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Overview: Rotenone, Parkinson Disease, and Evidence Biological Studies Rotenone is a pesticide and piscicide derived from the derris root. One known mechanism of Rotenone’s cytotoxicity is at the mitochondrial level affecting cellular respiration (Figure 1). Biological experimental studies show mitochondrial dysfunction is linked to the progression or pathogenesis of Parkinson Disease (PD) (Büeler, 2009; Schapira, 2004; Schapira, 2010, Van Laar & Berman, 2009; Winklhofer & Haass, 2010; Zhu & Chu, 2010). Specifically, PD tissues show reduced mitochondrial respiratory chain complex I activity in the substantia nigra pars compacta (Shapira et al., 1990), cerebral complex (Parker et al., 2008), skeletal muscles (Blin et al., 1994), and blood platelets (Cooper et al., 1992; Haas et al., 1995). Biologic experiments called cybrid experiments show transferred deficiencies in mitochondrial Complex I activity and respiratory capacity (Esteves et al., 2010; Trimmer & Bennett, 2009). In addition, direct molecular links between PD and mitochondrial dysfunction have been established by the discovery of disease-causing mutations in genes that encode proteins that modulate mitochondrial function: PINK1 (phosphate and tensin homolog-induced putative kinase 1), parkin, and DJ-1 (Bonifati et al., 2003; Burbulla et al., 2010; Kitada et al.,1998; Knott & Bossy-Wetzel, 2008;Paisen-Ruiz et al., 2004; Van Laar & Berman, 2009). Nature and Nurture: Disentangling the Effects of Genes and Environment. To continue the discussion on genes and exposure factors or environmental factors, such as pesticides, it may be helpful to understand what is meant by the relationship or interaction of genes to exposure factors or environmental factors. In short, family members share genes and a common environment. Family resemblance in traits, such as height, reflects both genes and environment (nature and nurture, respectively). For centuries people have debated the relative importance of these factors. It is a mistake, of course, to view them as mutually exclusive. Few traits are influenced only by genes or only by environmental factors. Most traits are influenced by both. It is useful to try and determine the relative influence of genetic and environmental factors and their interaction. This is a key concept with PD because only about 10% of PD is considered inherited from family, the familial form, and the majority of affected individuals are sporadic, that is, occurring at random or by chance and not as a result of an inherited trait (Jorde et al., 2010) The term “acquired” is sometimes used to mean a physical characteristic that is not inherited but is acquired in one’s lifetime and may be an effect of the environment. Thus researchers are studying environmental factors to better understand the cause of such diseases like PD to help in the planning and implementation of public health strategies. 1 Rotenone Complex I Inhibition (Widespread & uniform) DJ1 UCHL1 Parkin Oxidative Stress (Widespread, not uniform Proteasonal Dysfunction (Midbrain: lesioned rats only) ? α-Synuclein Accumulation (Midbrain only) α-synuclein Neurodegeneration Figure 1: Complex I inhibition is central to sporadic PD pathogenesis. The rotenone model of Parkinsonism, while substantiating the involvement of mitochondrial dysfunction and environmental exposure in PD pathogenesis, demonstrates that chronic, low levels of Complex I inhibition can result in oxidative stress-induced DJ-1 modifications, elevations, and modifications in α-synuclein protein, and proteasomal dysfunction features strongly implicated in PD pathogenesis. Note that, at each step, the effects become more regionally restricted such that systemic Complex I inhibition eventually results in highly selective degeneration of the nigrostriatal pathway. (Adapted from Betarbet et al., 2006; Schapira, 2010) 2 The functions of PD-associated genes and their gene modifiers, including pesticides, require many more genetic and epigenetic studies. The studies cited above, however, support a direct or indirect role for several of these genes in both mitochondrial function and the cellular response to oxidative stress (Henchcliffe & Beal, 2008). In addition, rare inherited mutations in genes encoding electron transport chain have been associated with PD (Henchcliffe & Beal, 2008). Instead, acquired somatic mutations (i.e., occurring during one’s lifetime) are more common, affect mitochondrial electron transport chain function, and are found in the substantia nigra in patients with PD (Henchcliffe & Beal, 2008). Thus, the products of several genes associated with PD are linked to mitochondrial function—the structure responsible for making energy in the cell—and mitochondrial