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BACKGROUND: Numerous studies have suggested that long-term exposure to particulate matter ≤2.5 μm (PM 2.5) may cause cardiovascular morbidity and mortality. However, susceptibility among those with a history of ischemic heart disease is less clearly understood. We aimed to evaluate whether long-term PM 2.5 exposure is related to mortality among patients with ischemic heart disease. METHODS: We followed up 306,418 patients hospitalized with ischemic heart disease in seven major cities in South Korea between 2008 and 2016 using the National Health Insurance Database. We linked the modeled PM 2.5 data corresponding to each patient's administrative districts and estimated hazard ratios (HRs) of cause-specific mortality associated with the long-term exposure to PM 2.5 in time-varying Cox proportional hazard models after adjusting for individual- and area-level characteristics. We also estimated HRs by sex, age group (65-74 vs. ≥75 years), and household income. RESULTS: Of the patients with ischemic heart disease, mean age at the discharge was 76.8 years, and 105,913 died during a mean follow-up duration of 21.4 months. The HR of all-cause mortality was 1.10 [95% confidence intervals (CI): 1.07, 1.14] per 10 μg/m 3 increase in a 12-month moving average PM 2.5. The HRs of cardiovascular, stroke, and ischemic heart disease were 1.17 (95% CI: 1.11, 1.24), 1.17 (95% CI: 1.06, 1.30), and 1.25 (95% CI: 1.15, 1.35), respectively. The subgroup analyses showed that participants aged 65-74 years were more susceptible to adverse effects of PM 2.5 exposure. We did not observe any differences in the risk by sex and household income. CONCLUSION: Mortality from all-cause and cardiovascular disease following hospitalization due to ischemic heart disease was higher among individuals with greater PM 2.5 exposure in seven major cities in South Korea. The result supports the association of long-term exposure to air pollution with poor prognosis among patients with ischemic heart disease.

Burning candles at home emit small particles and gases that pollute indoor air. Exposure to fine particles in outdoor air has been convincingly linked to cardiovascular and respiratory events, while the associations with fine and ultrafine particles from candle burning remain unexplored. We examined the association between the use of candles and incident cardiovascular and respiratory events. We collected data on 6757 participants of the Copenhagen Aging and Midlife Biobank cohort recruited in 2009 and followed them up for the first hospital contact for incident cardiovascular and respiratory events until 2018. We investigated an association between the self-reported frequency of candle use in wintertime and cardiovascular and respiratory events, using Cox regression models adjusting for potential confounders. During follow-up, 1462 and 834 were admitted for cardiovascular and respiratory events, respectively. We found null associations between candle use and a hospital contact due to cardiovascular and respiratory events, with hazard ratios (HRs) and 95% confidence intervals (CI) of 0.97 (95% CI: 0.84, 1.11) and 0.98 (95% CI: 0.81, 1.18), respectively, among those using candles4 times/week compared with1 time/week. For cause-specific cardiovascular diseases, HRs were 1.10 (95% CI: 0.85, 1.43) for ischemic heart disease and 1.18 (95% CI: 0.77, 1.81) for myocardial infarction. For chronic obstructive pulmonary disease, HR was 1.26 (95% CI: 0.81, 1.97). We found no statistically significant associations between candle use and the risk of cardiovascular and respiratory events. Studies with improved exposure assessments are warranted.

Ambient air pollution is an established risk factor for premature mortality from chronic cardiovascular, respiratory and metabolic diseases, while evidence on neurodegenerative diseases and psychiatric disorders remains limited. We examined the association between long-term exposure to air pollution and mortality from dementia, psychiatric disorders, and suicide in seven European cohorts. Within the multicenter project ‘Effects of Low-Level Air Pollution: A Study in Europe’ (ELAPSE), we pooled data from seven European cohorts from six countries. Based on the residential addresses, annual mean levels of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), ozone (O3), and 8 PM2.5 components were estimated using Europe-wide hybrid land-use regression models. We applied stratified Cox proportional hazard models to investigate the associations between air pollution and mortality from dementia, psychiatric disorders, and suicide. Of 271,720 participants, 900 died from dementia, 241 from psychiatric disorders, and 164 from suicide, during a mean follow-up of 19.7 years. In fully adjusted models, we observed positive associations of NO2 (hazard ratio [HR] = 1.38; 95 % confidence interval [CI]: 1.13, 1.70 per 10 µg/m3), PM2.5 (HR = 1.29; 95 % CI: 0.98, 1.71 per 5 µg/m3), and BC (HR = 1.37; 95 % CI: 1.11, 1.69 per 0.5 × 10−5/m) with psychiatric disorders mortality, as well as with suicide (NO2: HR = 1.13 [95 % CI: 0.92, 1.38]; PM2.5: HR = 1.19 [95 % CI: 0.76, 1.87]; BC: HR = 1.08 [95 % CI: 0.87, 1.35]), and no association with dementia mortality. We did not detect any positive associations of O3 and 8 PM2.5 components with any of the three mortality outcomes. Long-term exposure to NO2, PM2.5, and BC may lead to premature mortality from psychiatric disorders and suicide.

