Search

Background: Within the Multiethnic Cohort (MEC), we examined the association between air pollution and mortality among African American, European American, Japanese American, and Latina American women diagnosed with breast cancer. Methods: We used a land use regression (LUR) model and kriging interpolation to estimate nitrogen oxides (NOx , NO2) and particulate matter (PM2.5, PM10) exposures for 3,089 breast cancer cases in the MEC, who were diagnosed from 1993 through 2013 and resided largely in Los Angeles County, California. Cox proportional hazards models were used to examine the association of time-varying air pollutants with all-cause, breast cancer, cardiovascular disease (CVD), and non-breast cancer/non-CVD mortality, accounting for key covariates. Results: We identified 1,125 deaths from all causes (474 breast cancer, 272 CVD, 379 non-breast cancer/non-CVD deaths) among the 3,089 breast cancer cases with 8.1 years of average follow-up. LUR and kriged NOX (per 50 ppb) and NO2 (per 20 ppb), PM2.5 (per 10 µg/m3), and PM10 (per 10 µg/m3) were positively associated with risks of all-cause (Hazard Ratio (HR) range = 1.13–1.25), breast cancer (HR range = 1.19–1.45), and CVD mortality (HR range = 1.37–1.60). Associations were statistically significant for LUR NOX and CVD mortality (HR = 1.60; 95% CI: 1.08–2.37) and kriged NO2 and breast cancer mortality (HR = 1.45; 95% CI 1.02–2.07). Gaseous and PM pollutants were positively associated with breast cancer mortality across racial/ethnic group. Conclusion: In this study, air pollutants have a harmful impact on breast cancer survival. Additional studies should evaluate potential confounding by socioeconomic factors. These data support maintaining clean air laws to improve survival for women with breast cancer.

Background The effect of maternal diabetes on childhood cancer has not been widely studied. Methods We examined this in two population-based studies in Denmark (N = 6420 cancer cases, 160,484 controls) and Taiwan (N = 2160 cancer cases, 2,076,877 non-cases) using logistic regression and Cox proportional hazard regression adjusted for birth year, child’s sex, maternal age and birth order. Results Gestational diabetes in Denmark [odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.71–1.35] or type II and gestational diabetes in Taiwan (type II: hazard ratio (HR) = 0.81, 95% CI: 0.63–1.05; gestational diabetes: HR = 1.06, 95% CI: 0.92–1.22) were not associated with cancer (all types combined). In Denmark, maternal type I diabetes was associated with the risk of glioma (OR = 2.33, 95% CI: 1.04–5.22), while in Taiwan, the risks of glioma (HR = 1.59, 95% CI: 1.01–2.50) were elevated among children whose mothers had gestational diabetes. There was a twofold increased risk for hepatoblastoma with maternal type II diabetes (HR = 2.02, 95% CI: 1.02–4.00). Conclusions Our results suggest that maternal diabetes is an important risk factor for certain types of childhood cancers, emphasising the need for effective interventions targeting maternal diabetes to prevent serious health effects in offspring.

Summary Regional aggregates of health outcomes over delineated administrative units (e.g., states, counties, and zip codes), or areal units, are widely used by epidemiologists to map mortality or incidence rates and capture geographic variation. To capture health disparities over regions, we seek “difference boundaries” that separate neighboring regions with significantly different spatial effects. Matters are more challenging with multiple outcomes over each unit, where we capture dependence among diseases as well as across the areal units. Here, we address multivariate difference boundary detection for correlated diseases. We formulate the problem in terms of Bayesian pairwise multiple comparisons and seek the posterior probabilities of neighboring spatial effects being different. To achieve this, we endow the spatial random effects with a discrete probability law using a class of multivariate areally referenced Dirichlet process models that accommodate spatial and interdisease dependence. We evaluate our method through simulation studies and detect difference boundaries for multiple cancers using data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.

Acetaminophen is the most common over-the-counter pain and fever medication used by pregnant women. While European studies suggest acetaminophen exposure in pregnancy could affect childhood asthma development, findings are less consistent in other populations. We evaluated whether maternal prenatal acetaminophen use is associated with childhood asthmatic symptoms (asthma diagnosis, wheeze, dry cough) in a Los Angeles cohort of 1201 singleton births. We estimated risk ratio (RR) and 95% confidence interval (CI) for childhood asthmatic outcomes according to prenatal acetaminophen exposure. Effect modification by maternal race/ethnicity and psychosocial stress during pregnancy was evaluated. The risks for asthma diagnosis (RR = 1.39, 95% CI 0.96, 2.00), wheezing (RR = 1.25, 95% CI 1.01, 1.54) and dry cough (RR =1.35, 95% CI 1.06, 1.73) were higher in children born to mothers who ever used acetaminophen during pregnancy compared with non-users. Black/African American and Asian/Pacific Islander children showed a greater than two-fold risk for asthma diagnosis and wheezing associated with the exposure. High maternal psychosocial stress also modified the exposure-outcome relationships. Acetaminophen exposure during pregnancy was associated with childhood asthmatic symptoms among vulnerable subgroups in this cohort. A larger study that assessed prenatal acetaminophen exposure with other social/environmental stressors and clinically confirmed outcomes is needed.

