Pre-Conception And First Trimester Exposure To Pesticides And Associations With Stillbirth.

Associations of pesticide exposures during pre-conception with stillbirth have not been well explored. We linked Arizona pesticide use records with birth certificates from 2006-2020 and estimated associations of living within 500meters of any pyrethroid, organophosphate (OP), or carbamate pesticide applications during a 90 day pre-conception window or the first trimester, with stillbirth. We considered a binary measure of exposure (any exposure), as well as log-pounds and log-acres applied within 500m, in a negative control exposure framework with log-binomial regression. We included 1,237,750 births, 2,290 stillbirths, and 27 pesticides. During pre-conception, any exposure to pesticides were associated with stillbirth, including cyfluthrin (RR=1.97, 95% CI 1.17,3.32), zeta-cypermethrin (RR=1.81, 95%CI 1.20, 2.74), organophosphates as a class (RR=1.60, 95%CI 1.16, 2.19), malathion (RR=2.02, 95%CI 1.26, 3.24), carbaryl (RR=6.39, 95%CI 2.07, 19.74), and propamocarb hydrochloride (RR=7.72, 95%CI 1.10, 54.20) . During the first trimester, fenpropathrin (RR=4.36, 95%CI 1.09, 17.50), permethrin (RR=1.57, 95%CI 1.02, 2.42), organophosphates as a class (RR=1.50, 95%CI 1.11, 2.01), acephate (RR=2.31, 95%CI 1.22, 4.40), and formetanate hydrochloride (RR=7.22, 95%CI 1.03, 50.58) were associated with stillbirth. Interpretations were consistent when using continuous measures of pounds or acres of exposure. Pesticide exposures during pre-conception and first trimester may be associated with stillbirth.

Ambient exposure to fine particulate matter with oxidative potential affects oxidative stress biomarkers in pregnancy.

Prenatal exposures to ambient particulate matter (PM2.5) from traffic may generate oxidative stress, and thus contribute to adverse birth outcomes. We investigated whether PM2.5 constituents from brake and tire wear affect levels of oxidative stress biomarkers (malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG)) using urine samples collected up to three times during pregnancy in 156 women recruited from antenatal clinics at the University of California Los Angeles. Land use regression models with co-kriging were employed to estimate average residential outdoor concentrations of black carbon (BC), PM2.5 mass, PM2.5 metal components, and three PM2.5 oxidative potential metrics during the 4-weeks prior to urine sample collection. 8-OHdG concentrations in mid-pregnancy increased by 24.8% (95% CI: 9.0, 42.8) and 14.3% (95% CI: 0.4%, 30.0%) per interquartile range (IQR) increase in PM2.5 mass and BC, respectively. The brake wear marker (barium) and the oxidative potential metrics were associated with increased MDA concentration in the 1st sample collected (10-17 gestational week), but 95% CIs included the null. Traffic-related air pollution contributed in early to mid-pregnancy to oxidative stress generation previously linked to adverse birth outcomes.

Neonatal per- and polyfluoroalkyl substance exposure in relation to retinoblastoma.

BACKGROUND: Neonatal per- and polyfluoroalkyl substance (PFAS) exposure can disrupt hormonal homeostasis and induce neuro- and immunotoxicity in children. In this exploratory study, we investigated associations between PFAS levels in neonatal dried blood spots and retinoblastoma risk. MATERIALS AND METHODS: This study included 501 retinoblastoma cases born from 1983 to 2011 and 899 controls frequency-matched by birth year (20:1 matching ratio), born to 755 US-born and 366 Mexico-born mothers in California. Perfluorooctanesulfonic acid (PFOS), perflurooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) feature intensities were identified from neonatal blood spots from California newborn Genetic Disease Screening Program. Using logistic regression, we assessed whether an interquartile range (IQR) increase of PFAS levels or having above-mean levels of PFAS in blood affects retinoblastoma risk overall or its subtypes (i.e., unilateral, bilateral). We assessed children of US-born and Mexico-born mothers, separately. RESULTS AND DISCUSSION: Among all children, above-mean PFOS levels at birth increased the odds of retinoblastoma overall by 29% (95% Confidence Interval (CI): 1.00, 1.67) and unilateral retinoblastoma by 42% (95% CI: 1.03, 1.97). For children of Mexico-born mothers, we estimated the highest odds of retinoblastoma overall (adjusted odds ratio (aOR): 1.67; 95% CI: 1.06, 2.66) and bilateral retinoblastoma (aOR: 2.06; 95% CI: 1.12, 3.92) with above-mean PFOS levels. Among children of US-born mothers, higher PFOS levels increased the odds of unilateral retinoblastoma by 15% (95% CI: 0.99, 1.35) for each IQR increase and by 71% among children with above-mean PFOS levels (95% CI: 1.04, 2.90). In addition, for children of US-born mothers, PFOA increased the odds of retinoblastoma overall (aOR: 1.41; 95% CI: 1.00, 2.02 for above-mean levels, aOR: 1.06; 95% CI: 0.98, 1.16 per IQR increase). PFNA was not associated with retinoblastoma risk. CONCLUSIONS: Our results suggested that PFOS and PFOA might contribute to retinoblastoma risk in children born in California.

