Early Environmental Origins of Neurodegenerative Disease in Later Life

Abstract

Parkinson disease (PD) and Alzheimer disease (AD), the two most common neurodegenerative disorders in American adults, are of purely genetic origin in a minority of cases and appear in most instances to arise through interactions among genetic and environmental factors. In this article we hypothesize that environmental exposures in early life may be of particular etiologic importance and review evidence for the early environmental origins of neurodegeneration. For PD the first recognized environmental cause, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), was identified in epidemiologic studies of drug abusers. Chemicals experimentally linked to PD include the insecticide rotenone and the herbicides paraquat and maneb; interaction has been observed between paraquat and maneb. In epidemiologic studies, manganese has been linked to parkinsonism. In dementia, lead is associated with increased risk in chronically exposed workers. Exposures of children in early life to lead, polychlorinated biphenyls, and methylmercury have been followed by persistent decrements in intelligence that may presage dementia. To discover new environmental causes of AD and PD, and to characterize relevant gene–environment interactions, we recommend that a large, prospective genetic and epidemiologic study be undertaken that will follow thousands of children from conception (or before) to old age. Additional approaches to etiologic discovery include establishing incidence registries for AD and PD, conducting targeted investigations in high-risk populations, and improving testing of the potential neurologic toxicity of chemicals.

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

“…There is limited information linking altered expression of specific members of the wnt and fzd families to adverse neurobehavioral outcomes, but it is notable that wnt5a and fzd3, which we found to be reduced by both chlorpyrifos and diazinon, are key determinants in establishing the dopaminergic phenotype [12] and development of dopamine projections [96]. Here again, our results provide strong evidence for parallel or interactive participation of the wnt and fzd pathways with the fgf family, since we previously identified suppression of fgf members associated with the ontogeny of dopamine systems [79], which are especially sensitive to chlorpyrifos [3,25,76,78,80], and which likely underlie the association of organophosphate exposure with the subsequent development of Parkinson's Disease [43,47]. However, the potential impact of combined or overlapping disruption of fgf, wnt and fzd pathways during critical developmental periods extends further, to include other neurodegenerative syndromes or psychiatric disorders [10,13,15,71], such as schizophrenia [23,29,45,46,96].…”

Systems Medicine Approaches for the Definition of Complex Phenotypes in Chronic Diseases and Ageing. From Concept to Implementation and Policies

“…It is increasingly recognized that the in utero environment is an important determinant of adult NCDs including diabetes [23], CVD [24], asthma [25], COPD [26] or neuro-degenerative diseases [27]. Links with conserved foetal genes [28] and/or epigenetic mechanisms [25,29] have been proposed.…”

Strategies and tools for preventing neurotoxicity: To test, to predict and how to do it

“…However, the use of multiple in vitro models, including primary cultures of neurons obtained from specific brain areas, cell lines of different origin, co-culture systems with neuronal and glial cells, have been shown to be valuable in neurotoxicological research. The nervous system is particularly sensitive to alterations of the microenvironment occurring during development, and there is growing evidence pointing to developmental exposure to chemicals as possible cause of nervous system disorders (Landrigan et al, 2005). Well characterized in vitro model systems are therefore needed for large scale "animal-free" screening of chemicals and pharmaceutical drugs for the assessment of neurotoxic effects, with special focus on developmental neurotoxicity (DNT).…”