Background: Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides. Objectives: We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients. Methods: The Agricultural Lung Health Study is a case–control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina’s EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009–2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users. Results: Using family-wise error rate (p

Background: Type 2 diabetes is a leading contributor to the global burden of morbidity and mortality. Ozone (O3) exposure has previously been linked to diabetes. Objective: We studied the impact of O3 exposure on incident diabetes risk in elderly Mexican Americans and investigated whether outdoor physical activity modifies the association. Methods: We selected 1,090 Mexican American participants from the Sacramento Area Latino Study on Aging conducted from 1998 to 2007. Ambient O3 exposure levels were modeled with a land-use regression built with saturation monitoring data collected at 49 sites across the Sacramento metropolitan area. Using Cox proportional hazard models, we estimated the risk of developing incident diabetes based on average O3 exposure modeled for 5-y prior to incident diabetes diagnosis or last follow-up. Further, we estimated outdoor leisure-time physical activity at baseline and investigated whether higher vs. lower levels modified the association between O3 exposure and diabetes. Results: In total, 186 incident diabetes cases were identified during 10-y follow-up. Higher levels of physical activity were negatively associated with incident diabetes [hazard ratio (HR)=0.64 (95% CI: 0.43, 0.95)]. The estimated HRs for incident diabetes was 1.13 (95% CI: 1.00, 1.28) per 10-ppb increment of 5-y average O3 exposure; also, this association was stronger among those physically active outdoors [HR=1.52 (95% CI: 1.21, 1.90)], and close to null for those reporting lower levels of outdoor activity [HR=1.04 (95% CI: 0.90, 1.20), pinteraction=0.01]. Conclusions: Our findings suggest that ambient O3 exposure contributes to the development of type 2 diabetes, particularly among those with higher levels of leisure-time outdoor physical activity. Policies and strategies are needed to reduce O3 exposure to guarantee that the health benefits of physical activity are not diminished by higher levels of O3 pollution in susceptible populations such as older Hispanics. https://doi.org/10.1289/EHP8620

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.

Ultrafine particles (UFP; diameter less than or equal to 100 nm) may reach the brain via systemic circulation or the olfactory tract and have been implicated in the risk of brain tumors. The effects of airport-related UFP on the risk of brain tumors are not known. Here we determined the association between airport-related UFP and risk of incident malignant brain cancer (n = 155) and meningioma (n = 420) diagnosed during 16.4 years of follow-up among 75,936 men and women residing in Los Angeles County from the Multiethnic Cohort study. UFP exposure from aircrafts was estimated for participants who lived within a 53 km × 43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993–1996) through December 31, 2013. Cox proportional hazards models were used to estimate the effects of time-varying, airport-related UFP exposure on risk of malignant brain cancer and meningioma, adjusting for sex, race/ethnicity, education, and neighborhood socioeconomic status. Malignant brain cancer risk in all subjects combined increased 12% [95% confidence interval (CI), 0.98–1.27] per interquartile range (IQR) of airport-related UFP exposure (∼6,700 particles/cm3) for subjects with any address in the grid area surrounding the LAX airport. In race/ethnicity-stratified analyses, African Americans, the subgroup who had the highest exposure, showed a HR of 1.32 (95% CI, 1.07–1.64) for malignant brain cancer per IQR in UFP exposure. UFP exposure was not related to risk of meningioma overall or by race/ethnicity. These results support the hypothesis that airport-related UFP exposure may be a risk factor for malignant brain cancers. Significance: Malignant brain cancer risk increases with airport-related UFP exposure, particularly among African Americans, suggesting UFP exposure may be a modifiable risk factor for malignant brain cancer.

Objective It is unclear whether relatively low glycated haemoglobin (HbA1c) levels are beneficial or harmful for the long-term health outcomes among people without diabetes. We aimed to investigate the association between low HbA1c levels and mortality among the US general population. Methods This study includes a nationally representative sample of 39 453 US adults from the National Health and Nutrition Examination Surveys 1999–2014, linked to mortality data through 2015. We employed the parametric g-formula with pooled logistic regression models and the ensemble machine learning algorithms to estimate the time-varying risk of all-cause and cardiovascular mortality by HbA1c categories (low, 4.0 to Results Over a median follow-up of 7.5 years, 5118 (13%) all-cause deaths, and 1116 (3%) cardiovascular deaths were observed. Logistic regression models and machine learning algorithms showed nearly identical predictive performance of death and risk estimates. Compared with mid-level HbA1c, low HbA1c was associated with a 30% (95% CI, 16 to 48) and a 12% (95% CI, 3 to 22) increased risk of all-cause mortality at 5 years and 10 years of follow-up, respectively. We found no evidence that low HbA1c levels were associated with cardiovascular mortality risk. The diabetes group, but not the prediabetes group, also showed an increased risk of all-cause mortality. Conclusions Using the US national database and adjusting for an extensive set of potential confounders with flexible modelling, we found that adults with low HbA1c were at increased risk of all-cause mortality. Further evaluation and careful monitoring of low HbA1c levels need to be considered.

Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States.We evaluated the association between time-varying, 10-y average fine particulate matter (Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-basedWe report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean [mean ± standard deviation (SD)] 10-y averageIn this prospective cohort study with extensive exposure data and consensus-based outcome ascertainment, elevated long-term exposure to