Air pollution has been reported to be an environmental risk factor for autism spectrum disorder. However, the gut microbiome's role as a potential mediator has not been investigated. We aimed to clarify whether particulate matter with an aerodynamic diameter ≤10 μm (PMsub10/sub) and nitrogen dioxide (NOsub2/sub) exposure impact autistic traits through the gut microbiome. Using 170 mother-child pairs, PMsub10/suband NOsub2/subexposure levels during pregnancy (1st, 2nd, and 3rd trimesters) and annual residential PMsub10/sublevels at age 2, 4, and 6 years were estimated. Autistic traits and gut microbiome were assessed at age 6 years. The associations of PMsub10/subor NOsub2/subexposure, gut microbiome composition, and autistic traits were explored, and mediation analyses of statistically significant findings were also conducted. Exposure to PMsub10/subduring the 1st trimester of pregnancy was associated with increased autistic traits (10.6% change per interquartile range (IQR) increase, 95% confidence interval [CI]: 1.1, 21.0) and with Proteobacteria relative abundance at age 6 years (66.9% change per IQR increase, 95% CI: 21.3, 129.8). First trimester NOsub2/subexposure was associated with autistic traits (12.1% change, 95% CI: 0.1, 25.5) and Proteobacteria relative abundance at age 6 years (48.1% change, 95% CI: -0.1, 119.6). Proteobacteria relative abundance was related to autistic traits (4.4% change per 2-fold increase, 95% CI: 1.3, 7.5). Relations between PMsub10/subor NOsub2/subexposure during the 1st trimester and autistic traits at age 6 years were partially mediated by Proteobacteria (proportion mediated 23.2%, p = 0.01 and 16.7%, p = 0.06; respectively). PMsub10/suband possibly NOsub2/subexposure during early pregnancy may affect autistic traits at age 6 years through the alteration of Proteobacteria abundance.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurobehavioral disorder in children. There are limited studies for diet or dietary supplement effects on ADHD in preschool children in Asia. This study aimed to determine the association between dietary patterns in 4-year-old children and ADHD symptoms in 6-year-old children.We estimated dietary intake in 4-year-old children using a food frequency questionnaire. Using 33 food groups, major dietary patterns were identified in relation to the consumption of sweets, vegetables, meats, and carbohydrates. Parents of 6-year-old children used the Korean version of the ADHD Rating Scale for ADHD symptom assessment.A sweet dietary pattern was associated with a higher risk of attention deficit (AD) (relative risk [RR], 1.34; confidence interval [CI], 1.17-1.55), hyperactivity (RR, 1.40; CI, 1.19-1.64), and ADHD symptoms (RR, 1.37; CI, 1.23-1.52). A vegetable dietary pattern was associated with a lower risk of ADHD symptoms (RR, 0.81; CI, 0.72-0.90). Food item analysis of the sweet dietary pattern showed that intake scores for chocolate, chips, and fruit jams positively correlated with AD, hyperactivity, and ADHD symptoms.These findings can be useful to further understand the roles of dietary factors in ADHD.

Context The levels of adrenal androgens are increased through the action of steroidogenic enzymes with morphological changes in the adrenal zona reticularis. Objective We investigated longitudinal changes in androgen levels and steroidogenic enzyme activities during early childhood. Design and Participants From a prospective children’s cohort, the Environment and Development of Children cohort, 114 boys and 86 girls with available blood samples from ages 2, 4, and 6 years were included. Outcome Measurements Serum concentrations of adrenal androgens using liquid chromatography-tandem mass spectrometry and steroidogenic enzyme activity calculated by the precursor/product ratio. Results During ages 2 to 4 years, 17,20-lyase and dehydroepiandrosterone (DHEA) sulfotransferase activities increased (P Conclusion This study supports in vivo human evidence of increased 17,20-lyase and DHEA sulfotransferase activities and decreased 3β-HSD activity during early childhood.

Background/aims Seasonal variation is an environmental factor proposed to affect the incidence of venous thromboembolism (VTE). However, VTE seasonal variation is not well studied in Asian populations, which have different genetic determinants of VTE compared to Westerners. The present study aimed at investigating seasonal variation of VTE occurrence and the effect of various demographic factors (i.e., age, sex, and co-morbidities) on variation. Methods VTE seasonal variation was evaluated in 59,626 index cases (from January 2009 to December 2013) in the Korean Health Insurance Review and Assessment Service database. We quantified and compared VTE occurrence across four seasons, and additionally assessed monthly through a chronobiological analysis. Results VTE incidence varied both seasonally and monthly, with new cases peaking in the winter (January and February) and the lowest incidence in the summer (August and September). After adjusting for sex, age, type of VTE, and combined cancer diagnosis, winter remained a significant independent factor driving VTE incidence. Additionally, seasonal variation was prominent in patients aged 60 years or older and in patients with pulmonary embolism, but not so prominent in patients of aged less than 60 years and patients with deep vein thrombosis. Conclusion Seasonal variation was a weak but independent contributor to VTE incidence in a Korean population diagnosed from 2009 to 2013, especially in those individuals with old age or suffering from a pulmonary embolism.

