Frédéric Moisan

Professional exposure to pesticides and Parkinson disease.

We studied the relation between Parkinson disease (PD) and professional exposure to pesticides in a community‐based case‐control study conducted in a population characterized by a high prevalence of exposure. Our objective was to investigate the role of specific pesticide families and to perform dose‐effect analyses.

Update in the epidemiology of Parkinson's disease.

Purpose of reviewIn the past 18 months, several important studies on the epidemiology of Parkinsons disease have been published. In particular, large cohorts have identified sufficient incident patients with Parkinsons disease to study risk or protective factors of Parkinsons disease; one of the important recent events in the field is the publication of some of their findings. Recent findingsWe will first review findings of descriptive studies on the frequency of the disease and its geographic or temporal distribution. We will then summarize the findings of analytical studies dealing with risk or protective factors in the fields of dietary and lifestyle factors (cigarette smoking, coffee and tea drinking, uric acid, dairy products), environmental exposures (pesticides, lead, manganese, welding), hormonal factors (oophorectomy), vascular risk factors (diabetes, hypertension, cholesterol level), pharmacoepidemiology (NSAIDs, statins), and familial aggregation. SummaryEpidemiologic studies have consistently found that some exposures are inversely (e.g., cigarette smoking) or positively associated with Parkinsons disease (e.g., pesticides), while their findings are, at the present time, less consistent for other exposures (e.g., NSAIDs, vascular risk factors). Finally, recent studies have investigated new research fields (e.g., hormonal factors, uric acid, pharmacoepidemiology) and additional data need to be collected.

In vitro effects of nanoparticles on renal cells.

BackgroundThe ability of nanoparticles to cross the lung-blood barrier suggests that they may translocate to blood and to targets distant from their portal of entry. Nevertheless, nanotoxicity in organs has received little attention. The purpose of this study was to evaluate nanotoxicity in renal cells using in vitro models. Various carbon black (CB) (FW2–13 nm, Printex60-21 nm and LB101-95 nm) and titanium dioxide (TiO2-15 and TiO2-50 nm) nanoparticles were characterized on size by electron microscopy. We evaluated theirs effects on glomerular mesangial (IP15) and epithelial proximal tubular (LLC-PK1) renal cells, using light microscopy, WST-1 assay, immunofluorescence labeling and DCFH-DA for reactive oxygen species (ROS) assay.ResultsNanoparticles induced a variety of cell responses. On both IP15 and LLC-PK1 cells, the smallest FW2 NP was found to be the most cytotoxic with classic dose-behavior. For the other NPs tested, different cytotoxic profiles were found, with LLC-PK1 cells being more sensitive than IP15 cells. Exposure to FW2 NPs, evidenced in our experiments as the most cytotoxic particle type, significantly enhanced production of ROS in both IP15 and LLC-PK1 cells. Immunofluorescence microscopy using latex beads indicated that depending on their size, the cells internalized particles, which accumulated in the cell cytoplasm. Additionally using transmission electronic microscope micrographs show nanoparticles inside the cells and trapped in vesicles.ConclusionThe present data constitute the first step towards determining in vitro dose effect of manufactured CB and TiO2 NPs in renal cells. Cytotoxicological assays using epithelial tubular and glomerular mesangial cell lines rapidly provide information and demonstrated that NP materials exhibit varying degrees of cytotoxicity. It seems clear that in vitro cellular systems will need to be further developed, standardized and validated (relative to in vivo effects) in order to provide useful screening data about the relative toxicity of nanoparticles.

Independent and joint effects of the MAPT and SNCA genes in Parkinson disease.

We studied the independent and joint effects of the genes encoding alpha‐synuclein (SNCA) and microtubule‐associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta‐analysis of individual data from case–control studies participating in the Genetic Epidemiology of Parkinsons Disease (GEO‐PD) consortium.

Epidemiology of Parkinson's disease

Parkinsons disease (PD) is the second most common neurodegenerative disease after Alzheimers. PD is considered a multifactorial disorder that results, in most cases, from the combined effects of multiple risk and protective factors, including genetic and environmental ones. This review discusses some of the methodological challenges involved in assessing the descriptive, prognostic and etiological epidemiological studies of PD, and summarizes their main findings.

Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis

Background Parkinson’s disease (PD) is 1.5 times more frequent in men than women. Whether age modifies this ratio is unclear. We examined whether male-to-female (M–F) ratios change with age through a French nationwide prevalence/incidence study (2010) and a meta-analysis of incidence studies. Methods We used French national drug claims databases to identify PD cases using a validated algorithm. We computed M–F prevalence/incidence ratios overall and by age using Poisson regression. Ratios were regressed on age to estimate their annual change. We identified all PD incidence studies with age/sex-specific data, and performed a meta-analysis of M–F ratios. Results On the basis of 149 672 prevalent (50% women) and 25 438 incident (49% women) cases, age-standardised rates were higher in men (prevalence=2.865/1000; incidence=0.490/1000 person-years) than women (prevalence=1.934/1000; incidence=0.328/1000 person-years). The overall M–F ratio was 1.48 for prevalence and 1.49 for incidence. Prevalence and incidence M–F ratios increased by 0.05 and 0.14, respectively, per 10 years of age. Incidence was similar in men and women under 50 years (M–F ratio <1.2, p>0.20), and over 1.6 (p<0.001) times higher in men than women above 80 years (p trend <0.001). A meta-analysis of 22 incidence studies (14 126 cases, 46% women) confirmed that M– F ratios increased with age (0.26 per 10 years, p trend=0.005). Conclusions Age-increasing M–F ratios suggest that PD aetiology changes with age. Sex-related risk/protective factors may play a different role across the continuum of age at onset. This finding may inform aetiological PD research.

Association of Parkinson's Disease and Its Subtypes with Agricultural Pesticide Exposures in Men: A Case-Control Study in France.

Background Pesticides have been associated with Parkinson’s disease (PD), but there are few data on important exposure characteristics such as dose–effect relations. It is unknown whether associations depend on clinical PD subtypes. Objectives We examined quantitative aspects of occupational pesticide exposure associated with PD and investigated whether associations were similar across PD subtypes. Methods As part of a French population-based case–control study including men enrolled in the health insurance plan for farmers and agricultural workers, cases with clinically confirmed PD were identified through antiparkinsonian drug claims. Two controls were matched to each case. Using a comprehensive occupational questionnaire, we computed indicators for different dimensions of exposure (duration, cumulative exposure, intensity). We used conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) among exposed male farmers (133 cases, 298 controls). We examined the relation between pesticides and PD subtypes (tremor dominant/non-tremor dominant) using polytomous logistic regression. Results There appeared to be a stronger association with intensity than duration of pesticide exposure based on separate models, as well as a synergistic interaction between duration and intensity (p-interaction = 0.04). High-intensity exposure to insecticides was positively associated with PD among those with low-intensity exposure to fungicides and vice versa, suggesting independent effects. Pesticide exposure in farms that specialized in vineyards was associated with PD (OR = 2.56; 95% CI: 1.31, 4.98). The association with intensity of pesticide use was stronger, although not significantly (p-heterogeneity = 0.60), for tremor-dominant (p-trend < 0.01) than for non-tremor–dominant PD (p-trend = 0.24). Conclusions This study helps to better characterize different aspects of pesticide exposure associated with PD, and shows a significant association of pesticides with tremor-dominant PD in men, the most typical PD presentation. Citation Moisan F, Spinosi J, Delabre L, Gourlet V, Mazurie JL, Bénatru I, Goldberg M, Weisskopf MG, Imbernon E, Tzourio C, Elbaz A. 2015. Association of Parkinson’s disease and its subtypes with agricultural pesticide exposures in men: a case–control study in France. Environ Health Perspect 123:1123–1129; http://dx.doi.org/10.1289/ehp.1307970