The inorganic components of particulate matter (PM), especially transition metals, have been shown to contribute to PM toxicity. In this study, the spatial distribution of PM elements and their potential sources in the Greater Los Angeles area were studied. The mass concentration and detailed elemental composition of fine (PM2.5) and coarse (PM2.5-10) particles were assessed at 46 locations, including urban traffic, urban community, urban background, and desert locations. Crustal enrichment factors (EFs), roadside enrichments (REs), and bivariate correlation analysis revealed that Ba, Cr, Cu, Mo, Pd, Sb, Zn, and Zr were associated with traffic emissions in both PM2.5 and PM2.5-10, while Fe, Li, Mn, and Ti were affected by traffic emissions mostly in PM2.5. The concentrations of Ba, Cu, Mo, Sb, Zr (brake wear tracers), Pd (tailpipe tracer), and Zn (associated with tire wear) were higher at urban traffic sites than urban background locations by factors of 2.6–4.6. Both PM2.5 and PM2.5-10 elements showed large spatial variations, indicating the presence of diverse emission sources across sampling locations. Principal component analysis extracted four source factors that explained 88% of the variance in the PM2.5 elemental concentrations, and three sources that explained 86% of the variance in the PM2.5-10 elemental concentrations. Based on multiple linear regression analysis, the contribution of traffic emissions (27%) to PM2.5 was found to be higher than mineral dust (23%), marine aerosol (18%), and industrial emissions (8%). On the other hand, mineral dust was the dominant source of PM2.5-10 with 45% contribution, followed by marine aerosol (22%), and traffic emissions (19%). This study provides novel insight into the spatial variation of traffic-related elements in a large metropolitan area.

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Several studies have reported associations between prenatal acetaminophen exposure and behavioral outcomes in young children. We aimed to evaluate the associations of prenatal and postnatal exposures to acetaminophen with behavioral problems in children at age 11 years, using behavioral measures reported by parents and children. We studied 40,934 mother-child pairs from the Danish National Birth Cohort enrolled during 1996–2002. Parent-reported and child-reported Strengths and Difficulties Questionnaire (SDQ) responses were collected during the 11-year follow-up. We estimated risk ratios for behavioral problems including total difficulties as well as internalizing or externalizing behaviors following prenatal (during pregnancy) or postnatal (within the first 18 months after birth) acetaminophen exposure. Parent-reported and child-reported SDQ scores were moderately correlated; higher for externalizing (r = 0.59) than internalizing (r = 0.49) behaviors. Prenatal acetaminophen exposure was associated with 10%–40% higher risks for total difficulties and internalizing and externalizing problems based on parent- or child-reported SDQ, with the association being stronger for greater cumulative weeks of acetaminophen use. Postnatal exposure was associated with 16%–19% higher risks for parent-reported internalizing behaviors, but the associations were weak or null for child-reported scores except for prosocial behavior. Our study corroborates published associations between prenatal exposures to acetaminophen and behavioral problems and extends the literature to early adolescence.

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 β-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.

Purpose Diabetes and depression are risk factors for cardiovascular disease, but the evidence about their interaction effect on long-term health outcomes among Latinos is lacking. We aimed to investigate the joint association of diabetes and subsequent depressive symptoms with mortality among older Latinos, an understudied racial/ethnic group with high prevalence of diabetes. Methods This study included 1,495 adults from the Sacramento Area Latino Study on Aging. We employed Cox proportional-hazards models to estimate the adjusted hazard ratios [aHRs] for cardiovascular and all-cause mortality according to diabetes status at enrollment and depressive symptoms a year after the enrollment. We used marginal structural models to adjust for time-varying confounders. Results The mean age (standard deviation) of participants was 70 (6.6) years. Over follow-up (median 7.7 years), diabetes and depressive symptoms were individually associated with increased risk of cardiovascular mortality (diabetes, aHR[95% CI]=2.13[1.60–2.84]; depressive symptoms, aHR[95% CI]=1.62[1.09–2.39]) and all-cause mortality (diabetes, aHR[95% CI]=1.92[1.53–2.41]; depressive symptoms, aHR[95% CI]=1.41[1.02–1.94]). After adjusting for time-varying confounders, we found a multiplicative interaction between diabetes and subsequent depressive symptoms for cardiovascular mortality (aHR[95% CI]=2.94[1.07–8.39]), but not all-cause mortality (aHR[95% CI]=1.80[0.81–4.35]). Conclusions Using a longitudinal cohort of community-dwelling older Latinos, we found that diabetes and subsequent depressive symptoms were jointly associated with increased risk of cardiovascular mortality.

Author(s): Hall, Clinton; Heck, Julia E; Ritz, Beate; Cockburn, Myles; Escobedo, Loraine A; von Ehrenstein, Ondine S | Abstract: ObjectiveTo assess prenatal air toxics exposure and risk for childhood germ cell tumors (GCTs) by histological subtype (yolk sac tumor and teratoma).MethodsIn this case-control study, GCT cases less than 6 years (n = 243) identified from California Cancer Registry records were matched by birth year to cancer-free population controls (n = 147,100), 1984 to 2013. Routinely monitored air toxic exposures were linked to subjects' birth address. Logistic regression estimated GCT risks per interquartile range increase in exposure.ResultsPrenatal exposure to various highly-correlated, traffic-related air toxics during the second trimester increased GCT risk, particularly 1,3-butadiene (odds ratio [OR] = 1.51; 95% confidence interval [CI] = 1.01, 2.26) and meta/para-xylene (OR = 1.56; 95% CI = 1.10, 2.21). Analyses by subtype indicated elevated ORs for yolk sac tumors but not teratomas.ConclusionOur estimated ORs are consistent with positive associations between some prenatal traffic-related air toxics and GCT risk, notably yolk sac tumors.

