As our understanding of the cellular and molecular cascades that underlie many neurological diseases has vastly improved over the past several decades, our complementary study of the etiology of these diseases has revealed a complexity of risk factors that has proved difficult to disentangle. While genetics is still appreciated as a contributor, recent research in neurotoxicology has underscored the importance of chemical exposures as facilitators of neurological dysfunction.
Not surprisingly, the chemicals that receive the most attention are those we are routinely exposed to in our daily lives. The sources of these exposures are as varied as the chemicals themselves: pesticides on produce, flame-retardant compounds on furniture, metals in drinking water, and various chemicals used to manufacture consumer products that have simplified our lives.
While many of these chemicals have well-defined biological targets as a consequence of their utility (eg, pesticides), many other chemicals, such as bisphenol A and brominated flame retardants, were never manufactured or intended to target and disrupt biological systems. Yet, laboratory-based research has delineated the impact of these chemicals and highlighted several neurological targets that are disturbed. These findings are further supported through population-based studies that have established these chemicals as significant risk factors for neurological deficits.
While these exposures are usually thought of as occurring during adulthood, evidence points to prenatal and early postnatal periods as critical to brain development that can be upended by such chemical exposures.1,2 Indeed, recent findings indicate that exposure to environmental toxicants is a key risk factor for neurodevelopmental disorders, including ADHD and autism spectrum disorder (ASD).3,4 Moreover, these developmental exposures may initiate a pathological cascade that propagates over time and underlies some of the neurodegenerative or neurobehavioral disorders seen in adulthood.5 Although these findings have been supported by laboratory studies, such hypotheses require additional studies.
While the arduous task of characterizing neural targets affected by toxicants and their potential to alter neuronal function is ongoing, clinicians face an equally daunting challenge as they must determine whether a neurological impairment is the result of exposure to a toxicant or some other endogenous or exogenous factor. Beyond this initial diagnosis, they need to effectively monitor the progress of a neuro-toxicological deficit and evaluate the effectiveness of a treatment intervention.
Previously, clinicians relied on biomarkers of exposure isolated from blood or urine to determine biological levels of a toxicant or its metabolite and then coupled this information with a neurobehavioral examination to establish an association between toxicant exposure and neurological deficits. However, in many instances these associations are tenuous, and more sensitive and specific biomarkers are needed to diagnose, predict, and longitudinally evaluate a neurotoxicological event.
Fluid-based biomarkers of neurotoxicity
During the past several years, significant advances have been made to identify and characterize a variety of biomarkers that could be effectively used to delineate a neurotoxicological deficit in the clinical setting. Fluid-based biomarkers consisting of blood (plasma and serum), urine, or cerebrospinal fluid (CSF) tend to be the most accessible and have been adapted to a variety of biochemical assays aimed at interrogating neuronal dysfunction. In general, these assays have focused on alterations to axonal and dendritic integrity through the measurement of tau, alpha-synuclein, and microtubule- associated protein 27. In contrast, other assays have focused on measuring inflammation and oxidative stress using markers for glial fibrillary acidic protein (GFAP) as well as markers of oxidative stress.
While these biomarkers provide critical information regarding alterations in biological functions, there are several caveats that need to be considered. First, the use of peripheral fluids such as blood or urine poses the potential risk of detecting alterations in the periphery that are not related to alterations occurring in the CNS. In many instances, the deposition and biological impact of these chemicals is promiscuous, demonstrating minimal selectivity for a particular organ system. Thus, a change in biomarkers—especially markers of oxidative stress sampled from the blood or urine—may indicate a biological dysfunction in a peripheral organ system, such as the liver or kidneys, which makes it difficult to ascribe a change specific to CNS dysfunction.
Dr. Caudle is Assistant Professor, Department of Environmental Health, Rollins School of Public Health, and Assistant Professor, Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA. He reports no conflicts of interest concerning the subject matter of this article.
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