activity is affected by environmental factors, a so-called gene-exposure interaction. For example, to assess the relevance of experimental results to human PD a large collaborative effort conducted by researchers at the National Institute of Environmental Health (NIEHS), a division of the National Institutes of Health, and the Parkinson’s Institute in Sunnyvale California investigated the association of PD with use of pesticides linked to Complex I inhibition or oxidative stress (Tanner et al., 2011). In 110 cases of PD and 358 controls, PD was associated with use of a group of pesticides, including rotenone, that inhibit mitochondrial Complex I. These researchers found that rotenone directly inhibits the function of the mitochondria. Because rotenone is believed to have a relatively short environmental half-life and limited bioavailability, a relationship to human disease has been questioned (Hatcher et al., 2008; Li et al., 2005). However, very recent work in rodent models indicated that a temporally limited exposure (previous early exposure) to rotenone later caused progressive functional and pathologic changes in the nervous system of rodents, mimicking changes found in humans with PD; as in PD these nervous system changes preceded central nervous system pathology (Abbott et al., 2001; Braak et al., 2006; Drolet et al., 2009; Greene et al., 2009; Pan-Montojo et al., 2010). In the laboratory, chronic rotenone exposure has been reported to have additional effects associated with PD pathogenesis or progression, including ones similar to changes in monogenetic forms of PD (Henchcliffe & Beal, 2008). Rotenone toxicity, therefore, provides a conceptual link or bridge suggesting shared pathogenic mechanisms for both sporadic and inherited forms of PD (Tanner et al., 2011). Rotenone has been shown to reduce mitochondrial motility, membrane potential (ΔΨm), and respiration, and to alter mitochondrial structure, sub-cellular distribution, and fisson/fusion balance (chromosome) in nonastrocytic cells (Arnold et al., 2011; Barsoum et al. ,2006; Benard et al., 2007; Borland et al., 2008; Koopman, 2007; Mortiboys et al., 2008; Pham et al., 2004; Van Laar & Berman, 2009; Yadava & Nicholls, 2007). Pharmacologic inhibition of Complex I using 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) or pesticides (rotenone) causes mitochondrial dysfunction and experimental parkinsonism (Ballard et al., 1985; Betarbet et al., 2000; Cannon et al., 2009; Langston et al., 1984; Panov et al., 2005). 3 Epidemiological Studies The Utah Division of Wildlife Resources (UDWR) included comments throughout their Environmental Assessment on the epidemiologic science concerning Rotenone and PD connection. In effect, they dismiss the epidemiological science because of the “…difficulty in using epidemiological studies to evaluate a disease such as Parkinson’s where multiple causal factors (genetic susceptibility, age, and environmental exposures) are present” (Wirdefeldt et al., 2011). Lacking from the UDWR report is one of the most important known and documented findings from medical literature that monogenetic causes do not seem to have a primary role in most cases of PD (de Lau & Breteler, 2006). A positive family history found in some studies of PD has lead, in most cases, to no clear mode of inheritance (Alonso et al., 1986; Behari et al., 2001, Chan et al., 1998; Hardy et al., 2006; Korchounov et al., 2004; Martin et al., 1973; Marttila & Rinne, 1988; Mickel et al., 1997; Payami et al., 2002; Semchuk et al., 1993; Sveinbjornsdottir et al., 2000; Taylor et al., 1999). From epidemiological studies and laboratory genetic studies, the genetics of PD has resulted in valuable insights regarding PD pathogenesis. Yet, the known PD genes are still estimated to account for only a small proportion of all PD at the population level (Wirdefeldt et al., 2011). Thus the epidemiological studies are crucial for comparing populations around the world to understand and disentangle risk factors. Breast cancer, for example, is prevalent among northern Europeans and Americans but is relatively rare among women in developing countries. If ethnicity plays a major role, immigrants should retain the same cancer incidence rates of their country of origin. Instead, immigrants acquire the cancer rates of the geographical area they move to within one or two generations (Jorde et al., 2010). Particularly important and instructive studies are epidemiologic studies that assist with interethnic comparisons and disentangle the effects of genes, the environment, and lifestyle on disease rates, including PD. Recent Epidemiological International Review: From the most recent international review article on the epidemiology and etiology of PD the evidence is synthesized in Table 1 