Previous studies using different exposure methods to assess air pollution and breast cancer risk among primarily whites have been inconclusive. Air pollutant exposures of particulate matter and oxides of nitrogen were estimated by kriging (NOx , NO2 , PM10 , PM2.5 ), land use regression (LUR, NOx , NO2 ) and California Line Source Dispersion model (CALINE4, NOx , PM2.5 ) for 57,589 females from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993-1996) through 2010. Cox proportional hazards models were used to examine the associations between time-varying air pollution and breast cancer incidence adjusting for confounding factors. Stratified analyses were conducted by race/ethnicity and distance to major roads. Among all women, breast cancer risk was positively but not significantly associated with NOx (per 50 parts per billion [ppb]) and NO2 (per 20 ppb) determined by kriging and LUR and with PM2.5 and PM10 (per 10 μg/m3 ) determined by kriging. However, among women who lived within 500 m of major roads, significantly increased risks were observed with NOx (hazard ratio [HR] = 1.35, 95% confidence interval [95% CI]: 1.02-1.79), NO2 (HR = 1.44, 95% CI: 1.04-1.99), PM10 (HR = 1.29, 95% CI: 1.07-1.55) and PM2.5 (HR = 1.85, 95% CI: 1.15-2.99) determined by kriging and NOx (HR = 1.21, 95% CI:1.01-1.45) and NO2 (HR = 1.26, 95% CI: 1.00-1.59) determined by LUR. No overall associations were observed with exposures assessed by CALINE4. Subgroup analyses suggested stronger associations of NOx and NO2 among African Americans and Japanese Americans. Further studies of multiethnic populations to confirm the effects of air pollution, particularly near-roadway exposures, on the risk of breast cancer is warranted.

Cancer patients are at lower risk of developing Parkinson’s disease (PD) compared with the general population. One explanation is the negative association between smoking and PD, but PD risk is also lower for cancers not related to smoking. Another explanation is survival bias where death from cancer may act as a competing risk. We conducted a large population-based case-control study in Denmark and investigated whether cancer diagnosis reduced the risk of developing PD even after adjusting for important risk factors including smoking, physical activity, and lifetime oestrogen status. Using probabilistic bias analysis we quantified the influence of survival bias. We estimated negative point estimates (ORs) between cancers and PD for all cancers except skin, female breast, and ill-defined and unspecified 0.85 (95% CI 0.59–1.21); smoking-related cancers 0.75 (95% CI 0.45–1.23); and cancers not related to smoking 0.82 (95% CI 0.49–1.38) that are very similar to those previously reported for a much larger Danish register only based study, even though our confidence intervals include the null. These effect estimates shifted towards the null after accounting for survival bias but most bias-adjusted ORs remained below 1 within the range of priors considered in simulations. Overall, cancer patients have a lower risk of developing PD even after controlling for cancer-related lifestyles factors and correcting for survival bias.

Objectives Recent meta-analyses suggest a physical activity health paradox: high levels of occupational physical activity (OPA) increase cardiovascular disease (CVD) risk, while leisure-time physical activity (LTPA) decreases risk. However, studies of women and cerebrovascular disease are limited. This report examines physical activity effects on stroke and transient ischemic attack (TIA) among working women in the United States. Methods OPA history, health status, and lifestyle were assessed by baseline interviews of 31 270 employed Sister Study participants aged 35-74 years. OPA was assessed at six intensity levels (lowest: "mostly sitting"); the highest three were combined as "high intensity work." Independent OPA and LTPA effects on 6-year cerebrovascular disease incidence were estimated in adjusted Cox proportional hazard models. Results Stroke (N=441) and TIA (N=274) risk increased with more standing and higher intensity work at current and longest held job. Compared with mostly sitting, high intensity work at the current job increased TIA risk by 57%25 [hazard ratio (HR) 1.57, 95%25 confidence interval (CI) 1.04-2.38]. High intensity OPA at the longest held job increased risk for stroke by 44%25 (HR 1.44; 95%25 CI 1.08-1.93). Among women with CVD, sitting and standing equally, especially at the current job, increased risks up to two-fold (TIA HR 1.98, 95%25 CI 1.10-3.55) compared with mostly sitting at work. LTPA showed inverse associations. Conclusions Higher intensity levels of OPA increased stroke and TIA risks, while LTPA decreased risks; results corroborate the physical activity health paradox for women and cerebrovascular disease. More standing at work increased cerebrovascular disease risks, especially for women with CVD.

Background Pesticide exposures have been examined previously as risk factors for childhood brain cancers, but few studies were able to assess risk from specific agents. Objective To evaluate risks for childhood central nervous system tumors associated with residential proximity to agricultural pesticide applications. Methods Using the California Cancer Registry, we identified cancer cases less than 6 years of age and frequency matched them by year of birth to 20 cancer-free controls identified from birth certificates. We restricted analyses to mothers living in rural areas and births occurring between 1998 and 2011, resulting in 667 cases of childhood central nervous system tumors and 123,158 controls. Possible carcinogens were selected per the Environmental Protection Agency's (US. EPA) classifications, and prenatal exposure was assessed according to pesticides reported by the California Department of Pesticide Regulation's (CDPR) Pesticide Use Reporting (PUR) system as being applied within 4000m of the maternal residence at birth. We computed odds ratios for individual pesticide associations using unconditional logistic and hierarchical regression models. Results We observed elevated risks in the hierarchical models for diffuse astrocytoma with exposure to bromacil (OR: 2.12, 95% CI: 1.13–3.97), thiophanate-methyl (OR: 1.64, 95% CI: 1.02–2.66), triforine (OR: 2.38, 95% CI: 1.44–3.92), and kresoxim methyl (OR: 2.09, 95% CI: 1.03–4.21); elevated risks for medulloblastoma with exposure to chlorothalonil (OR: 1.78, 95% CI: 1.15–2.76), propiconazole (OR: 1.60, 95% CI: 1.02, 2.53), dimethoate (OR: 1.60, 95% CI: 1.06, 2.43), and linuron (OR: 2.52, 95% CI: 1.25, 5.11); and elevated risk for ependymoma with exposure to thiophanate-methyl (OR: 1.72, 95% CI: 1.10–2.68). Conclusion Our study suggests that exposure to certain pesticides through residential proximity to agricultural applications during pregnancy may increase the risk of childhood central nervous system tumors.