Pesticide Exposure and Depression Among Agricultural Workers in France

Pesticides are ubiquitous neurotoxicants, and several lines of evidence suggest that exposure may be associated with depression. Epidemiologic evidence has focused largely on organophosphate exposures, while research on other pesticides is limited. We collected detailed pesticide use history from farmers recruited in 1998-2000 in France. Among 567 farmers aged 37-78 years, 83 (14.6%) self-reported treatment or hospitalization for depression. On the basis of the reported age at the first such instance, we used adjusted Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for depression (first treatment or hospitalization) by exposure to different pesticides. The hazard ratio for depression among those who used herbicides was 1.93 (95% confidence interval (CI): 0.95, 3.91); there was no association with insecticides or fungicides. Compared with nonusers, those who used herbicides for <19 years and ≥19 years (median for all herbicide users, 19 years) had hazard ratios of 1.51 (95% CI: 0.62, 3.67) and 2.31 (95% CI: 1.05, 5.10), respectively. Similar results were found for total hours of use. Results were stronger when adjusted for insecticides and fungicides. There is widespread use of herbicides by the general public, although likely at lower levels than in agriculture. Thus, determining whether similar associations are seen at lower levels of exposure should be explored.

The relation between type of farming and prevalence of Parkinson's disease among agricultural workers in five french districts†

Retrospective assessment of pesticide exposure is complex; however, patterns of pesticide use strongly depend on farming type, which is easier to assess than pesticide exposure. Our aim was to estimate Parkinsons disease (PD) prevalence in five French districts in 2007 among affiliates of Mutualité Sociale Agricole (MSA) and to investigate the relation between PD prevalence and farming type. We identified PD cases from administrative files as persons who used levodopa and/or benefited from free health care for PD. Densities of 16 farming types were defined at the canton of residence level (1988 French agricultural census). We used logistic regression to study the relation between PD prevalence and density of farming types and a semi‐Bayes approach to deal with correlated exposures. We identified 1,659 PD cases, yielding an age‐ and sex‐standardized PD prevalence of 3.01/1,000. Prevalence increased with age and was higher in men than women. We found a higher PD prevalence among affiliates living in cantons characterized by a higher density of farms specialized in fruits and permanent crops (multivariable semi‐Bayes model: OR4+5 vs 1+2+3 quintiles = 1.21, 95% CI = 1.08–1.36; test for trend, P = 0.035). In France, farms specialized in fruits and permanent crops rank first in terms of insecticide use per hectare. Our findings are consistent with studies reporting an association between PD and insecticide use and show that workers in farms specialized in fruits or permanent crops may be an occupational group at higher PD risk.

The scientific bases to consider Parkinson's disease an occupational disease in agriculture professionals exposed to pesticides in France

Parkinson’s disease (PD) is the most common cause of parkinsonism and neurodegenerative disorder after Alzheimer’s disease. It is caused by the progressive loss of dopaminergic neurons of the substantia nigra pars compacta which is accompanied by the presence of Lewy bodies. Its diagnosis is clinical and there is a risk of misdiagnosis with other causes of parkinsonism. PD is exceptional before age 50, and its frequency increases with age, with an incidence of about 1 to 5 per 1000 person-years after age 60. PD has consistently been shown to be about 1.5 times more common in men than in women. PD is considered as a multifactorial disease resulting in the majority of cases of multiple factors. Monogenic PD occurs in a minority of patients, but several small-effects susceptibility genes are implicated in sporadic forms. Heritability is however small, and it is generally considered that environmental factors are involved in PD aetiology. The hypothesis of a link between PD and pesticide exposure appeared in the early 1980s’, after several cases of parkinsonism occurred following intravenous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP can cross the blood–brain barrier and is metabolised in glial cells by enzyme monoamine oxidase B into 1-methyl-4-phenylpyridinium (MPP+), a substrate of the dopamine transporter that inhibits the complex I of the mitochondrial electron transport chain and leads to the degeneration of nigral dopaminergic neurons. MPTP-induced animal models represent one of the main tools for investigations into the mechanisms involved in the death of dopaminergic neurons in PD.1 This molecule has a chemical structure similar to that of paraquat, a non-selective herbicide marketed since the 1960s and widely used since. Following this accidental observation, numerous epidemiological studies have examined the relationship of farming and pesticides exposure with PD, and toxicological studies have investigated some of the mechanisms involved for specific …