Long-term exposure to ambient particulate matter and stroke etiology: Results from the Women's Health Initiative.

BACKGROUND: Ambient particulate matter (PM) air pollution is a leading cause of global disability and accounts for an annual 2.9 million deaths globally. PM is established as an important risk factor for cardiovascular disease, however the evidence supporting a link specifically between long-term exposure to ambient PM and incident stroke is less clear. We sought to evaluate the association of long-term exposure to different size fractions of ambient PM with incident stroke (overall and by etiologic subtypes) and cerebrovascular deaths within the Women's Health Initiative, a large prospective study of older women in the US. METHODS: We studied 155,410 postmenopausal women without previous cerebrovascular disease enrolled into the study between 1993 and 1998, with follow-up through 2010. We assessed geocoded participant address-specific concentrations of ambient PM (fine [PM2.5], respirable [PM10] and coarse [PM10-2.5]), as well as nitrogen dioxide [NO2] using spatiotemporal models. We classified hospitalization events into ischemic, hemorrhagic, or other/unclassified stroke. Cerebrovascular mortality was defined as death from any stroke etiology. We used Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for individual and neighborhood-level characteristics. RESULTS: During a median follow-up time of 15 years, participants experienced 4,556 cerebrovascular events. The hazard ratio for all cerebrovascular events was 2.14 (95% CI: 1.87, 2.44) comparing the top versus bottom quartiles of PM2.5. Similarly, there was a statistically significant increase in events comparing the top versus bottom quartiles of PM10 and NO2 (HR: 1.17; 95% CI: 1.03, 1.33 and HR:1.26; 95% CI: 1.12, 1.42). The strength of association did not vary substantially by stroke etiology. There was little evidence of an association between PMcoarse and incident cerebrovascular events. CONCLUSIONS: Long-term exposure to fine (PM2.5) and respirable (PM10) particulate matter as well as NO2 was associated with a significant increase of cerebrovascular events among postmenopausal women. Strength of the associations were consistent by stroke etiology.

Long-term aircraft noise exposure and risk of hypertension in postmenopausal women.

BACKGROUND: Studies of the association between aircraft noise and hypertension are complicated by inadequate control for potential confounders and a lack of longitudinal assessments, and existing evidence is inconclusive. OBJECTIVES: We evaluated the association between long-term aircraft noise exposure and risk of hypertension among post-menopausal women in the Women's Health Initiative Clinical Trials, an ongoing prospective U.S. METHODS: Day-night average (DNL) and night equivalent sound levels (Lnight) were modeled for 90 U.S. airports from 1995 to 2010 in 5-year intervals using the Aviation Environmental Design Tool and linked to participant geocoded addresses from 1993 to 2010. Participants with modeled exposures ≥45 A-weighted decibels (dB [A]) were considered exposed, and those outside of 45 dB(A) who also did not live in close proximity to unmodeled airports were considered unexposed. Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg or inventoried/self-reported antihypertensive medication use. Using time-varying Cox proportional hazards models, we estimated hazard ratios (HRs) for incident hypertension when exposed to DNL or Lnight ≥45 versus <45 dB(A), controlling for sociodemographic, behavioral, and environmental/contextual factors. RESULTS/DISCUSSION: There were 18,783 participants with non-missing DNL exposure and 14,443 with non-missing Lnight exposure at risk of hypertension. In adjusted models, DNL and Lnight ≥45 db(A) were associated with HRs of 1.00 (95% confidence interval [CI]: 0.93, 1.08) and 1.06 (95%CI: 0.91, 1.24), respectively. There was no evidence supporting a positive exposure-response relationship, and findings were robust in sensitivity analyses. Indications of elevated risk were seen among certain subgroups, such as those living in areas with lower population density (HRinteraction: 0.84; 95%CI: 0.72, 0.98) or nitrogen dioxide concentrations (HRinteraction: 0.82; 95%CI: 0.71, 0.95), which may indicate lower ambient/road traffic noise. Our findings do not suggest a relationship between aircraft noise and incident hypertension among older women in the U.S., though associations in lower ambient noise settings merit further investigation.

Gestational Perfluoroalkyl Substance Exposure and DNA Methylation at Birth and 12 Years of Age: A Longitudinal Epigenome-Wide Association Study.