BACKGROUND: Previously, numerous epidemiologic studies reported an association between autism spectrum disorder (ASD) and exposure to air pollution during pregnancy. However, there have been no metabolomics studies investigating the impact of pregnancy pollution exposure to ASD risk in offspring. OBJECTIVES: To identify differences in maternal metabolism that may reflect a biological response to exposure to high air pollution in pregnancies of offspring who later did or did not develop ASD. METHODS: We obtained stored mid-pregnancy serum from 214 mothers who lived in California’s Central Valley and experienced the highest levels of air pollution during early pregnancy. We estimated each woman’s average traffic-related air pollution exposure (carbon monoxide, nitric oxides, and particulate matter

Lead, a known neurotoxicant, has previously received attention in Parkinson’s disease (PD) research, but epidemiologic studies have been limited in sample size and findings are equivocal. We generated two methylation-based biomarkers for cumulative tibia and patella bone-measured lead exposure in 1528 PD patients and 1169 controls. PD status was associated with increased levels of the DNAm biomarker for tibia-lead levels. We estimated a meta-OR for PD of 1.89 per unit DNAm tibia-lead increase (95% CI 1.59, 2.24; p = 8.1E−13). The current study supports the notion that chronic and long-term lead exposure tracked via DNAm may contribute to PD pathogenesis.

Pyrethroid pesticide exposures may be associated with the onset of depression in later life via disruption of dopaminergic, serotonergic, and neurological functioning. We sought to investigate the association between living near agricultural pyrethroid pesticide applications and depression measures in central California, using two waves (PEG 1&2, total N = 1,654) of a case control study of Parkinson's disease (PD). At enrollment, participants self-reported history of use of depression medications and dates of MD-diagnosed depression and anxiety. Participants also completed a Geriatric Depression Scale-Short Form upon enrollment. We used the California Pesticide Use Registry to assign estimated ambient pyrethroid pesticide exposures at participant's home addresses over the 5 years before the index date (date of outcome, or an age-matched year for participants without the outcome). We used logistic and linear regression to evaluate associations between living near any pyrethroid applications over the 5-year index period and measures of depression and anxiety. We also evaluated modification by study wave and PD status. We observed associations of pyrethroids with depression, depression medications, and anxiety (adjusted odds ratio [aOR] depression = 1.54, 95% confidence interval [CI] 1.14, 2.07; aOR depression medications = 1.68, 95% CI 1.25, 2.25; aOR anxiety = 1.60, 95% CI 1.17, 2.18). However, we observed no associations with mild/moderate depressive symptoms according to the GDS score at enrollment (aOR = 1.04, 95% CI 0.77, 1.42). We did not observe a consistent modification of the pyrethroid-depression associations by study wave and PD status. Ambient pyrethroid pesticide exposures may be associated with measures of depression in later life.

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.

DNA methylation data have been successfully used to develop highly accurate estimators of age (“epigenetic clocks”) in many mammalian species. With a view of extending such epigenetic clocks to all primate species, we analyzed DNA methylation profiles of 2400 tissues derived from 37 primate species including 11 haplorhine species (baboons, marmosets, vervets, rhesus macaque, chimpanzees, gorillas, orangutan, humans) and 26 strepsirrhine species (suborders Lemuriformes and Lorisiformes). From these we present here, pan-primate epigenetic clocks which are highly accurate for all primates including humans (age correlation R=0.98). We also carried out in-depth analysis of baboon DNA methylation profiles and generated five epigenetic clocks for baboons (Olive-yellow baboon hybrid), one of which, the pan-tissue epigenetic clock, was trained on seven tissue types (fetal cerebral cortex, adult cerebral cortex, cerebellum, adipose, heart, liver, and skeletal muscle) with ages ranging from late fetal life to 22.8 years of age. To facilitate translation of findings in baboons to humans, we further constructed two dual-species, human-baboon clocks. We also identified and present here, epigenetic predictors of sex that apply to all primate species. Low overlap can be observed between age- and sex-related CpGs. Overall, this study advances our understanding of conserved age- and sex-related epigenetic changes in primates, and provides biomarkers to study the aging of all primate species with the facility to readily translate any findings between primate species.

Background/Aim: The International Agency for Research on Cancer has classified benzo(a)pyrene (BaP) as carcinogenic to humans, based on sufficient evidence of carcinogenicity in experimental animal...

Background: The gut-brain axis theory hypothesizes that gut microbiota play a role in the development and progression of Parkinson disease (PD). However, the direction and magnitude of the crosstal...