Particulate matter air pollution and diesel engine exhaust have been classified as carcinogenic for lung cancer, yet few studies have explored associations with liver cancer. We used six European adult cohorts which were recruited between 1985 and 2005, pooled within the “Effects of low-level air pollution: A study in Europe” (ELAPSE) project, and followed for the incidence of liver cancer until 2011 to 2015. The annual average exposure to nitrogen dioxide (NO 2), particulate matter with diameter 2.5), black carbon (BC), warm-season ozone (O 3), and eight elemental components of PM 2.5 (copper, iron, zinc, sulfur, nickel, vanadium, silicon, and potassium) were estimated by European-wide hybrid land-use regression models at participants' residential addresses. We analyzed the association between air pollution and liver cancer incidence by Cox proportional hazards models adjusting for potential confounders. Of 330 064 cancer-free adults at baseline, 512 developed liver cancer during a mean follow-up of 18.1 years. We observed positive linear associations between NO 2 (hazard ratio, 95% confidence interval: 1.17, 1.02-1.35 per 10 μg/m 3), PM 2.5 (1.12, 0.92-1.36 per 5 μg/m 3), and BC (1.15, 1.00-1.33 per 0.5 10 −5/m) and liver cancer incidence. Associations with NO 2 and BC persisted in two-pollutant models with PM 2.5. Most components of PM 2.5 were associated with the risk of liver cancer, with the strongest associations for sulfur and vanadium, which were robust to adjustment for PM 2.5 or NO 2. Our study suggests that ambient air pollution may increase the risk of liver cancer, even at concentrations below current EU standards.

BackgroundRoad traffic noise has been linked to increased risk of ischemic heart disease, yet evidence on stroke shows mixed results. We examine the association between long-term exposure to road traffic noise and incidence of stroke, overall and by subtype (ischemic or hemorrhagic), after adjustment for air pollution.MethodsTwenty-five thousand six hundred and sixty female nurses from the Danish Nurse Cohort recruited in 1993 or 1999 were followed for stroke-related first-ever hospital contact until December 31st, 2014. Full residential address histories since 1970 were obtained and annual means of road traffic noise (Lden[dB]) and air pollutants (particulate matter with diameter 2.5and PM10], nitrogen dioxide [NO2], nitrogen oxides [NOx]) were determined using validated models. Time-varying Cox regression models were used to estimate hazard ratios (HR) (95% confidence intervals [CI]) for the associations of one-, three-, and 23-year running means of Ldenpreceding stroke (all, ischemic or hemorrhagic), adjusting for stroke risk factors and air pollutants. The World Health Organization and the Danish government’s maximum exposure recommendations of 53 and 58 dB, respectively, were explored as potential Ldenthresholds.ResultsOf 25,660 nurses, 1237 developed their first stroke (1089 ischemic, 148 hemorrhagic) during 16 years mean follow-up. For associations between a 1-year mean of Ldenand overall stroke incidence, the estimated HR (95% CI) in the fully adjusted model was 1.06 (0.98–1.14) per 10 dB, which attenuated to 1.01 (0.93–1.09) and 1.00 (0.91–1.09) in models further adjusted for PM2.5or NO2, respectively. Associations for other exposure periods or separately for ischemic or hemorrhagic stroke were similar. There was no evidence of a threshold association between Ldenand stroke.ConclusionsLong-term exposure to road traffic noise was suggestively positively associated with the risk of overall stroke, although not after adjusting for air pollution.

Background We examined the association of long‐term exposure to air pollution and road traffic noise with incident heart failure (HF). Methods And Results Using data on female nurses from the Danish Nurse Cohort (aged >44 years), we investigated associations between 3‐year mean exposures to air pollution and road traffic noise and incident HF using Cox regression models, adjusting for relevant confounders. Incidence of HF was defined as the first hospital contact (inpatient, outpatient, or emergency) between cohort baseline (1993 or 1999) and December 31, 2014, based on the Danish National Patient Register. Annual mean levels of particulate matter with a diameter 2 and road traffic noise since 1970 were estimated at participants' residences. Of the 22 189 nurses, 484 developed HF. We detected associations with all 3 pollutants, with hazard ratios (HRs) of 1.17 (95% CI, 1.01–1.36), 1.10 (95% CI, 0.99–1.22), and 1.12 (95% CI, 0.99–1.26) per increase of 5.1 µg/m 3 in particulate matter with a diameter 3 in NO 2 , and 9.3 dB in road traffic noise, respectively. We observed an enhanced risk of HF incidence for those exposed to high levels of the 3 pollutants; however, the effect modification of coexposure was not statistically significant. Former smokers and nurses with hypertension showed the strongest associations with particulate matter with a diameter P effect modification Conclusions We found that long‐term exposures to air pollution and road traffic noise were independently associated with HF.