BACKGROUND: DNA methylation alterations may underlie associations between gestational perfluoroalkyl substances (PFAS) exposure and later-life health outcomes. To the best of our knowledge, no longitudinal studies have examined the associations between gestational PFAS and DNA methylation. OBJECTIVES: We examined associations of gestational PFAS exposure with longitudinal DNA methylation measures at birth and in adolescence using the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006; Cincinnati, Ohio). METHODS: We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in mothers during pregnancy. We measured DNA methylation in cord blood (n=266) and peripheral leukocytes at 12 years of age (n=160) using the Illumina HumanMethylation EPIC BeadChip. We analyzed associations between log2-transformed PFAS concentrations and repeated DNA methylation measures using linear regression with generalized estimating equations. We included interaction terms between children's age and gestational PFAS. We performed Gene Ontology enrichment analysis to identify molecular pathways. We used Project Viva (1999-2002; Boston, Massachusetts) to replicate significant associations. RESULTS: After adjusting for covariates, 435 cytosine-guanine dinucleotide (CpG) sites were associated with PFAS (false discovery rate, q<0.05). Specifically, we identified 2 CpGs for PFOS, 12 for PFOA, 8 for PFHxS, and 413 for PFNA; none overlapped. Among these, 2 CpGs for PFOA and 4 for PFNA were replicated in Project Viva. Some of the PFAS-associated CpG sites annotated to gene regions related to cancers, cognitive health, cardiovascular disease, and kidney function. We found little evidence that the associations between PFAS and DNA methylation differed by children's age. DISCUSSION: In these longitudinal data, PFAS biomarkers were associated with differences in several CpGs at birth and at 12 years of age in or near genes linked to some PFAS-associated health outcomes. Future studies should examine whether DNA methylation mediates associations between gestational PFAS exposure and health. https://doi.org/10.1289/EHP10118.

A core of differentially methylated CpG loci in gMDSCs isolated from neonatal and adult sources.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs), which include monocytic (mMDSCs) and granulocytic (gMDSCs) cells, are an immunosuppressive, heterogeneous population of cells upregulated in cancer and other pathologic conditions, in addition to normal conditions of stress. The origin of MDSCs is debated, and the regulatory pattern responsible for gMDSC differentiation remains unknown. Since DNA methylation (DNAm) contributes to lineage differentiation, we have investigated whether it contributes to the acquisition of the gMDSC phenotype. RESULTS: Using the Illumina EPIC array to measure DNAm of gMDSCs and neutrophils from diverse neonatal and adult blood sources, we found 189 differentially methylated CpGs between gMDSCs and neutrophils with a core of ten differentially methylated CpGs that were consistent across both sources of cells. Genes associated with these loci that are involved in immune responses include VCL, FATS, YAP1, KREMEN2, UBTF, MCC-1, and EFCC1. In two cancer patient groups that reflected those used to develop the methylation markers (head and neck squamous cell carcinoma (HNSCC) and glioma), all of the CpG loci were differentially methylated, reaching statistical significance in glioma cases and controls, while one was significantly different in the smaller HNSCC group. CONCLUSIONS: Our findings indicate that gMDSCs have a core of distinct DNAm alterations, informing future research on gMDSC differentiation and function.

Estimated Cardiorespiratory Hospitalizations Attributable to Influenza and Respiratory Syncytial Virus Among Long-term Care Facility Residents.

Importance: Older adults residing in long-term care facilities (LTCFs) are at a high risk of being infected with respiratory viruses, such as influenza and respiratory syncytial virus (RSV). Although these infections commonly have many cardiorespiratory sequelae, the national burden of influenza- and RSV-attributable cardiorespiratory events remains unknown for the multimorbid and vulnerable LTCF population. Objective: To estimate the incidence of cardiorespiratory hospitalizations that were attributable to influenza and RSV among LTCF residents and to quantify the economic burden of these hospitalizations on the US health care system by estimating their associated cost and length of stay. Design, Setting, and Participants: This retrospective cohort study used national Medicare Provider Analysis and Review inpatient claims and Minimum Data Set clinical assessments for 6 respiratory seasons (2011-2017). Long-stay residents of LTCFs were identified as those living in the facility for at least 100 days (index date), aged 65 years or older, and with 6 months of continuous enrollment in Medicare Part A were included. Follow-up occurred from the resident's index date until the first hospitalization, discharge from the LTCF, disenrollment from Medicare, death, or the end of the study. Residents could re-enter the sample; thus, long-stay episodes of care were identified. Data analysis was performed between January 1 and September 30, 2020. Exposures: Seasonal circulating pandemic 2009 influenza A(H1N1), human influenza A(H3N2), influenza B, and RSV. Main Outcomes and Measures: Cardiorespiratory hospitalizations (eg, asthma exacerbation, heart failure) were identified using primary diagnosis codes. Influenza- and RSV-attributable cardiorespiratory events were estimated using a negative binomial regression model adjusted for weekly circulating influenza and RSV testing data. Length of stay and costs of influenza- and RSV-attributable events were then estimated. Results: The study population comprised 2 909 106 LTCF residents with 3 138 962 long-stay episodes and 5 079 872 person-years of follow-up. Overall, 10 939 (95% CI, 9413-12 464) influenza- and RSV-attributable cardiorespiratory events occurred, with an incidence of 215 (95% CI, 185-245) events per 100 000 person-years. The cost of influenza- and RSV-attributable cardiorespiratory events was $91 055 393 (95% CI, $77 885 316-$104 225 470), and the length of stay was 56 858 (95% CI, 48 757-64 968) days. Conclusions and Relevance: This study found that many cardiorespiratory hospitalizations among LTCF residents in the US were attributable to seasonal influenza and RSV. To minimize the burden these events place on the health care system and residents of LTCFs and to prevent virus transmission, additional preventive measures should be implemented.