Background: Benzene is classified as a Group 1 carcinogen in humans. A major pathway of benzene exposure is through the inhalation of ambient air contaminated by emissions from motor vehicle exhaust, gas stations, industries, tobacco smoke, and other consumer products. Past studies on benzene and breast cancer based on job titles or occupational history have yielded mixed results and the role of ambient benzene and breast cancer risk has been sparsely studied. Within the California component of the Multiethnic Cohort study, we examined the association between outdoor exposure to benzene and breast cancer risk among four major U.S. racial/ethnic groups―African Americans, Latinos, Japanese Americans, and Whites. Methods: Outdoor ambient benzene exposure was estimated from U.S. EPA measurements from air monitoring stations that were within 15 km of residences of 57,589 female MEC participants, largely from Los Angeles County, from time of recruitment (1993-1996) through study end date (12/31/2010). Cox proportional hazards models were used to examine the associations between time-varying benzene exposure and invasive breast cancer risk (cases=2,388), adjusting for age, race/ethnicity, education, smoking pack-years, family history of breast cancer, body mass index, physical activity, parity and age at first live birth, age at menarche, menopausal status, use of hormone therapy, alcohol consumption, intake of total calories, and neighborhood (block group) socioeconomic status. Stratified analyses were conducted by race/ethnicity, smoking history, and hormone receptor status. Results: Outdoor ambient benzene exposure (average median level from 1993-2010 was 0.94 ppb) was associated with an increased risk of breast cancer (per 1 ppb hazard ratio [HR]=1.40, 95% confidence interval [CI]: 1.24-1.58). This positive association was observed across all racial/ethnic groups; HR ranged from 1.23 to 1.67 (p values were Citation Format: Ugonna Ihenacho, Jun Wu, Chiu-Chen Tseng, Juan Yang, Scott Fruin, Timothy Larson, Salma Shariff-Marco, Loic Le Marchand, Daniel Stram, Beate Ritz, Iona Cheng, Anna H. Wu. Association between outdoor ambient benzene and invasive breast cancer incidence: The Multiethnic Cohort Study [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-170.

Background Social stress and strain, especially discrimination and inequality might have an impact on memory and cognitive function. This is a major concern for older individuals, their families, communities and societies. We sought to assess changes in episodic memory (EM) and executive functioning (EF) among men and women in the 'Midlife in the United States' (MIDUS) cohort study, to delineate variations in EM and EF by gender, and to determine the impact of social stress/strain at three levels (family, work, society) on longitudinal changes in EM and EF in men and women. Methods We used data from the MIDUS study - a national probability sample of non-institutionalized, English speaking respondents aged 25-74 living in the 48 contiguous states of the United States. The initial wave in our study (1995) included 4963 non-institutionalized adults aged 32 to 84 (M = 55, SD = 12.4). The dependent variables are EM and EF, which were assessed with the Brief Test for Cognition. The independent variables were social stress and discrimination variables at the family/partner level, the work level and the society level, assessed with validated discrimination measures. To assess cognition changes we estimated adjusted linear regression models. Results Women report more perceived inequality for their family and more family strain than men across all age groups. After controlling for other explanatory variables, the main effect on cognition for all age groups was found for perceived inequality of one's family opportunities. Conclusions Reducing social stress and providing opportunities might be an important measure to support episodic memory and executive functioning in aging populations.

Sustained and inadequately controlled hypertension can promote the development of age-related macular degeneration (AMD) through multiple biologic pathways. Epidemiologic studies of high blood pressure, antihypertensive therapies, and the risk of AMD thus far have been inconclusive. However, few studies evaluated risks according to the use of different classes of antihypertensive drugs or took combinations of use into account. We performed a prospective cohort study by linking the California Teachers Study (CTS) cohort (N = 88 481) to statewide hospital discharge records up to December 31, 2012. History of high blood pressure, regular use of antihypertensive medications, and comprehensive risk factor information was collected via self-administered questionnaires at baseline in 1995-1996, and information on specific classes of antihypertensive drugs was provided by a subsample of CTS participants who completed a follow-up questionnaire in 2000. We identified 1762 female teachers with AMD during 14.8 years of follow-up on average. Applying Cox proportional hazard regression, we estimated increased risks of AMD among women treated for hypertension at baseline (HR = 1.15, 95% CI: 1.03, 1.30); the magnitude of the association increased with longer duration of antihypertensive treatment. In the subsample with more specific information on type of medication use, we estimated a 45% increased risk of AMD among women receiving diuretics as monotherapy compared to women with medications more potent than diuretics (HR = 1.45, 95% CI 1.10, 1.90). In women treated with a combination of antihypertensive drugs, we observed no increased risk of AMD for any individual class of drugs.

Supplemental Digital Content is available in the text., Background: Cognitive impairment has been linked to traffic-related air pollution and noise exposure as well as to metabolic syndrome or some of its individual components. Here, we investigate whether the presence of metabolic dysfunction modifies associations between air pollution or noise exposures and incident dementia or cognitive impairment without dementia (CIND). Methods: For 1,612 elderly Mexican-American participants of the Sacramento Area Latino Study on Aging (SALSA) followed for up to 10 years, we estimated residential-based local traffic-related exposures relying on the California Line Source Dispersion Model version 4 (CALINE4) for nitrogen oxides (NOx) and the SoundPLAN software package (Version 8.0; NAVCON, Fullerton, CA) that implements the Federal Highway Administration Traffic Noise Model (TNM) for noise, respectively. We used Cox proportional hazard models to estimate the joint effects of NOx or noise exposures and obesity, hyperglycemia, or low high-density lipoprotein (HDL) cholesterol. Results: The risk of developing dementia/CIND among participants with hyperglycemia who also were exposed to high levels of NOx (≥3.44 parts per billion [ppb] [75th percentile]) or noise (≥65 dB) was 2.4 (1.4, 4.0) and 2.2 (1.7, 3.9), respectively. For participants with low HDL-cholesterol, the estimated hazard ratios for dementia/CIND were 2.5 (1.4, 4.3) and 1.8 (1.0, 3.0) for those also exposed to high levels of NOx (≥3.44 ppb) or noise (≥65 dB), respectively, compared with those without metabolic dysfunction exposed to low traffic-related air pollution or noise levels. Conclusions: Exposure to traffic-related air pollution or noise most strongly increases the risk of dementia/CIND among older Mexican-Americans living in California who also exhibit hyperglycemia or low HDL-cholesterol.