BACKGROUND AND AIM: Ambient air pollution exposure has been linked to neurodegenerative and psychiatric disorders, but evidence remains limited. We examined the association between long-term air po...

BACKGROUND: Associations between long-term exposure to air pollution and road traffic noise have been established for ischemic heart disease, but findings have been mixed for atrial fibrillation (AF). OBJECTIVES: The goal of the study was to examine associations of long-term exposure to road traffic noise and air pollution with AF. METHODS: Time-varying Cox regression models were used to estimate associations of 1-, 3-, and 23-y mean road traffic noise and air pollution exposures with AF incidence in 23,528 women enrolled in the Danish Nurse Cohort (age >44 y at baseline in 1993 or 1999). AF diagnoses were ascer-tained via the Danish National Patient Register. Annual mean weighted 24-h average road traffic noise levels (L den) at the nurses’ residences, since 1970, were estimated using the Nord2000 model, and annual mean levels of particulate matter with a diameter 2:5) and nitrogen dioxide (NO 2) were estimated using the DEHM/UBM/AirGIS model. RESULTS: Of 23,528 nurses with no prior AF diagnosis at the cohort baseline, 1,522 developed AF during follow-up. In a fully adjusted model (including PM 2:5), the estimated risk of AF was 18% higher [hazard ratio (HR); 95% confidence interval (CI): 1.18; 1.02, 1.36] in nurses with residential 3-y mean L den levels >58 dB vs. 3 increase in 3-y mean PM 2:5 was associated with incident AF before and after adjustment for concurrent exposure to road traffic noise (HR 1.09; 95% CI: 1.00, 1.20 and 1.08; 95% CI: 0.97, 1.19, respectively). Associations with 1-y mean PM 2:5 exposures were positive but closer to the null and not significant. Associations with NO 2 were null for all time periods before and after adjustment for road traffic noise and inverse when adjusted for concurrent PM 2:5. CONCLUSION: Our analysis of prospective data from a cohort of Danish female nurses followed for up to 14 y provided suggestive evidence of independent associations between incident AF and 1-and 3-y exposures to road traffic noise and PM 2:5. https://doi.org/10.1289/EHP8090.

The incidence of many hormone-dependent diseases, including testicular cancer, has sharply increased in all high-income countries during the 20th century. This is not fully explained by established risk factors. Concurrent, increasing exposure to antiandrogenic environmental endocrine disrupting chemicals (EDCs) in fetal life may partially explain this trend. This systematic review assessed available evidence regarding the association between environmental EDC exposure and risk of testicular cancer (seminomas and nonseminomas). Following PRISMA guidelines, a search of English peer-reviewed literature published prior to December 14, 2020 in the databases PubMed and Embase® was performed. Among the 279 identified records, 19 were eligible for quality assessment and 10 for further meta-analysis. The completeness of reporting was high across papers, but over 50% were considered subject to potential risk of bias. Mean age at diagnosis was 31.9 years. None considered effects of EDC multipollutant mixtures. The meta-analyses showed that maternal exposure to combined EDCs was associated with a higher risk of testicular cancer in male offspring [summary risk ratios: 2.16, (95% CI:1.78-2.62), 1.93 (95% CI:1.49-2.48), and 2.78 (95% CI:2.27-3.41) for all, seminoma, and nonseminoma, respectively]. Similarly, high maternal exposures to grouped organochlorines and organohalogens were associated with higher risk of seminoma and nonseminoma in the offspring. Summary estimates related to postnatal adult male EDC exposures were inconsistent. Maternal, but not postnatal adult male, EDC exposures were consistently associated with a higher risk of testicular cancer, particularly risk of nonseminomas. However, the quality of studies was mixed, and considering the fields complexity, more prospective studies of prenatal EDC multipollutant mixture exposures and testicular cancer are needed.

Climate change is predicted to increase the frequency, intensity, and duration of extreme cold events in the mid-latitudes. However, although diabetes is one of the most critical metabolic diseases due to its high and increasing prevalence worldwide, few studies have investigated the short-term association between cold exposure and diabetes-related outcomes.The aim of this study was to investigate the associations between cold spells and their characteristics (intensity, duration, and seasonal timing) and hospital admission and mortality due to diabetes.This study used claims data from the National Health Insurance Service and cause-specific mortality data from Statistics Korea (2010-2019). Cold spells were defined as ≥2 consecutive days with a daily mean temperature lower than the region-specific 5th percentile during the cold season (November-March). Quasi-Poisson regressions combined with distributed lag models were used to assess the associations between exposures and outcomes in 16 regions across the Republic of Korea. Meta-analyses were conducted to pool the region-specific estimates.Exposure to cold spells was associated with an increased risk of hospital admission [relative risk (RR) = 1.45, 95% confidence interval (CI): 1.26, 1.66] and mortality (RR = 2.02, 95% CI: 1.37, 2.99) due to diabetes. The association between cold spells and hospital admission due to diabetes was stronger for cold spells that were more intense, longer, and occurred later during the cold season. The association between cold spells and diabetes-related mortality was stronger for more intense and longer cold spells.This study emphasizes the importance of developing effective interventions against cold spells, including education on the dangers of cold spells and early alarm systems. Further studies are needed to create real-world interventions and evaluate their effectiveness in improving diabetes-related outcomes.