Placental gene networks at the interface between maternal PM2.5 exposure early in gestation and reduced infant birthweight.

BACKGROUND: A growing body of evidence links maternal exposure to particulate matter <2.5 µM in diameter (PM2.5) and deviations in fetal growth. Several studies suggest that the placenta plays a critical role in conveying the effects of maternal PM2.5 exposure to the developing fetus. These include observed associations between air pollutants and candidate placental features, such as mitochondrial DNA content, DNA methylation and telomere length. However, gaps remain in delineating the pathways linking the placenta to air pollution-related health effects, including a comprehensive profiling of placental processes impacted by maternal PM2.5 exposure. In this study, we examined alterations in a placental transcriptome-wide network in relation to maternal PM2.5 exposure prior to and during pregnancy and infant birthweight. METHODS: We evaluated PM2.5 exposure and placental RNA-sequencing data among study participants enrolled in the Rhode Island Child Health Study (RICHS). Daily residential PM2.5 levels were estimated using a hybrid model incorporating land-use regression and satellite remote sensing data. Distributed lag models were implemented to assess the impact on infant birthweight due to PM2.5 weekly averages ranging from 12 weeks prior to gestation until birth. Correlations were assessed between PM2.5 levels averaged across the identified window of susceptibility and a placental transcriptome-wide gene coexpression network previously generated using the WGCNA R package. RESULTS: We identified a sensitive window spanning 12 weeks prior to and 13 weeks into gestation during which maternal PM2.5 exposure is significantly associated with reduced infant birthweight. Two placental coexpression modules enriched for genes involved in amino acid transport and cellular respiration were correlated with infant birthweight as well as maternal PM2.5 exposure levels averaged across the identified growth restriction window. CONCLUSION: Our findings suggest that maternal PM2.5 exposure may alter placental programming of fetal growth, with potential implications for downstream health effects, including susceptibility to cardiometabolic health outcomes and viral infections.

Per- and polyfluoroalkyl substance mixtures and gestational weight gain among mothers in the Health Outcomes and Measures of the Environment study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals commonly used in the production of household and consumer goods. While exposure to PFAS has been associated with greater adiposity in children and adults, less is known about associations with gestational weight gain (GWG). METHODS: We quantified using mass spectrometry perfluorooctanoate (PFOA), perfluorooctanesulfonate (PFOS), perfluorohexanesulfanoate (PFHxS) and perfluorononanoate (PFNA) in maternal serum from 18 ± 5 weeks' gestation (mean ± standard deviation (std)) in a prospective pregnancy and birth cohort (2003-2006, Cincinnati, Ohio) (n = 277). After abstracting weight data from medical records, we calculated GWG from 16 ± 2 weeks' gestation (mean ± std) to the measured weight at the last visit or at delivery, rate of weight gain in the 2nd and 3rd trimesters (GWR), and total weight gain z-scores standardized for gestational age at delivery and pre-pregnancy BMI. We investigated covariate-adjusted associations between individual PFAS using multivariable linear regression; we assessed potential effect measure modification (EMM) by overweight/obese status (pre-pregnancy BMI<25 kg/m2 v. ≥25 kg/m2). Using weighted quantile sum regression, we assessed the combined influence of these four PFAS on GWG and GWR. RESULTS: Each doubling in serum concentrations of PFOA, PFOS, and PFNA was associated with a small increase in GWG (range 0.5-0.8 lbs) and GWR (range 0.03-0.05 lbs/week) among all women. The association of PFNA with GWG was stronger among women with BMI≥25 kg/m2 (ß = 2.6 lbs; 95% CI:-0.8, 6.0) than those with BMI<25 kg/m2 (ß = -1.0 lbs; 95% CI:-3.8, 1.8; p-EMM = 0.10). We observed associations close to the null between PFAS and z-scores and between the PFAS exposure index (a combined summary measure) and the outcomes. CONCLUSION: Although there were consistent small increases in gestational weight gain with increasing PFOA, PFOS, and PFNA serum concentrations in this cohort, the associations were imprecise. Additional investigation of the association of PFAS with GWG in other cohorts would be informative and could consider pre-pregnancy BMI as a potential modifier.