Traffic-related air pollution and Parkinson's disease in central California.

BACKGROUND: Prior studies suggested that air pollution exposure may increase the risk of Parkinson's Disease (PD). We investigated the long-term impacts of traffic-related and multiple sources of particulate air pollution on PD in central California. METHODS: Our case-control analysis included 761 PD patients and 910 population controls. We assessed exposure at residential and occupational locations from 1981 to 2016, estimating annual average carbon monoxide (CO) concentrations - a traffic pollution marker - based on the California Line Source Dispersion Model, version 4. Additionally, particulate matter (PM2.5) concentrations were based on a nationwide geospatial chemical transport model. Exposures were assessed as 10-year averages with a 5-year lag time prior to a PD diagnosis for cases and an interview date for controls, subsequently categorized into tertiles. Logistic regression models were used, adjusting for various factors. RESULTS: Traffic-related CO was associated with an increased odds ratio for PD at residences (OR for T3 vs. T1: 1.58; 95% CI: 1.20, 2.10; p-trend = 0.02) and workplaces (OR for T3 vs. T1: 1.91; 95% CI: 1.22, 3.00; p-trend <0.01). PM2.5 was also positively associated with PD at residences (OR for T3 vs. T1: 1.62; 95% CI: 1.22, 2.15; p-trend <0.01) and workplaces (OR for T3 vs. T1: 1.85; 95% CI: 1.21, 2.85; p-trend <0.01). Associations remained robust after additional adjustments for smoking status and pesticide exposure and were consistent across different exposure periods. CONCLUSION: We found that long-term modeled exposure to local traffic-related air pollution (CO) and fine particulates from multiple sources (PM2.5) at homes and workplaces in central California was associated with an increased risk of PD.

Among men, androgens are associated with a decrease in Alzheimer's disease risk.

INTRODUCTION: Increased levels of sex hormones have been hypothesized to decrease Alzheimer's disease (AD) risk. We assessed the association between sex steroid hormones with AD using a Mendelian randomization (MR) approach. METHODS: An inverse-variance weighting (IVW) MR analysis was performed using effect estimates from external genome-wide association study (GWAS) summary statistics. We included independent variants (linkage disequilibrium R2  < 0.001) and a p-value threshold of 5 × 10-8 . RESULTS: An increase in androgens was associated with a decreased AD risk among men: testosterone (odds ratio [OR]: 0.53; 95% confidence interval [CI]: 0.32-0.88; p-value: 0.01; false discovery rate [FDR] p-value: 0.03); dehydroepiandrosterone sulfate (DHEAS; OR: 0.56; 95% CI: 0.38-0.85; p-value: 0.01; FDR p-value: 0.03); and androsterone sulfate (OR: 0.69; 95% CI: 0.46-1.02; p-value: 0.06; FDR p-value: 0.10). There was no association between sex steroid hormones and AD among women, although analysis for estradiol had limited statistical power. DISCUSSION: A higher concentration of androgens was associated with a decreased risk of AD among men of European ancestry, suggesting that androgens among men might be neuroprotective and could potentially prevent or delay an AD diagnosis. HIGHLIGHTS: Sex hormones are hypothesized to play a role in developing Alzheimer's disease (AD). The effect of sex hormones on AD was assessed using Mendelian randomization (MR) analysis. Among women, genetically determined effects of sex hormones were limited or null. Among men, a higher concentration of androgens decreased AD risk. This study suggests a causal relationship between androgens and AD among men.

Accelerated hematopoietic mitotic aging measured by DNA methylation, blood cell lineage, and Parkinson's disease.

