elderly populations. Given possible links to neurological
disease, critical analyses of possible mechanisms of neurotoxic action
are necessary to advance the field. This paper critically reviews
studies that investigated potential mechanistic causes for neurotoxicity
including (1) a change in neurotransmitter levels, (2) dysfunction
of synaptic calcium homeostasis, and (3) alteration of synaptic and
neuronal protein expression and function. We found growing evidence
that PFAS exposure causes neurotoxicity through the disruption of
neurotransmission, particularly the dopamine and glutamate systems,
which are implicated in age-related psychiatric illnesses and neurodegenerative
diseases. Evaluated research has shown there are highly reproduced
increased glutamate levels in the hippocampus and catecholamine levels
in the hypothalamus and decreased dopamine in the whole brain after
PFAS exposure. There are significant gaps in the literature relative
to the assessment of the nigrostriatal system (striatum and ventral
midbrain) among other regions associated with PFAS-associated neurologic
dysfunction observed in humans. In conclusion, evidence suggests that
PFAS may be neurotoxic and associated with chronic and age-related
psychiatric illnesses and neurodegenerative diseases. Thus, it is
imperative that future mechanistic studies assess the impact of PFAS
and PFAS mixtures on the mechanism of neurotransmission and the consequential
functional effects.