Short-term exposure to air pollution and incidence of stroke in the Women's Health Initiative.

BACKGROUND: Evidence of the association between daily variation in air pollution and risk of stroke is inconsistent, potentially due to the heterogeneity in stroke etiology. OBJECTIVES: To estimate the associations between daily variation in ambient air pollution and risk of stroke and its subtypes among participants of the Women's Health Initiative, a large prospective cohort study in the United States. METHODS: We used national-scale, log-normal ordinary kriging models to estimate daily concentrations of fine particulate matter (PM2.5), respirable particulate matter (PM10), nitrogen dioxide (NO2), nitrogen oxides (NOx), sulphur dioxide, and ozone at participant addresses. Stroke was adjudicated by trained neurologists and classified as ischemic or hemorrhagic. Ischemic strokes were further classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. We used a time-stratified case-crossover approach to estimate the odds ratio (OR) of the risk of stroke associated with an interquartile range (IQR) increase in concentrations of each air pollutant. We performed stratified analysis to examine whether associations varied across subgroups defined by age at stroke onset, US census region, smoking status, body mass index, and prior history of diabetes mellitus, hypertension, heart or circulation problems, or arterial fibrillation at enrollment. RESULTS: Among 5417 confirmed strokes between 1993 and 2012, 4300 (79.4%) were classified as ischemic and 924 (17.1%) as hemorrhagic. No association was observed between day-to-day variation in any pollutant and risk of total stroke, ischemic stroke, or specific etiologies of ischemic stroke. We observed a positive association between risk of hemorrhagic stroke and NO2 and NOx in the 3 days prior to stroke with OR of 1.24 (95% CI: 1.01, 1.52) and 1.18 (95% CI: 1.03, 1.34) per IQR increase, respectively. The observed associations with hemorrhagic stroke were more pronounced among non-obese participants. CONCLUSIONS: In this large cohort of post-menopausal US women, daily NO2 and NOx were associated with higher risk of hemorrhagic stroke, but ambient levels of four other air pollutants were not associated with higher risk of total stroke, ischemic stroke, or ischemic stroke subtypes.

Neonatal Adipocytokines and Longitudinal Patterns of Childhood Growth.

OBJECTIVE: Adipocytokines are markers of fetal metabolism, but their association with childhood growth is unclear. This study examined associations of neonatal adipocytokines with longitudinal childhood adiposity measures in a prospective cohort of pregnant women and their children. METHODS: Leptin and adiponectin concentrations at delivery and children's BMI z scores between age 4 weeks and 8 years were measured. Differences in BMI z scores and rates of BMI z score change by leptin (n = 257) and adiponectin (n = 271) terciles were estimated. RESULTS: Children in the middle (mean difference: 0.2; 95% CI: -0.1 to 0.4) and highest (0.4; 95% CI: 0.1 to 0.6) leptin terciles had greater BMI z scores than children in the lowest tercile. Associations were null after adjustment for birth weight z score. Children in the lowest adiponectin tercile had greater gains in BMI z score (change per year: 0.10; 95% CI: 0.08 to 0.13) than children in the middle (0.07; 95% CI: 0.04 to 0.09) and highest terciles (0.04; 95% CI: -0.01 to 0.05) (adiponectin × age interaction P < 0.001). CONCLUSIONS: Lower adiponectin levels were associated with increased rates of BMI gains in the first 8 years of life. Though leptin was positively associated with BMI, this association may be confounded by birth weight.

Ambient air pollution during pregnancy and risk of gestational diabetes in New York City.