BACKGROUND: Aging and inflammation are important components of Parkinson's disease (PD) pathogenesis and both are associated with changes in hematopoiesis and blood cell composition. DNA methylation (DNAm) presents a mechanism to investigate inflammation, aging, and hematopoiesis in PD, using epigenetic mitotic aging and aging clocks. Here, we aimed to define the influence of blood cell lineage on epigenetic mitotic age and then investigate mitotic age acceleration with PD, while considering epigenetic age acceleration biomarkers. RESULTS: We estimated epigenetic mitotic age using the "epiTOC" epigenetic mitotic clock in 10 different blood cell populations and in a population-based study of PD with whole-blood. Within subject analysis of the flow-sorted purified blood cell types DNAm showed a clear separation of epigenetic mitotic age by cell lineage, with the mitotic age significantly lower in myeloid versus lymphoid cells (p = 2.1e-11). PD status was strongly associated with accelerated epigenetic mitotic aging (AccelEpiTOC) after controlling for cell composition (OR = 2.11, 95 % CI = 1.56, 2.86, p = 1.6e-6). AccelEpiTOC was also positively correlated with extrinsic epigenetic age acceleration, a DNAm aging biomarker related to immune system aging (with cell composition adjustment: R = 0.27, p = 6.5e-14), and both were independently associated with PD. Among PD patients, AccelEpiTOC measured at baseline was also associated with longitudinal motor and cognitive symptom decline. CONCLUSIONS: The current study presents a first look at epigenetic mitotic aging in PD and our findings suggest accelerated hematopoietic cell mitosis, possibly reflecting immune pathway imbalances, in early PD that may also be related to motor and cognitive progression.

α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy.

The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain's biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies.

Increased Menopausal Age Reduces the Risk of Parkinson's Disease: A Mendelian Randomization Approach.

BACKGROUND: Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur. OBJECTIVE: We used MR to assess the association between age at menopause and age at menarche with PD risk. METHODS: We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics. RESULTS: For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73-0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85-1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90-0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89-0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44-1.29; P = 0.29). CONCLUSIONS: A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD. © 2021 International Parkinson and Movement Disorder Society.

High-Resolution Metabolomic Assessment of Pesticide Exposure in Central Valley, California.

Pesticides are widely used in the agricultural Central Valley region of California. Historically, this has included organophosphates (OPs), organochlorines (OCs), and pyrethroids (PYRs). This study aimed to identify perturbations of the serum metabolome in response to each class of pesticide and mutual associations between groups of metabolites and multiple pesticides. We conducted high-resolution metabolomic profiling of serum samples from 176 older adults living in the California Central Valley using liquid chromatography with high-resolution mass spectrometry. We estimated chronic pesticide exposure (from 1974 to year of blood draw) to OPs, OCs, and PYRs from ambient sources at homes and workplaces with a geographic information system (GIS)-based model. Based on partial least-squares regression and pathway enrichment analysis, we identified metabolites and metabolic pathways associated with one or multiple pesticide classes, including mitochondrial energy metabolism, fatty acid and lipid metabolism, and amino acid metabolism. Utilizing an integrative network approach, we found that the fatty acid ß-oxidation pathway is a common pathway shared across all three pesticide classes. The disruptions of the serum metabolome suggested that chronic pesticide exposure might result in oxidative stress, inflammatory reactions, and mitochondrial dysfunction, all of which have been previously implicated in a wide variety of diseases. Overall, our findings provided a comprehensive view of the molecular mechanisms of chronic pesticide toxicity, and, for the first time, our approach informs exposome research by moving from macrolevel population exposures to microlevel biologic responses.

Incidence, gender influence, and neuropsychological predictors of all cause dementia in the Faroe Islands-the Faroese Septuagenarian cohort.

BACKGROUND: Using the Faroese Septuagenarian cohort, we aimed to describe the incidence of dementia and assess the validity of neurocognitive tests to predict subsequent dementia diagnosis. METHODS: In this population-based cohort, 713 Faroese septuagenarians aged 70-74 years without dementia, underwent clinical and neuropsychological examinations. After 10-years of follow-up, information was collected on all participants referred for cognitive evaluations and diagnosed with dementia. Incidence rates were calculated and presented with 95% confidence intervals (CIs), assuming a Poisson distribution. We then performed discriminant analysis to determine the best set of neuropsychological tests to identify those who would develop dementia. RESULTS: Over the 10-years, 65 participants (9.1%) were diagnosed with dementia, with a 10-year incidence rate of 1063 cases per 100,000 person years (95% CI 825, 1343). Women had a greater incidence than men (incidence rate ratio (IRR) = 1.58; 95% CI 0.93, 2.71). After stepwise selection, gender and six neuropsychological measures were selected to discriminate between those who would and would not develop dementia. Overall, the model was able to correctly identify 82% of those who would not develop dementia (specificity) and 71% of those who would (sensitivity). CONCLUSIONS: These results indicate that among a greater number of tests covering a broad range of cognitive abilities, tests reflecting verbal and visual learning and recall, visuospatial function, attention, and encoding into and retrieval from long-term memory may be helpful in identifying patients in the pre-symptomatic phase of dementia. Thus, helping care-givers identify patients at a higher risk of developing dementia and adjusting management of care accordingly.

