Neurotransmission Targets of Per- and Polyfluoroalkyl Substance Neurotoxicity: Mechanisms and Potential Implications for Adverse Neurological Outcomes

Abstract

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.

Figure 1.

PFAS neurotoxicity through dopamine and calcium signaling. This figure illustrates the synaptic pathways connecting PFAS, dopamine, and calcium. The key concept is that dopamine, like glutamate, is a target for PFAS-induced modulation of calcium currents. Importantly, PFAS interacts with many known proteins that are a part of dopaminergic postsynaptic signal transduction, but future studies need to investigate the interaction of PFAS and dopamine receptors (DRs) 1 and 2 and the DR1–2 dimer as well as DR3, −4, and −5 (not depicted in the figure). Some evidence suggests DR2 activity, protein levels, and RNA expression may decrease with PFAS exposure. This would result in PFAS inhibiting DR2’s inhibition of AC, resulting in the upregulation of the L-VGCC’s activity. PFAS has been extensively demonstrated to induce increased cytosolic calcium through the L-VGCC and to a lesser extent in the IP₃R. Future studies also need to investigate PFAS’s effect on the monoamine metabolic enzymes and transporters. AADC, aromatic amino acid decarboxylase; AC, adenylyl cyclase; CAM, calmodulin; CAMKIIa, CAM kinase IIa; cAMP, cyclic adenosine monophosphate; COMT, catechol-O-methyltransferase; CREB, cAMP-response element-binding; DA, dopamine; DAT, dopamine transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; DR1, dopamine receptor 1; DR1-DR2, DR1–DR2 dimer; DR2, dopamine receptor 2; IP₃, inositol triphosphate; IP₃R, inositol triphosphate receptor; L-DOPA, l-3,4-dihydroxyphenylalanine; HVA, homovanillic acid; L-VGCC, L-type voltage-gated calcium channel; MAO, monoamine oxidase; pDARPP-32, dopamine and cAMP-regulated phosphor-protein 32 kDa; PKA, protein kinase A; PLC, protein lipase C; P,Q,N-VGCC, P,Q,N-type voltage-gated calcium channel; PP1, protein phosphatase 1; VMAT, vesicular monoamine transporter.