Current evidence on the effects of prenatal exposure to endocrine disrupting chemicals on birth size remains largely inconclusive. We aimed to investigate sex-specific associations between maternal exposure to parabens, phenols and phthalates during pregnancy and birth weight, length and head/abdominal circumferences. We performed a prospective study of 88 pregnant women who underwent amniocentesis in the period 2012 to 2014. Maternal urine samples were collected during pregnancy in weeks 12 to 36 (median: 18 weeks). The concentrations of parabens, phenols and individual phthalate diester metabolites were analyzed by isotope-diluted liquid chromatography-tandem mass spectrometry and osmolality adjusted. Linear regression models estimated the associations between urinary levels of selected compounds (tertile(T2-T3) medium/high versus T1 low exposure) and birth size, stratified by offspring sex. A total of three parabens, two phenols, four individual phthalate metabolites and four sums of diester metabolites were detectable above limits of detection in at least 60% of urine samples. Overall, we observed few statistically significant associations, but medium/high exposure to bisphenol A (BPA) in male offspring was associated with statistically significant lower birth size across most outcomes [birth weight: -428 g (95% CI -756 to -99.4); birth length: -1.76 cm (95% CI -3.28 to -0.25); abdominal circumference: -1.97 cm (95% CI -3.55 to -0.39)]. Similarly, medium/high exposure to methyl paraben (MeP) in male offspring was associated with lower birth weight (-661 g, 95% CI -1251 to -70.7) and length (-3.11 cm, 95% CI -5.76 to -0.46) compared to low exposure. None of these associations were statistically significant in female offspring. Across all compounds, individual exposures were associated with more negative estimates of birth weight for male than for female offspring. Our study indicates that prenatal exposure to BPA and MeP may negatively affect birth size outcomes, with a possible sex effect. Given the small sample size, these findings need to be replicated in future larger studies.

Environmental exposure constantly changes with time and various interactions that can affect health outcomes. Machine learning (ML) or deep learning (DL) algorithms have been used to solve complex problems, such as multiple exposures and their interactions. This study developed predictive models for cause-specific mortality using ML and DL algorithms with the daily or hourly measured meteorological and air pollution data. The ML algorithm improved the performance compared to the conventional methods, even though the optimal algorithm depended on the adverse health outcomes. The best algorithms were extreme gradient boosting, ridge, and elastic net, respectively, for non-accidental, cardiovascular, and respiratory mortality with daily measurement; they were superior to the generalized additive model reducing a mean absolute error by 4.7%, 4.9%, and 16.8%, respectively. With hourly measurements, the ML model tended to outperform the conventional models, even though hourly data, instead of daily data, did not enhance the performance in some models. The proposed model allows a better understanding and development of robust predictive models for health outcomes using multiple environmental exposures.

Ultrafine particles (UFP; particulate matter, Graphical abstract Unlabelled Image

In 2016, South Korea experienced extremely high temperatures and the Korea Centre for Disease Control and Prevention (KCDC) reported 17 heat-caused deaths during these heat waves, most due to heat stroke. Because the reported number of heat-caused deaths is only part of the total deaths associated with heat waves, we aimed to estimate attributable deaths during heat wave episodes. We linked mortality to meteorological data in 16 regions in South Korea and estimated relative risk at or above threshold of maximum temperature during summer using generalized linear regression models after controlling for confounders. We computed overall, age-, sex-, and cause-specific attributable deaths from 2006 to 2017. With a 1.5% increase in all-cause mortality per 1 °C increase in concurrent days' maximum temperature during summer, this study estimates a total of 1440 all-cause deaths associated with heat waves during the 2006-2017 study period in South Korea. We estimate that 343 deaths in 2016 can be ascribed to heat waves, which is approximately 20 times more than the number reported by the KCDC (17 heat-caused deaths). This study addresses attributable heat wave deaths in South Korea and illustrates that the reports of medically classified heat-caused deaths seriously underestimate the number of deaths attributable to heat waves. Our findings may enable the implementation and reinforcement of government- and individual-level management strategies for heat waves.

Although varicella zoster (VZ) and herpes zoster (HZ) are caused by the same varicella zoster virus (VZV), the former is caused by primary infection while the latter is caused by reactivation of latent VZV, and their relationships with ambient temperature are also different. It is relatively well-established that VZ incidence declines with ambient temperature, but the relationship between HZ and ambient temperature is inconclusive. Thus, we investigated the effects of ambient temperature on the incidence of HZ in time-series analysis by using data from the Korean National Emergency Department Information System between 2014 and 2016. We applied a generalized linear model to investigate the relationship between ambient temperature and emergency room (ER) visits due to HZ, after controlling for confounders in seven metropolitan cities and nine provinces in South Korea. Region-specific estimates were pooled to obtain the national average estimates. There were a total of 61,957 ER visits nationwide for HZ during the study period. HZ significantly increased by 2.03% to 2.94% in the moving average lag models throughout 0 to 11 days with maximum percent increase of 2.94% (95% CI: 2.20, 3.68) in the 6-day moving average lag model.