Mediation of the Associations of Physical Activity With Cardiovascular Events and Mortality by Diabetes in Older Mexican Americans.

Low physical activity (PA) among older adults increases the risk of cardiovascular disease (CVD) and mortality through metabolic disorders such as type 2 diabetes. We aimed to elucidate the extent to which diabetes mediates the effect of nonoccupational PA levels on CVD and mortality among older Mexican Americans. This study included 1,676 adults from the Sacramento Area Latino Study on Aging (1998-2007). We employed Cox proportional hazards regression models to investigate associations of PA level with all-cause mortality, fatal CVD, and nonfatal CVD events. Utilizing causal mediation analysis within a counterfactual framework, we decomposed the total effect of PA into natural indirect and direct effects. Over a median of 8 years of follow-up, low PA (<25th percentile) was associated with increased risks of all-cause mortality (hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.06, 1.75), fatal CVD (HR = 2.05, 95% CI: 1.42, 2.97), and nonfatal CVD events (HR = 1.67, 95% CI: 1.18, 2.37) in comparison with high PA (>75th percentile). Diabetes mediated 11.0%, 7.4%, and 5.2% of the total effect of PA on all-cause mortality, fatal CVD, and nonfatal CVD events, respectively. Our findings indicate that public health interventions targeting diabetes prevention and management would be a worthwhile strategy for preventing CVD and mortality among older Mexican Americans with insufficient PA levels.

Traffic-related Noise Exposure and Late-life Dementia and Cognitive Impairment in Mexican-Americans.

BACKGROUND: Recently, it has been suggested that environmental exposures from traffic sources including noise may play a role in cognitive impairment in the elderly. The objective of the study was to investigate the association between local traffic-related noise pollution and incident dementia or cognitive impairment without dementia (CIND) during a 10-year follow-up period. METHODS: 1612 Mexican-American participants from the Sacramento Area Latino Study on Aging (SALSA) were followed every 12-15 months via home visits from 1998 to 2007. We used the SoundPLAN software package to estimate noise originating from local traffic with the input of Annual Average Daily Traffic (AADT) data from Metropolitan Planning Organizations (MPO) based on geocoded residential addresses at baseline (1998-1999). We estimated the risks of incident dementia or CIND from 24-hour and nighttime noise exposure using Cox proportional hazard models. RESULTS: During the follow-up, we identified 159 incident dementia or CIND cases in total. Per 11.6 dB (interquartile range width) increase in 24-hour noise, the hazard of developing dementia or CIND increased (hazard ratio = 1.3 [1.0, 1.6]) during follow-up; estimates were slightly lower (hazard ratio = 1.2 [0.97, 1.6]) when adjusting for modeled local air pollution exposure from traffic sources. Overall, the risk of dementia/CIND was elevated when 24-hour and nighttime noise were higher than 75 and 65 dB respectively. See video Abstract: http://links.lww.com/EDE/B728. CONCLUSIONS: In our study, traffic-related noise exposure was associated with increased risk of dementia or CIND in elderly Mexican-Americans. Future studies taking into account other noise sources and occupational noise exposure before retirement are needed.

The Roles of Physical Activity and Inflammation in Mortality, Cognition, and Depressive Symptoms Among Older Mexican Americans.