BACKGROUND: Emerging evidence suggests a potential association between ambient air pollution and risk of gestational diabetes mellitus (GDM), but results have been inconsistent. Accordingly, we assessed the associations between ambient fine particulate matter (PM2.5) and nitrogen dioxide (NO2) levels with risk of GDM. METHODS: Using linked data from birth certificates, hospital discharge diagnoses, and air pollution estimates informed by the New York City Community Air Survey, we fit conditional logistic regression models to evaluate the association between residential levels of PM2.5 and NO2 with risk of GDM among 256,372 singleton live births of non-smoking mothers in New York City born 2008-2010, adjusting for sociodemographic factors and stratified on zip code of maternal address. RESULTS: GDM was identified in 17,065 women, yielding a risk of GDM in the study sample of 67 per 1000 deliveries. In single pollutant models, 1st and 2nd trimester PM2.5 was associated with a lower and higher risk of GDM, respectively. In models mutually adjusting for PM2.5 levels in both trimesters, GDM was associated with PM2.5 levels in the 2nd trimester (OR: 1.06, 95% CI: 1.02, 1.10 per interquartile range increase in PM2.5), but not the 1st trimester (OR: 0.99, 95% CI: 0.96, 1.02). Conversely, GDM was associated with NO2 during the 1st trimester (OR: 1.05, 95% CI: 1.01, 1.09), but not the 2nd trimester (OR: 1.02, 95% CI: 0.98, 1.06). The positive associations between pollutants and GDM were robust to different model specifications. PM2.5 in the 2nd trimester was more strongly associated with GDM among mothers who were aged <35 years and not Medicaid recipients. NO2 in the 1st trimester was more strongly associated with GDM among overweight and parous women. CONCLUSIONS: In this large cohort of singleton births in New York City, NO2 in the 1st trimester and PM2.5 in the 2nd trimester were associated with higher odds of GDM, while 1st trimester PM2.5 was weakly and inconsistently associated with lower odds of GDM.

Ambient temperature and preterm birth: A retrospective study of 32 million US singleton births.

BACKGROUND: Days of extreme temperature may be associated with transiently higher risk of preterm birth, but prior studies have been limited and results have been heterogeneous. OBJECTIVES: To evaluate the association between days of extreme heat and cold and risk of preterm birth among ~32 million live singleton births between 1989 and 2002 across 403 counties in the contiguous United States (US). METHODS: We used a distributed lag nonlinear model to estimate the association between population-weighted daily mean temperature and risk of preterm birth in each county and then pooled results across geographic regions and climate zones. We defined extreme heat and cold as the 95th and 5th percentile of the county-specific temperatures, respectively. RESULTS: Preterm birth accounted for 9.3% of deliveries. There was a monotonic association between ambient temperature and risk of preterm birth. Days of extreme heat and cold were associated with a relative risk of preterm birth of 1.025 (95% CI: 1.015, 1.036) and 0.985 (95% CI: 0.976, 0.993) over the subsequent four days, respectively, relative to the county-specific median temperature. If causal, the fraction of preterm births attributable to extreme heat was 0.17% (empirical 95% CI: 0.14%, 0.19%), corresponding to 154 (empirical 95% CI: 127, 173) preterm births per million births. Extreme heat was more strongly associated with preterm birth in regions with colder and drier climates, and among younger women. Days of extreme cold temperature were associated with lower rather than higher risk of preterm birth. CONCLUSIONS: Days of extreme heat, but not extreme cold, are associated with higher risk of preterm birth in the contiguous US. If causal, these results may have important implications for the management of pregnant women during forecasted periods of extreme heat.

Should we adjust for delivery hospital in studies of air pollution and pregnancy outcomes?