BackgroundPyrethroid pesticide use is increasing worldwide, although the full extent of associated health effects is unknown. An epigenome-wide association study (EWAS) with exploratory pathway analysis may help identify potential pyrethroid-related health effects.MethodsWe performed an exploratory EWAS of chronic ambient pyrethroid exposure using control participants' blood in the Parkinson's Environment and Genes Study in the Central Valley of California (N=237). We estimated associations of living and working near agricultural pyrethroid pesticide applications in the past 5 years (binary) with site-specific differential methylation, and used a false discovery rate (FDR) cut off of 0.05 for significance. We controlled for age, sex, education, cell count, and an ancestral marker for Hispanic ethnicity. We normalized methylation values for Type I/II probe bias using Beta-Mixture Quantile (BMIQ) normalization, filtered out cross-reactive probes, and evaluated for remaining bias with Surrogate Variable Analysis (SVA). We also evaluated the effects of controlling for cell count and normalizing for Type I/II probe bias by comparing changes in effect estimates and p-values for the top hits across BMIQ and GenomeStudio normalization methods, and controlling for cell count. To facilitate broader interpretation, we annotated genes to the CpG sites and performed gene set overrepresentation analysis, using genes annotated to CpG sites that were associated with pyrethroids at a raw p&nbsp

Cerebral palsy (CP) is the most common neuro-motor disability in young children. Disruptions of maternal hormone function during pregnancy have been linked to CP risk. We investigated whether prenatal exposure to pesticide compounds with endocrine-disrupting action affect CP risk. We conducted a case-control study of 3905 CP cases and 39,377 controls born between 1998 and 2010 in California to mothers who lived in proximity (within 2 km) to any agricultural pesticide application recorded in the California Pesticide Use Reporting (PUR) system. We focused on 23 pesticides considered endocrine disruptors that are frequently used, and we found that exposure to any of the 23 pesticides in the first trimester was associated with elevated CP risks in female offspring (OR = 1.19; 95% CI: 1.05–1.35) but not males (OR = 0.99; 95% CI: 0.89–1.09) compared to the unexposed offspring. Positive associations were estimated for 15 pesticides suspected to affect the estrogen and 7 pesticides suspected to affect the thyroid hormone system. Our study suggests that first trimester exposure to pesticides that are suspected endocrine disruptors are associated with CP risk in female offspring. Pesticide exposures in early pregnancy may have sex-specific influences on the neuro-motor development of the fetus by interfering with endocrine systems.

Biological ageing estimators derived from DNA methylation (DNAm) data are heritable and correlate with morbidity and mortality. Leveraging DNAm and SNP data from >41,000 individuals, we identify 137 genome-wide significant loci (113 novel) from meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We report strong genetic correlations with longevity and lifestyle factors such as smoking, education, and obesity. Significant associations are observed in polygenic risk score analysis and to a lesser extent in Mendelian randomization analyses. This study illuminates the genetic architecture underlying epigenetic ageing and its shared genetic contributions with lifestyle factors and longevity.

DNA methylation (DNAm) age estimators are widely used to study aging-related conditions. It is not yet known whether DNAm age is associated with the accumulation of stochastic epigenetic mutations (SEMs), which reflect dysfunctions of the epigenetic maintenance system. Here, we defined epigenetic mutation load (EML) as the total number of SEMs per individual. We assessed associations between EML and DNAm age acceleration estimators using biweight midcorrelations in four population-based studies (total n = 6,388). EML was not only positively associated with chronological age (meta r = 0.171), but also with four measures of epigenetic age acceleration: the Horvath pan tissue clock, intrinsic epigenetic age acceleration, the Hannum clock, and the GrimAge clock (meta-analysis correlation ranging from r = 0.109 to 0.179). We further conducted pathway enrichment analyses for each participant's SEMs. The enrichment result demonstrated the stochasticity of epigenetic mutations, meanwhile implicated several pathways: signaling, neurogenesis, neurotransmitter, glucocorticoid, and circadian rhythm pathways may contribute to faster DNAm age acceleration. Finally, investigating genomic-region specific EML, we found that EMLs located within regions of transcriptional repression (TSS1500, TSS200, and 1stExon) were associated with faster age acceleration. Overall, our findings suggest a role for the accumulation of epigenetic mutations in the aging process.

Recent, non-peer-reviewed reports and meta-analyses suggest that smoking may reduce the risk of hospitalization with COVID-19, because the prevalence of smoking among hospitalized COVID-19 is less than that of the general population. However, there are two alternative classes of explanations for this phenomenon. Class (1) is the failure to report, or to accurately record, smoking history during emergency hospital admissions and other interviews. Face-to-face interviews can introduce bias into the responses to attitudinal and behavioral questions not present in the self-completion interviews typically used to measure smoking prevalence in the general population. Subjects in face-to-face interviews may be unwilling to admit socially undesirable behavior and attitudes under direct questioning. For example, urine testing of hospitalized patients for cotinine showed that smokers were under-counted by 37% because incoming patients failed to inform staff about their smoking behavior. Class (2), various types of “reverse” causation, including a pre-disposition to avoid smoking among COVID-19 patients with tobacco-related comorbidities, may also contribute to the difference between smoking prevalence in the COVID-19 and general population. Patient cohorts hospitalized with COVID-19 may be less prone to use tobacco than the general population. A potentially robust “reverse causation” hypothesis for reduced prevalence of smokers in the COVID-19 population is enrichment of patients in the population with serious comorbidities that have previously motivated them to quit smoking. We ask whether this “smoking cessation” mechanism accounts for a detectable fraction of the reduced prevalence of smokers in the COVID-19 population. Testing this hypothesis will require a focused research program.