A higher level of physical activity (PA) is associated with decreased risk of mortality, dementia, and depression, yet the mechanisms involved are not well understood, and little evidence exists for Mexican Americans. With data from the Sacramento Area Latino Study on Aging (1998-2007), we used Cox proportional hazards regression to separately evaluate associations of baseline PA level with mortality, dementia/cognitive impairment without dementia (CIND), and depressive symptoms, and we estimated the mediating effects of inflammatory markers in additive hazard models. A low level of PA (<35 metabolic equivalent of task-hours/week) was associated with increased mortality (hazard ratio (HR) = 1.50, 95% confidence interval (CI): 1.20, 1.88), dementia/CIND (HR = 1.37, 95% CI: 0.96, 1.96), and depressive symptoms (HR = 1.23, 95% CI: 1.00, 1.52). A low PA level added 512 (95% CI: -34, 1,058) cases of dementia/CIND per 100,000 person-years at risk (direct effect), while, through a mediating path, interleukin 6 (IL-6) added another 49 (95% CI: 5, 94) cases, or 9% of the total effect. For mortality, 8%-10% of the PA total effect was mediated through IL-6, tumor necrosis factor α (TNF-α), or TNF-α receptors. None of the inflammatory markers mediated the association between PA and depressive symptoms. Our results suggest that antiinflammation (especially as assessed by IL-6 and TNF-α levels) may partly explain how PA protects against dementia/CIND and mortality.

Ambient Air Pollution, Noise, and Late-Life Cognitive Decline and Dementia Risk.

Exposure to ambient air pollution and noise is ubiquitous globally. A strong body of evidence links air pollution, and recently noise, to cardiovascular conditions that eventually may also affect cognition in the elderly. Data that support a broader influence of these exposures on cognitive function during aging is just starting to emerge. This review summarizes current findings and discusses methodological challenges and opportunities for research. Although current evidence is still limited, especially for chronic noise exposure, high exposure has been associated with faster cognitive decline either mediated through cerebrovascular events or resulting in Alzheimer's disease. Ambient environmental exposures are chronic and affect large populations. While they may yield relatively modest-sized risks, they nevertheless result in large numbers of cases. Reducing environmental pollution is clearly feasible, though lowering levels requires collective action and long-term policies such as standard setting, often at the national level as well as at the local level.

The association between lifestyle factors and Parkinson's disease progression and mortality.

BACKGROUND: Lifestyle factors may contribute to the development of Parkinson's disease, but little is known about factors that influence progression. The objective of the current study was to examine whether caffeine or alcohol consumption, physical activity, or cigarette smoking is associated with progression and survival among PD patients. METHODS: We assessed lifelong coffee, tea, and alcohol consumption, smoking, and physical activity in a prospective community-based cohort (n = 360). All patients were passively followed for mortality (2001-2016); 244 were actively followed on average ± SD 5.3 ± 2.1 years (2007-2014). Movement disorder specialists repeatedly assessed motor function (Hoehn & Yahr) and cognition (Mini-Mental State Exam). We used Cox proportional hazards models and inverse probability weights to account for censoring. RESULTS: Coffee, caffeinated tea, moderate alcohol consumption, and physical activity were protective against at least 1 outcome. Smoking and heavy alcohol consumption were associated with increased risks. Coffee was protective against time to Hoehn & Yahr stage 3 (hazard ratio, 0.52; 95% confidence interval, 0.28-1.01), cognitive decline (hazard ratio, 0.23; 95% confidence interval, 0.11, 0.48), and mortality (hazard ratio, 0.47; 95% confidence interval, 0.32-0.69). Relative to moderate drinkers, those who never drank liquor and those who drank more heavily were at an increased risk of Hoehn & Yahr 3 (hazard ratio, 3.48; 95% confidence interval, 1.90-6.38; and hazard ratio, 2.16; 95% confidence interval, 1.03, 4.54, respectively). A history of competitive sports was protective against cognitive decline (hazard ratio, 0.46; 95% confidence interval, 0.22-0.96) and Hoehn & Yahr 3 (hazard ratio, 0.42; 95% confidence interval, 0.23-0.79), as was physical activity measured by metabolic-equivalent hours. Current cigarette smoking was associated with faster cognitive decline (hazard ratio, 3.20; 95% confidence interval, 1.02-10.01). CONCLUSIONS: This population-based study suggests that lifestyle factors influence PD progression and mortality. © 2019 International Parkinson and Movement Disorder Society.

Cognitive decline, mortality, and organophosphorus exposure in aging Mexican Americans.