In conducting a study of ambient air pollution and pregnancy outcome in New York City, we identified delivery hospital as a potential confounder, given its association with both maternal residence and therefore air pollution exposure, and with clinical practices and as a potential marker of outcome misclassification in the coding of pregnancy complications. Motivated by evidence that adjustment for delivery hospital affected associations between air pollution and pregnancy outcome, we undertook a detailed empirical examination of the role of delivery hospital that warrants consideration by others addressing this topic. METHODS: In a study of air pollution and pregnancy outcome, we identified births from 2008 to 2010 to residents of New York City and, after restrictions, included 238,960 in the analysis. Air pollution exposure estimates for ambient fine particles (PM2.5) and nitrogen dioxide (NO2) were derived from a community-wide exposure study and assigned based on geocoded maternal residence. We examined the impact of adjusting for delivery hospital and explored the relationship between delivery hospital and both exposure and pregnancy outcomes. RESULTS: Statistical adjustment for delivery hospital markedly attenuated the relationship of air pollution with birth weight and gestational hypertension, with smaller effects on preterm birth and preeclampsia. Delivery hospital was associated with estimated maternal air pollution levels after adjusting for individual-level patient characteristics, more strongly for PM2.5 than for NO2. Delivery hospital predicted pregnancy outcome after adjustment for individual attributes, with larger hospitals and those that managed a greater volume of complicated cases having lower birth weight, more medically indicated preterm births, and more diagnosed gestational hypertension. Evaluation through the use of directed acyclic graphs illustrates the potential for adjustment for hospital to reduce residual spatial confounding, but also indicates the possibility of introducing bias through adjustment of a mediator. CONCLUSIONS: Based on these results, delivery hospital warrants closer consideration in studies of air pollution and other spatial factors in relation to pregnancy outcomes. The possibility of confounding by delivery hospital needs to be balanced with the risk of adjusting for a mediator of the air pollution-pregnancy outcome association in studies of this type.

Smoking induces coordinated DNA methylation and gene expression changes in adipose tissue with consequences for metabolic health.

BACKGROUND: Tobacco smoking is a risk factor for multiple diseases, including cardiovascular disease and diabetes. Many smoking-associated signals have been detected in the blood methylome, but the extent to which these changes are widespread to metabolically relevant tissues, and impact gene expression or metabolic health, remains unclear. METHODS: We investigated smoking-associated DNA methylation and gene expression variation in adipose tissue biopsies from 542 healthy female twins. Replication, tissue specificity, and longitudinal stability of the smoking-associated effects were explored in additional adipose, blood, skin, and lung samples. We characterized the impact of adipose tissue smoking methylation and expression signals on metabolic disease risk phenotypes, including visceral fat. RESULTS: We identified 42 smoking-methylation and 42 smoking-expression signals, where five genes (AHRR, CYP1A1, CYP1B1, CYTL1, F2RL3) were both hypo-methylated and upregulated in current smokers. CYP1A1 gene expression achieved 95% prediction performance of current smoking status. We validated and replicated a proportion of the signals in additional primary tissue samples, identifying tissue-shared effects. Smoking leaves systemic imprints on DNA methylation after smoking cessation, with stronger but shorter-lived effects on gene expression. Metabolic disease risk traits such as visceral fat and android-to-gynoid ratio showed association with methylation at smoking markers with functional impacts on expression, such as CYP1A1, and at tissue-shared smoking signals, such as NOTCH1. At smoking-signals, BHLHE40 and AHRR DNA methylation and gene expression levels in current smokers were predictive of future gain in visceral fat upon smoking cessation. CONCLUSIONS: Our results provide the first comprehensive characterization of coordinated DNA methylation and gene expression markers of smoking in adipose tissue. The findings relate to human metabolic health and give insights into understanding the widespread health consequence of smoking outside of the lung.

Prenatal exposure to perfluoroalkyl substances and adipocytokines: the HOME Study.

OBJECTIVE: Gestational perfluoroalkyl substances exposure has been associated with decreased birthweight. We determined if gestational perfluoroalkyl substances exposure was associated with fetal metabolic markers using data from the HOME Study, a prospective birth cohort of pregnant women and their children in Cincinnati, Ohio. METHODS: Maternal serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid, and perfluorohexane sulfonic acid were quantified. We measured neonatal adipocytokine (leptin and adiponectin) concentrations in umbilical cord serum, and estimated percent differences with a 2-fold increase in maternal perfluoroalkyl substances concentrations among 230 mother-infant pairs. RESULTS: Median maternal serum PFOA and PFOS concentrations were 5.6 ng/mL and 14 ng/mL, respectively. Leptin was positively correlated with infant birthweight (p < 0.001). There were no statistically significant associations between maternal perfluoroalkyl substances and neonatal adipocytokine concentrations; each 2-fold increase in PFOA was associated with a non-significant increase in leptin (5%; 95% CI: -10, 22) and adiponectin (7%; 95% CI: -4, 19). CONCLUSION: Despite known associations with reduced birthweight, gestational serum perfluoroalkyl substances concentrations were not associated with neonatal adipocytokine concentrations. Further exploration of pathways of perfluoroalkyl substances associated changes in birthweight may help identify biomarkers that could be used to identify at-risk populations and develop interventions.

Air pollution, land use, and complications of pregnancy.