Background Pyrethroid pesticides are reported to be the most commonly used residential insecticides worldwide. We aimed to investigate the relationship between prenatal and postnatal 3-phenoxybenzoic acid (3-PBA) concentrations, and growth and adiposity parameters in 4-year-old children. Method We obtained data from 578 children who participated in the prospective Environment and Development of Children (EDC) study at around 4 years of age (45–55 months) between August 2008 and July 2011. Anthropometric measurements were obtained at age 4 years. Prenatal and postnatal urinary 3-PBA concentration was measured in maternal urine samples at around 20 weeks of gestation, and in the 4-year-old children, respectively. Result The detection frequency of urinary 3-PBA (geometric mean concentration) was 98–99% (0.98 μg/g Cr) in maternal urine, and almost 99–100% (1.34 μg/g Cr) in 4-year-old children. Prenatal urinary3-PBA concentration was not associated with height, weight, or body mass index (BMI) z-scores at 4 years of age, regardless of sex. Postnatal urinary3-PBA concentration was not related to height z-scores, but was positively associated with weight z-scores with marginal significance among only girls (p = 0.058). Analyzed by sex, there was a significant relationship between postnatal urinary 3-PBA concentration and BMI z-scores (p = 0.015) among girls, after adjusting for covariates. Conclusion Childhood urinary 3-PBA concentration measured at 4 years of age was positively associated with BMI z-scores in 4-year-old girls, but prenatal urinary 3-PBA concentration at midterm pregnancy exhibited no association.

Objectives In recent years, serious concerns have been raised regarding the impacts of rising temperatures on health. The present study was conducted to investigate the relationship between elevated temperatures and kidney disease through a systematic review and meta-analysis. Methods In October 2017, 2 researchers independently searched related studies in PubMed and Embase. A meta-analysis was conducted using a random-effects model, including only studies that presented odds ratios, relative risks, or percentage changes, along with 95% confidence intervals (CIs). The characteristics of each study were summarized, and the Egger test and funnel plots were used to evaluate publication bias. Results Eleven studies that met the criteria were included in the final analysis. The pooled results suggest an increase of 30% (95% CI, 20 to 40) in kidney disease morbidity with high temperatures. In a disease-specific subgroup analysis, statistically significant results were observed for both renal colic or kidney stones and other renal diseases. In a study design-specific subgroup analysis, statistically significant results were observed in both time-series analyses and studies with other designs. In a temperature measure-specific subgroup analysis, significant results were likewise found for both studies using mean temperature measurements and studies measuring heat waves or heat stress. Conclusions Our results indicate that morbidity due to kidney disease increases at high temperatures. We also found significant results in subgroup analyses. However, further time-series analyses are needed to obtain more generalizable evidence.

Background: Long-term road traffic noise exposure is linked to cardio-metabolic disease morbidity, whereas evidence on mortality remains limited. Objectives: We investigated association of long-term exposure to road traffic noise with all-cause and cause-specific mortality. Methods: We linked 22,858 females from the Danish Nurse Cohort (DNC), recruited into the Danish Register of Causes of Death up to 2014. Road traffic noise levels since 1970 were modelled by Nord2000 as the annual mean of a weighted 24 h average (Lden). Cox regression models examined the associations between Lden (5-year and 23-year means) and all-cause and cause-specific mortalities, adjusting for lifestyle and exposure to PM2.5 (particulate matter with diameter < 2.5 μm) and NO2 (nitrogen dioxide). Results: During follow-up (mean 17.4 years), 3902 nurses died: 1622 from cancer, 922 from CVDs (289 from stroke), 338 from respiratory diseases (186 from chronic obstructive pulmonary disease, 114 from lower respiratory tract infections [ALRIs]), 234 from dementia, 95 from psychiatric disorders, and 79 from diabetes. Hazard ratios (95% confidence intervals) for all-cause mortality from fully-adjusted models were 1.06 (1.01, 1.11) and 1.09 (1.03, 1.15) per 10 dB of 5-year and 23-year mean Lden, respectively, which attenuated slightly in our main model (fully-adjusted plus PM2.5: 1.04 [1.00, 1.10]; 1.08 [1.02, 1.13]). Main model estimates suggested the strongest associations between 5-year mean Lden and diabetes (1.14: 0.81, 1.61), ALRIs (1.13: 0.84, 1.54), dementia (1.12: 0.90, 1.38), and stroke (1.10: 0.91, 1.31), whereas associations with 23-year mean Lden were suggested for respiratory diseases (1.15: 0.95, 1.39), psychiatric disorders (1.11: 0.78, 1.59), and all cancers (1.08: 0.99, 1.17). Discussion: Among the female nurses from the DNC, we observed that long-term exposure to road traffic noise led to premature mortality, independently of air pollution, and its adverse effects may extend well beyond those on the cardio-metabolic system to include respiratory diseases, cancer, neurodegenerative and psychiatric disorders.