BACKGROUND: Cognitive impairment is a major health concern among older Mexican Americans, associated with significant morbidity and mortality, and may be influenced by environmental exposures. OBJECTIVES: To investigate whether agricultural based ambient organophosphorus (OP) exposure influences 1) the rate of cognitive decline and mortality and 2) whether these associations are mediated through metabolic or inflammatory biomarkers. METHODS: In a subset of older Mexican Americans from the Sacramento Area Latino Study on Aging (n = 430), who completed modified mini-mental state exams (3MSE) up to 7 times (1998-2007), we examined the relationship between estimated ambient OP exposures and cognitive decline (linear repeated measures model) and time to dementia or being cognitively impaired but not demented (CIND) and time to mortality (cox proportional hazards model). We then explored metabolic and inflammatory biomarkers as potential mediators of these relationships (additive hazards mediation). OP exposures at residential addresses were estimated with a geographic information system (GIS) based exposure assessment tool. RESULTS: Participants with high OP exposure in the five years prior to baseline experienced faster cognitive decline (ß = 0.038, p = 0.02) and higher mortality over follow-up (HR = 1.91, 95% CI = 1.12, 3.26). The direct effect of OP exposure was estimated at 241 (95% CI = 27-455) additional deaths per 100,000 person-years, and the proportion mediated through the metabolic hormone adiponectin was estimated to be 4% 1.5-19.2). No other biomarkers were associated with OP exposure. CONCLUSIONS: Our study provides support for the involvement of OP pesticides in cognitive decline and mortality among older Mexican Americans, possibly through biologic pathways involving adiponectin.

Genetic variability in ABCB1, occupational pesticide exposure, and Parkinson's disease.

BACKGROUND: Studies suggested that variants in the ABCB1 gene encoding P-glycoprotein, a xenobiotic transporter, may increase susceptibility to pesticide exposures linked to Parkinson's Disease (PD) risk. OBJECTIVES: To investigate the joint impact of two ABCB1 polymorphisms and pesticide exposures on PD risk. METHODS: In a population-based case control study, we genotyped ABCB1 gene variants at rs1045642 (c.3435C/T) and rs2032582 (c.2677G/T/A) and assessed occupational exposures to organochlorine (OC) and organophosphorus (OP) pesticides based on self-reported occupational use and record-based ambient workplace exposures for 282 PD cases and 514 controls of European ancestry. We identified active ingredients in self-reported occupational use pesticides from a California database and estimated ambient workplace exposures between 1974 and 1999 employing a geographic information system together with records for state pesticide and land use. With unconditional logistic regression, we estimated marginal and joint contributions for occupational pesticide exposures and ABCB1 variants in PD. RESULTS: For occupationally exposed carriers of homozygous ABCB1 variant genotypes, we estimated odds ratios of 1.89 [95% confidence interval (CI): (0.87, 4.07)] to 3.71 [95% CI: (1.96, 7.02)], with the highest odds ratios estimated for occupationally exposed carriers of homozygous ABCB1 variant genotypes at both SNPs; but we found no multiplicative scale interactions. CONCLUSIONS: This study lends support to a previous report that commonly used pesticides, specifically OCs and OPs, and variant ABCB1 genotypes at two polymorphic sites jointly increase risk of PD.

Agricultural paraquat dichloride use and Parkinson's disease in California's Central Valley.

BACKGROUND: Paraquat dichloride is currently among the most widely used commercial herbicides in the USA. In the present study, we provide epidemiological assessment of ambient paraquat exposure and Parkinson's disease (PD) risk in a population-based study of PD in agricultural regions of Central California. METHODS: Based on 829 PD patients and 824 community controls, we assessed associations between ambient paraquat dichloride exposure and PD. We estimated residential and workplace proximity to commercial agricultural applications in three California counties since 1974 using the CA pesticide use reporting (PUR) data and land use maps. We evaluated any, duration and average intensity [pounds (0.45 kilograms) per acre per year] of exposure for paraquat in four time windows. RESULTS: Ambient paraquat exposure assessed at both residence and workplace was associated with PD, based on several different exposure measures. The PD patients both lived and worked near agricultural facilities applying greater amounts of the herbicide than community controls. For workplace proximity to commercial applications since 1974, working near paraquat applications every year in the window [odds ratio (OR) = 2.15, 95% confidence interval (CI) = 1.46, 3.19] and a higher average intensity of exposure [per 10 pounds (4.54 kilograms), OR = 2.08, 95% CI = 1.31, 3.38] were both associated with an increased odds of PD. Similar associations were observed for residential proximity (duration: OR = 1.91, 95% CI = 1.30, 2.83; average intensity: OR = 1.72, 95% CI = 0.99, 3.04). Risk estimates were comparable for men and women, and the strongest odds were observed for those diagnosed at ≤60 years of age. CONCLUSION: This study provides further indication that paraquat dichloride exposure increases the risk of Parkinson's disease.