below. For the first time, the epidemiological evidence was categorized according to the first three categories of the Institute of Medicine (IOM) classification used in a consensus statement on environmental risk factors in PD (Bronstein et al., 2009). This review is the most comprehensive review available and is based internationally on 675 references. The categories are described as follows: (1) Sufficient evidence of an association. In this category, a consistent association has been observed between an exposure and a health outcome in human studies, in which chance and bias, including confounding, could be ruled out with reasonable confidence. (2) Limited suggestive evidence of an association. In this category, evidence suggests an association, but chance, bias, and confounding could not be ruled out with confidence. (3) Inadequate or insufficient evidence to determine whether an association exist. In this category, evidence is of insufficient quantity, quality, or consistency to permit a conclusion regarding an association between an exposure and a health outcome. Although some studies are negative, an association seems to be stronger and more consistent for pesticides in general and particularly 4 for insecticides than for any other compound (see Table 1) (Wirdefeldt et al., 2011). These data are important because for the first time rigorous analyses on bias, quality, consistency, and confounding have been done and reported. Table 1. Exposure Epidemiologic Evidence Pesticides Limited Metals Inadequate Organic solvents Inadequate Magnetic fields Inadequate Smoking Sufficient Alcohol Limited Physical activity Limited Adiposity Inadequate Coffee Sufficient Intake of dairy products Limited Intake of macronutrients Inadequate Dietary intake of Limited antioxidants Dietary intake of minerals Inadequate (Table adapted from Wirdefeldt et al., 2011.) Direction of Association Positive Negative Negative Negative Negative Positive Negative Most Recent Case-Control Study: The first study of its kind was the analysis of pesticides classified by presumed mechanism of disease causation for PD, rather than by functional categories (e.g., organochlorines). The investigators found significant associations of PD with use of groups of pesticides classified as Complex I inhibitors or as oxidative stressors, providing support in humans for findings from decades of experimental studies. Most important, PD was strongly associated with rotenone and paraquat, two individual pesticides used extensively in the laboratory to model PD in the laboratory (Tanner et al., 2011). In the nested case-control study of participants in the Agricultural Health Study, researchers compared 110 persons with Parkinson disease with 358 controls and found that individuals who used paraquat or rotenone had 2.5 times higher odds of developing PD (Tanner et al., 2011). An association also was observed even though exposure was discontinued up to 15 years before PD was diagnosed (Tanner et al., 2011).This is a strong study because the investigators evaluated rotenone use before PD diagnosis (not retrospectively) and during a comparable time period in neurologically healthy controls (Tanner et al., 2011). This study was reviewed and included in the Journal of the American Medical Association (Kuehn, 2011). Occupational Exposures: Human occupational exposure to pesticides, including rotenone, is epidemiologically-linked with an increased risk for PD (Ascherio et al., 2006; Brown et al., 2006; Gash et al., 2008; Sherer et al., 2007; Tanner et al., 2011). The evidence is limited on the role of metals, chemicals, and magnetic fields, 5 however, there is suggestive evidence overall for pesticides using the IOM criteria (Wirdefeldt et al., 2011). Summary There are no home garden or residential uses of rotenone or paraquat currently registered. Rotenone was withdrawn from use in Canada and Europe in 2007 (Schapira, 2010). Part of the withdrawal was based on the data concerning health effects. Contamination by Rotenone and other mixtures of chemicals used as piscicides is a concern for farming communities such as Boulder, Utah. Repeated applications of these chemicals overtime especially without knowing their residues or persistence in the environment, is a major concern. ( appeal from Matt Cochran on aquatic poison and environmental fate section). There is strong opposition in Boulder to the use of Rotenone, petroleum dispersing chemicals, and oxidizing agents. References Abbott, R.D., et al. (2001). Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology, 57(3):456-462. Alonso M.E. et al. (1986). Parkinson’s disease: A genetic study. Canadian Journal Neurologic Science, 13, 248-251. Arnold, B., et al. (2011). 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