Background Di-(2-ethylhexyl) phthalate (DEHP), the most widely used phthalate, has recently been associated with neurodevelopmental disturbances in children. However, the risk is yet to be quantified. Therefore, a systematic review and meta-analysis focusing on the association between exposure to DEHP and neurodevelopmental outcomes is necessary, with particular attention to study design (longitudinal vs. cross-sectional). Methods We performed a comprehensive literature search for associations between exposure to DEHP and neurodevelopmental outcomes. Among 106 published studies found in public databases, eight longitudinal studies and two cross-sectional studies were included in the meta-analysis. Results We observed a statistically significant association between the concentrations of DEHP metabolites and the neurodevelopment outcomes of children among cross-sectional results, and found significant association between DEHP exposure measured in prenatal period and the psychomotor development outcomes measured later in childhood. Conclusions To our knowledge, this is the first meta-analysis of studies investigating the association between DEHP exposure and neurodevelopment in children. A need exists for more researches and a precautionary policy for potential health hazard of DEHP, the most commonly used phthalate, to promote healthier neurodevelopment in children.

People use a particulate respirator in order to reduce exposure to ambient fine particulate matter (PM2.5). Acute exposure to PM2.5 is known to increase blood pressure. However, systematic reviews or meta-analyses on blood pressure-related benefits of using a particulate respirator is lacking. Therefore, we reviewed randomized crossover intervention studies on blood pressure-related effects of particulate matter respirator use. We conducted a literature review of articles found on Embase, Medline, and Cochrane library on August 31, 2020. The study outcomes were systolic and diastolic blood pressure and mean arterial pressure. A random-effect model was used in the meta-analysis. Subgroup analyses, based on age (adult

BACKGROUND: Phthalates are synthetic chemicals with endocrine-disrupting properties. They are reportedly associated with various neurotoxic outcomes. Studies on exposure to phthalates and children's autistic traits have shown inconsistent results with respect to sex and susceptible time periods. We investigated the association of phthalate exposure during the prenatal period and childhood with autistic traits over time using a birth cohort in South Korea.METHODS: Five phthalate metabolites were measured during mid-term pregnancy and children's follow-up at ages of 4, 6, and 8 years among a total of 547 mother-child pairs. The social communication questionnaire (SCQ) was used to assess autistic traits of children at each time point. The relationship between phthalate metabolites and SCQ scores were analyzed by exposure windows and sex.RESULTS: A 2.7 fold increase in di-(2-ethylhexyl) phthalate metabolite levels, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) during pregnancy was associated with increased SCQ scores at 4 years by 8.5% (95% confidence intervals [CI]: 1.9%, 15.5%) and 7.4% (95% CI: 0.3%, 15.0%), respectively, but not at the age of 6 or 8 years. Moreover, MEHHP levels at ages of 4 and 8 years were associated with increased SCQ scores at 8 years by 9.9% (95% CI: 1.8%, 18.6%) and 9.6% (95% CI: 1.3%, 18.6%), respectively. Boys showed stronger associations between phthalate exposure and SCQ scores than girls.CONCLUSION: The study suggested different susceptible time windows of phthalate exposure: exposure during pregnancy is associated with autistic traits in young children, whereas exposure during early childhood years leads to autistic traits in school-aged children, particularly boys.

Epigenetics is known to be involved in regulatory pathways through which greenness exposure influences child development and health. We aimed to investigate the associations between residential surrounding greenness and DNA methylation changes in children, and further assessed the association between DNA methylation and children’s intelligence quotient (IQ) in a prospective cohort study. We identified cytosine-guanine dinucleotide sites (CpGs) associated with cognitive abilities from epigenome- and genome-wide association studies through a systematic literature review for candidate gene analysis. We estimated the residential surrounding greenness at age 2 using a geographic information system. DNA methylation was analyzed from whole blood using the HumanMethylationEPIC array in 59 children at age 2. We analyzed the association between greenness exposure and DNA methylation at age 2 at the selected CpGs using multivariable linear regression. We further investigated the relationship between DNA methylation and children’s IQ. We identified 8743 CpGs associated with cognitive ability based on the literature review. Among these CpGs, we found that 25 CpGs were significantly associated with greenness exposure at age 2, including cg26269038 (Bonferroni-corrected p ≤ 0.05) located in the body of SLC6A3, which encodes a dopamine transporter. DNA methylation at cg26269038 at age 2 was significantly associated with children’s performance IQ at age 6. Exposure to surrounding greenness was associated with cognitive ability-related DNA methylation changes, which was also associated with children’s IQ. Further studies are warranted to clarify the epigenetic pathways linking greenness exposure and neurocognitive function.