BACKGROUND: Mounting evidence suggests that the natural and built environment can affect human health, but relatively few studies have considered links between features of the residential natural and built environment other than air pollution and complications of pregnancy. OBJECTIVES: To quantify the impact of features of the maternal residential natural and built environments on risk of gestational diabetes mellitus (GDM), gestational hypertension and preeclampsia among 61,640 women who delivered at a single hospital in Rhode Island between 2002 and 2012. METHODS: We estimated residential levels of ambient fine particulate matter (PM2.5) and black carbon (BC) using spatiotemporal models, neighborhood green space using remote sensing and proximity to recreational facilities, and neighborhood blue space using distance to coastal and fresh water. We used logistic regression to separately estimate the association between each feature and GDM, gestational hypertension, and preeclampsia, adjusting for individual and neighborhood markers of socioeconomic status. RESULTS: GDM, gestational hypertension, and preeclampsia were diagnosed in 8.0%, 5.0%, and 3.6% of women, respectively. We found 2nd trimester PM2.5 (OR = 1.08, 95% CI: 1.00, 1.15 per interquartile range increase in PM2.5) and living close to a major roadway (1.09, 95% CI: 1.00, 1.19) were associated with higher odds of GDM, while living <1 km from the coast was associated with lower odds of GDM (0.87, 95% CI: 0.78, 0.96). Living <500 m from a recreational facility was associated with lower odds of gestational hypertension (0.89, 95% CI: 0.80, 0.99). None of these features were associated with odds of preeclampsia. Results were qualitatively similar in mutually-adjusted models and sensitivity analyses. CONCLUSIONS: In this small coastal US state, risk of GDM was positively associated with PM2.5 and proximity to busy roadways, and negatively associated with proximity to blue space, highlighting the importance of the natural and built environment to maternal health.

Variability and predictors of serum perfluoroalkyl substance concentrations during pregnancy and early childhood.

Exposure to poly- and perfluoroalkyl substances (PFAS), ubiquitous and persistent environmental contaminants, could be associated with adverse health outcomes, but there are limited longitudinal data assessing patterns and predictors of exposure during childhood. We quantified concentrations of eight different PFAS in sera collected from women during pregnancy and children at delivery and ages 3 and 8 years in 367 mother-child pairs enrolled in a prospective cohort from 2003 to 2006. In general, median childhood PFAS concentrations increased from birth to age 3 and then decreased by age 8. Maternal serum PFAS concentrations during pregnancy were strongly correlated with cord serum concentrations (0.76 < r < 0.94), but were weakly correlated with childhood concentrations (0.12 < r < 0.30). Several sociodemographic factors were associated with maternal PFAS concentrations, including income, race, and parity. In children, serum PFAS concentrations were associated with maternal age at delivery, race, parity, and child age. Breastfeeding duration was positively associated with childhood PFAS concentrations at ages 3 and 8 years. In addition, stain repellant use was associated with higher perfluorooctanoic acid and perfluorohexane sulfonic acid concentrations at age 8 years. Serum PFAS concentrations are higher during early childhood, a potentially sensitive period of development, and were highest among breastfed children.

Maternal urinary phthalate metabolites during pregnancy and thyroid hormone concentrations in maternal and cord sera: The HOME Study.

BACKGROUND: Phthalates, endocrine-disrupting chemicals that are commonly found in consumer products, may adversely affect thyroid hormones, but findings from prior epidemiologic studies are inconsistent. OBJECTIVES: In a prospective cohort study, we investigated whether maternal urinary phthalate metabolite concentrations and phthalate mixtures measured during pregnancy were associated with thyroid hormones among pregnant women and newborns. METHODS: We measured nine phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate, mono-isobutyl phthalate, monobenzyl phthalate (MBzP), and four monoesthers of di(2-ethylhexyl) phthalate] in urine collected at approximately 16 and 26 weeks' gestation among women in the Health Outcomes and Measures of the Environment Study (2003-2006, Cincinnati, Ohio). Thyroid stimulating hormone (TSH) and free and total thyroxine and triiodothyronine were measured in maternal serum at 16 weeks' gestation (n = 202) and cord serum at delivery (n = 276). We used multivariable linear regression to assess associations between individual urinary phthalate metabolites and concentrations of maternal or cord serum thyroid hormones. We used weighted quantile sum regression (WQS) to create a phthalate index describing combined concentrations of phthalate metabolites and to investigate associations of the phthalate index with individual thyroid hormones. RESULTS: With each 10-fold increase in 16-week maternal urinary MEP, maternal serum total thyroxine (TT4) decreased by 0.52 µg/dL (95% CI: -1.01, -0.03). For each 10-fold increase in average (16- and 26-week) maternal urinary MBzP, cord serum TSH decreased by 19% (95% CI: -33.1, -1.9). Among mothers, the phthalate index was inversely associated with maternal serum TT4 (WQS beta = -0.60; 95% CI: -1.01, -0.18). Among newborns, the phthalate index was inversely associated with both cord serum TSH (WQS beta = -0.11; 95% CI: -0.20, -0.03) and TT4 (WQS beta = -0.53; 95% CI: -0.90, -0.16). CONCLUSION: Our results suggest that co-exposure to multiple phthalates was inversely associated with certain thyroid hormones (TT4 in pregnant women and newborns, and TSH in newborns) in this birth cohort. These findings highlight the need to study chemical mixtures in environmental epidemiology.

