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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.
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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)
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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).
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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
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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,
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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.
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