Early Environmental Origins of Neurodegenerative Disease in Later Life

Center for Children's Health and the Environment, Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Environmental Health Perspectives (Impact Factor: 7.98). 10/2005; 113(9):1230-3. DOI: 10.1289/ehp.7571
Source: PubMed


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.

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    • "Early-life exposure to certain natural and synthetic chemicals may increase the risk of 41 neurodegenerative and other diseases later in life (Spencer, 1987; Landrigan et al., 2005; 42 Kisby and Spencer, 2011; Fox et al., 2012). The increase in childhood pathologies, such as 43 hyperactivity or memory alterations, and the occurrence of neurodegenerative diseases such 44 as Alzheimer's and Parkinson's diseases in the elderly, may be due in part to the early chronic 45 exposure of pollutants and their related impacts in early stages of life (Corrigan et al., 2000; 46 Bihaqi et al., 2011, 2013, 2014a; Medehouenou et al., 2011, 2014; Jurewicz et al., 2013; 47 Grandjean and Landrigan, 2014). "
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    ABSTRACT: Lactational exposure to low levels of the sum of the six indicator polychlorinated biphenyls (∑6 NDL-PCBs, 10ng/kg/day) is known to lead to persistent anxious behavior in young and adult offspring mice at postnatal days 40 and 160, respectively. At more advanced life stages, we evaluated the effects on the mouse brain of neuronal stress induced by the synaptotoxic amyloid-beta (Aβ) peptide. Perinatal exposure of lactating mice to ∑6 NDL-PCBs did not affect short-term memory performances of their offspring male mice aged 14 months as compared to control PCB-naive mice. However, following intracerebroventricular injection of soluble Aβ oligomers, significant impairments in long-term memory were detected in the mice that had been lactationally treated with ∑6 NDL-PCBs. In addition, immunoblot analyses of the synaptosomal fraction of hippocampal tissues from treated mice revealed a lower expression of the synaptic proteins synaptophysin and PSD-95. Though preliminary, our findings suggest for the first time that early exposure to low levels of NDL-PCBs induce late neuronal vulnerability to amyloid stress. Additional experiments are needed to confirm whether early environmental influences are involved in the etiology of brain aging and cognitive decline.
    NeuroToxicology 10/2015; DOI:10.1016/j.neuro.2015.10.003 · 3.38 Impact Factor
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    • "We tested the viability of control (e.g. subject CA) versus patient SM derived neuroprogenitors by MTT assay after 48 hour exposure to Mn, Cu, Cd, and MeHg, all of which have been implicated in PD-relevant neurodegenerative processes and/or as PD environmental risk factors (Buzanska et al., 2009; Gorell et al., 1999; Götz et al., 2002; Jomova et al., 2010; Landrigan et al., 2005; Rivera-Mancía et al., 2010; Squitti et al., 2009; Weiss et al., 2002; Willis et al., 2010; Xu et al., 2011). To control for cell line dependent variability , we used multiple clonal hiPSC lines (lines CA4 and CA6 for subject CA; lines SM3, SM4, and SM5 for subject SM). "
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    ABSTRACT: Poorly-defined interactions between environmental and genetic risk factors underlie Parkinson's disease (PD) etiology. Here we tested the hypothesis that human stem cell derived forebrain neuroprogenitors from patients with known familial risk for early onset PD will exhibit enhanced sensitivity to PD environmental risk factors compared to healthy control subjects without a family history of PD. Two male siblings (SM and PM) with biallelic loss-of-function mutations in PARK2 were identified. Human induced pluripotent stem cells (hiPSCs) from SM, PM, and four control subjects with no known family histories of PD or related neurodegenerative diseases were utilized. We tested the hypothesis that hiPSC-derived neuroprogenitors from patients with PARK2 mutations would show heightened cell death, mitochondrial dysfunction, and reactive oxygen species generation compared to control cells as a result of exposure to heavy metals (PD environmental risk factors). We report that PARK2 mutant neuroprogenitors showed increased cytotoxicity with copper (Cu) and cadmium (Cd) exposure but not manganese (Mn) or methyl mercury (MeHg) relative to control neuroprogenitors. PARK2 mutant neuroprogenitors also showed a substantial increase in mitochondrial fragmentation, initial ROS generation, and loss of mitochondrial membrane potential following Cu exposure. Our data substantiate Cu exposure as an environmental risk factor for PD. Furthermore, we report a shift in the lowest observable effect level (LOEL) for greater sensitivity to Cu-dependent mitochondrial dysfunction in patients SM and PM relative to controls, correlating with their increased genetic risk for PD.
    Neurobiology of Disease 10/2014; 73. DOI:10.1016/j.nbd.2014.10.002 · 5.08 Impact Factor
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    • "Parkinson's disease (PD) is characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta and subsequent loss of DA function in the projection area, namely the striatum. A number of researchers have reported the association between exposure insecticides and herbicides as increasing risk for developing PD (Hertzman et al., 1990; Liou et al., 1997; Landrigan et al., 2005; McCormack et al., 2005; Tanner et al., 2011). In a meta-analysis of 19 studies, Priyadarshi et al. (2000) reported an association between high pesticide use and increased risk for PD with combined odds ratio of 2.15 among farmers, people living close to farms, and those exposed to farm animals. "
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    ABSTRACT: Heavy metals, various pesticide and herbicides are implicated as risk factors for human health. Paraquat, maneb, and rotenone, carbamate, and organophosphorous insecticides are examples of toxicants for which acute and chronic exposure are associated with multiple neurological disorders including Parkinson's disease. Nevertheless, the role of pesticide exposure in neurodegenerative diseases is not clear-cut, as there are inconsistencies in both the epidemiological and preclinical research. The aim of this short review is to show that at least, some of the inconsistencies are related to individual differences in susceptibility to the effects of neurotoxicants, individual differences that can be traced to the genetic constitution of the individuals and animals studies, i.e., host-based susceptibility.
    Frontiers in Genetics 09/2014; 5:327. DOI:10.3389/fgene.2014.00327
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