Projected Changes in Temperature-related Morbidity and Mortality in Southern New England.

BACKGROUND: Climate change is expected to result in more heat-related, but potentially fewer cold-related, emergency department visits and deaths. The net effect of projected changes in temperature on morbidity and mortality remains incompletely understood. We estimated the change in temperature-related morbidity and mortality at two sites in southern New England, United States, through the end of the 21st century. METHODS: We used distributed lag Poisson regression models to estimate the present-day associations between daily mean temperature and all-cause emergency department visits and deaths in Rhode Island and in Boston, Massachusetts. We estimated the change in temperature-related visits and deaths in 2045-2054 and 2085-2094 (relative to 2001-2010) under two greenhouse gas emissions scenarios (RCP4.5 and RCP8.5) using downscaled projections from an ensemble of over 40 climate models, assuming all other factors remain constant. RESULTS: We observed U-shaped relationships between temperature and morbidity and mortality in Rhode Island, with minima at 10.9°C and 22.5°C, respectively. We estimated that, if this population were exposed to the future temperatures projected under RCP8.5 for 2085-2094, there would be 5,976 (95% eCI = 1,630, 11,379) more emergency department visits but 218 (95% eCI = -551, 43) fewer deaths annually. Results were similar in Boston and similar but less pronounced in the 2050s and under RCP4.5. CONCLUSIONS: We estimated that in the absence of further adaptation, if the current southern New England population were exposed to the higher temperatures projected for future decades, temperature-related emergency department visits would increase but temperature-related deaths would not.

Residential green space and birth outcomes in a coastal setting.

BACKGROUND: Residential green space may improve birth outcomes, with prior studies reporting higher birthweight among infants of women living in greener areas. However, results from studies evaluating associations between green space and preterm birth have been mixed. Further, the potential influence of residential proximity to water, or 'blue space', on health has not previously been evaluated. OBJECTIVES: To evaluate associations between green and blue space and birth outcomes in a coastal area of the northeastern United States. METHODS: Using residential surrounding greenness (measured by Normalized Difference Vegetation Index [NDVI]) and proximity to recreational facilities, coastline, and freshwater as measures of green and blue space, we examined associations with preterm birth (PTB), term birthweight, and term small for gestational age (SGA) among 61,640 births in Rhode Island. We evaluated incremental adjustment for socioeconomic and environmental metrics. RESULTS: In models adjusted for individual - and neighborhood-level markers of socioeconomic status (SES), an interquartile range (IQR) increase in NDVI was associated with a 12% higher (95% CI: 4, 20%) odds of PTB and, conversely, living within 500 m of a recreational facility was associated with a 7% lower (95% CI: 1, 13%) odds of PTB. These associations were eliminated after further adjustment for town of residence. NDVI was associated with higher birthweight (7.4 g, 95% CI: 0.4-14.4 g) and lower odds of SGA (OR = 0.92, 95% CI: 0.87-0.98) when adjusted for individual-level markers of SES, but not when further adjusted for neighborhood SES or town. Living within 500 m of a freshwater body was associated with a higher birthweight of 10.1 g (95% CI: 2.0, 18.2) in fully adjusted models. CONCLUSIONS: Findings from this study do not support the hypothesis that residential green space is associated with reduced risk of preterm birth or higher birthweight after adjustment for individual and contextual socioeconomic factors, but variation in results with incremental adjustment raises questions about the optimal degree of control for confounding by markers of SES. We found that living near a freshwater body was associated with higher birthweight. This result is novel and bears further investigation in other settings and populations.