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 (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.

Spina bifida has been reported to co-occur with pediatric cancer, but comprehensive evaluations remained elusive. We investigated this co-occurrence in two large, population-based studies in Taiwan (N = 1900 cancer cases, 2,077,137 controls) and Denmark (N = 5508 cases, 137,700 controls). Analyses in Denmark were restricted to the period before prenatal diagnostics became available (2004) and pregnancy terminations of fetuses with birth defects became more common. Using national patient and cancer registries, we linked spina bifida and cancer diagnoses among cases and non-cases. The risk of spina bifida among all cancer cases was increased and similar in Denmark [odds ratio (OR)=8.4, 95% confidence interval (CI) 5.1-13.8] and Taiwan (OR = 8.5, 95% CI 4.0-17.8), particularly for central nervous system (CNS) tumors (Denmark: OR = 16.3, 95% CI 8.1-33.0; Taiwan: OR = 26.6, 95% CI 8.5, 83.1), including benign CNS tumors (Denmark: OR = 41.5, 95% CI 21.2, 81.4). These findings suggest the need for comprehensive investigation of shared risk factors in the link between spina bifida and pediatric cancer.

Background: Subclinical hypothyroidism is a common clinical entity among the United States (U.S) adults and has been associated with increased risk of cardiovascular disease (CVD) and mortality in some studies. However, the mediation effect of CVD from elevated serum thyroid stimulating hormone (TSH) to mortality has not yet been well established or sufficiently quantified. In this study, we aimed to elucidate the extent to which subclinical hypothyroidism or high-normal thyroid stimulating hormone [TSH] concentrations (i.e. upper normative-range TSH concentrations) contribute to mortality through its effect on CVD among U.S. adults. Methods: This study relies on the U.S. representative samples of 9,020 adults enrolled in the National Health and Nutrition Examination Surveys (NHANES) 2001-2002, 2007-2012 and their mortality data through 2015. We employed Cox proportional hazards regression models to investigate associations between the TSH concentration categories (subclinical hypothyroidism or tertiles of serum TSH concentrations within the reference range) and all-cause mortality. Utilizing mediation analysis within the counterfactual framework, we estimated the mediation effect of CVD on the association between TSH and all-cause mortality. Results: The median duration of follow-up for mortality ascertainment was 7.3 (interquartile range, 5.4–8.3) years, during which 435 deaths from all causes were identified. Subjects with TSH in the subclinical hypothyroidism and the high-normal TSH tertile concentrations were associated with increased all-cause mortality (subclinical hypothyroidism: hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.14–3.19; high-normal TSH: HR, 1.36; 95% CI, 1.07–1.73) compared with the middle-normal TSH tertile concentration. CVD mediated 14.3% and 5.9% of the effects of subclinical hypothyroidism and high-normal TSH on all-cause mortality, respectively, with the CVD mediation effect being most pronounced in women and subjects ≥60 years old. No mediation through CVD was found for low-normal TSH levels and all-cause mortality. Conclusion: CVD mediated the effects of subclinical hypothyroid and high-normal TSH concentrations on all-cause mortality in the U.S. general population. These findings may have potential implications for treatment, and early and more aggressive CVD screening for such at risk populations. Further studies are needed to examine the clinical impact of targeted therapy towards mid-normal TSH concentration.

Introduction: Ambient air pollution is a known risk factor for adverse birth outcomes, but the role of ultrafine particles (UFPs) is not well understood. Aircraft-origin UFPs adversely affect air quality over large residential areas downwind of airports, but their reproductive health burden remains uninvestigated. Objectives: This analysis evaluated whether UFPs from jet aircraft emissions are associated with increased rates of preterm birth (PTB) among pregnant mothers living downwind of Los Angeles International Airport (LAX). Methods: This population-based study used birth records, provided by the California Department of Public Health, to ascertain birth outcomes and a novel, validated geospatial UFP dispersion model approach to estimate in utero exposures. All mothers who gave birth from 2008 to 2016 while living within 15km of LAX were included in this analysis (N=174,186; including 15,134 PTBs). Results: In utero exposure to aircraft-origin UFPs was positively associated with PTB. The odds ratio (OR) per interquartile range (IQR) increase [9,200 particles per cubic centimeter (cc)] relative UFP exposure was 1.04 [95% confidence interval (CI): 1.02, 1.06]. When comparing the fourth quartile of UFP exposure to the first quartile, the OR for PTB was 1.14 (95% CI: 1.08, 1.20), adjusting for maternal demographic characteristics, exposure to traffic-related air pollution, and airport-related noise. Conclusion: Our results suggest that emissions from aircraft play an etiologic role in PTBs, independent of noise and traffic-related air pollution exposures. These findings are of public health concern because UFP exposures downwind of airfields are common and may affect large, densely populated residential areas. https://doi.org/10.1289/EHP5732

Author(s): Heck, Julia E; Huang, Xiwen; Calkins, Kara L; Sun, Yuelian; Olsen, Jorn; Ritz, Beate; Hansen, Johnni

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ~1 in 3,000 and ~1 in 6,000 respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of SNV data and monozygous twin pairs suggests that approximately two thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one third are likely sproradic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, and validated the presence of novel CGG expansions at several of these, identifying the molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many novel hypermethylated CGG repeat expansions.