The neurotoxic impact of food chemical contaminants: a growing concern?

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), pose significant global health challenges, with rising prevalence and socioeconomic burdens. While genetic factors play a role, environmental and dietary exposure to toxicants, including food chemical contaminants (FCCs), are modifiable risk factors to disease progression. This work consolidates the evidence linking FCC exposure to ND pathogenesis, emphasizing key neurotoxicity mechanisms and identifying critical areas for future research. FCCs, such as pesticides, heavy metals, mycotoxins, and processing- and packaging-related contaminants (e.g., polycyclic aromatic hydrocarbons, acrylamide, bisphenols, per-/poly-fluoroalkyl substances, and micro/nano-plastics), trigger oxidative responses, mitochondrial dysfunction, loss of blood-brain barrier integrity, and activate neuroinflammatory pathways. These mechanisms contribute to hallmark neurodegenerative processes, such as amyloid β aggregation, α-synuclein pathology, and disruptions in synaptic signaling. Additionally, FCCs may act as neurotoxicants through unexplored pathways, including disruptions in gut-brain axis communication, epigenetic regulation, and endocrine signaling. Emerging factors, such as dietary modulation and the role of adipose tissue as an FCC reservoir, are considered potential amplifiers of FCCs' neurotoxic effects. Recent advancements in toxicological evaluation, including new approach methodologies (NAMs) and adverse outcome pathways (AOPs), offer promising tools for assessing FCC-related neurotoxicity using integrated approaches and realistic exposure scenarios. Addressing the cumulative and synergistic impacts of FCC mixtures remains a critical priority for research and regulatory frameworks. Advancing our understanding of FCC neurotoxicity and integrating innovative assessment strategies will be pivotal in mitigating their contribution to ND risk and safeguarding brain health. • FCCs are linked to neurodegenerative diseases via oxidative stress and inflammation. • Dietary FCCs cross barriers like BBB, impacting brain function and health. • Chronic, low-dose FCC exposure may potentiate neurodegenerative processes. • Research gaps include mixture effects and long-term FCC exposure risks. • Advanced NAMs are critical for FCC risk assessment and regulatory actions.