Environmental determinants of neurotoxicity: role of heavy metals in neurological disorders

Abstract

Neurodevelopmental and neurodegenerative disorders are related disorders lying on a spectrum of neural dysfunction with overlapping molecular and cellular mechanisms. Early-life diseases like autism spectrum disorder and attention-deficit/hyperactivity disorder are the result of disturbed neurodevelopment, while late-onset diseases such as Alzheimer’s disease and Parkinson’s disease are defined by progressive neuronal loss and loss of function. Emerging evidence shows that environmental exposures are important, modifiable factors that affect brain health throughout the lifespan. Factors such as air pollution, heavy metals, pesticides, and endocrine-disrupting chemicals act in combination with genetic susceptibility to disrupt neurogenesis, synaptic plasticity, and neuro-immune signaling. These exposures cause persistent epigenetic modifications, oxidative stress, mitochondrial dysfunction, and chronic neuro-inflammation, linking early developmental insults to neurodegenerative processes later in life. The concepts of the exposome and the developmental origins of health and disease provide additional support for the cumulative, lifelong impact of environmental interactions. Mechanistically, the recurrent process of neuronal damage is caused by impaired proteostasis, microglial stimulation, and blood–brain barrier dysfunction. Furthermore, the gut-brain axis is a hyperactive system in which immune responses and microbial metabolites trigger neurobiological responses to external stimuli. This review integrates multidisciplinary evidence to elucidate the mechanism and emphasizes environmental risk mitigation and translational strategies to reduce disease burden and promote lifelong brain resilience.