Background Transportation noise is increasingly acknowledged as a cardiovascular risk factor, but the evidence base for an association with stroke is sparse. Objective We aimed to investigate the association between transportation noise and stroke incidence in a large Scandinavian population. Methods We harmonized and pooled data from nine Scandinavian cohorts (seven Swedish, two Danish), totaling 135,951 participants. We identified residential address history and estimated road, railway, and aircraft noise for all addresses. Information on stroke incidence was acquired through linkage to national patient and mortality registries. We analyzed data using Cox proportional hazards models, including socioeconomic and lifestyle confounders, and air pollution. Results During follow-up ( median = 19.5 y ), 11,056 stroke cases were identified. Road traffic noise ( L den ) was associated with risk of stroke, with a hazard ratio (HR) of 1.06 [95% confidence interval (CI): 1.03, 1.08] per 10-dB higher 5-y mean time-weighted exposure in analyses adjusted for individual- and area-level socioeconomic covariates. The association was approximately linear and persisted after adjustment for air pollution [particulate matter (PM) with an aerodynamic diameter of ≤ 2.5 μ m ( PM 2.5 ) and NO 2 ]. Stroke was associated with moderate levels of 5-y aircraft noise exposure (40-50 vs. ≤ 40 dB ) ( HR = 1.12 ; 95% CI: 0.99, 1.27), but not with higher exposure ( ≥ 50 dB , HR = 0.94 ; 95% CI: 0.79, 1.11). Railway noise was not associated with stroke. Discussion In this pooled study, road traffic noise was associated with a higher risk of stroke. This finding supports road traffic noise as an important cardiovascular risk factor that should be included when estimating the burden of disease due to traffic noise. https://doi.org/10.1289/EHP8949.

BACKGROUND: Humans are exposed to a mixture of metals during their lifetime; however, evidence of neurotoxicity of such mixtures in critical time windows is still insufficient. We aimed to elucidate the associations of four metals mixture across multiple time points with children's intelligence quotient (IQ) in a prospective cohort study.METHODS: Prenatal exposure and exposure at age 4 and 6 years to four types of blood metals, namely lead, mercury, cadmium, and manganese were quantified in 502 pregnant women and their children who participated in the Environment and Development Cohort study. Children' s IQ scores were assessed using the Wechsler Intelligence Scale at age 6. Bayesian kernel machine regression (BKMR), quantile g-computation models, and elastic net (ENET) models were used to assess the associations of their blood metals mixture with IQ scores.RESULTS: Multivariate linear regression models indicated that postnatal blood manganese exposure at the age of 4 years was significantly negatively associated with children's IQ [β = - 5.99, 95% confidence interval (CI): -11.37 to - 0.61]. In the multi-chemical BKMR and quantile g-computation model, statistically significant inverse associations were found between the mixture of prenatal and postnatal metals and children's IQ score (Difference in children' IQ per quartile increase: -2.83; 95% CI: -5.28, -0.38). Interestingly, we found that manganese levels at both age of 4 and 6 years were contributing factors to children's IQ in the mixture models, namely, BKMR, quantile g-computation, and ENET models.CONCLUSIONS: Multi-pollutant mixtures of prenatal and postnatal exposures to four metals affected child IQ at 6 years of age. We found a relationship between manganese exposure at both age 4, and 6 years and children's IQ. Additional studies are warranted to confirm these associations and to control the exposure to different metals during pregnancy and preschool childhood.

Background: Knowledge of the role of melatonin, xenograft experiments, and epidemiological studies suggests that exposure to light at night (LAN) may disturb circadian rhythms, possibly increasing the risk of developing breast cancer. Objectives: We examined the association between residential outdoor LAN and the incidence of breast cancer: overall and subtypes classified by estrogen (ER) and progesterone (PR) receptor status. Methods: We used data on 16,941 nurses from the Danish Nurse Cohort who were followed-up from the cohort baseline in 1993 or 1999 through 2012 in the Danish Cancer Registry for breast cancer incidence and the Danish Breast Cancer Cooperative Group for breast cancer ER and PR status. LAN exposure data were obtained from the U.S. Defense Meteorological Satellite Program (DMSP) available for 1996, 1999, 2000, 2003, 2004, 2006, and 2010 in nW/cm2/sr unit, and assigned to the study participants’ residence addresses during the follow-up. Time-varying Cox regression models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between LAN and breast cancer, adjusting for individual characteristics, road traffic noise, and air pollution. Results: Of 16,941 nurses, 745 developed breast cancer in total during 320,289 person-years of follow-up. We found no association between exposure to LAN and overall breast cancer. In the fully adjusted models, HRs for the highest (65.8–446.4 nW/cm2/sr) and medium (22.0–65.7 nW/cm2/sr) LAN tertiles were 0.97 (95% CI: 0.77, 1.23) and 1.09 (95% CI: 0.90, 1.31), respectively, compared to the lowest tertile of LAN exposure (0–21.9 nW/cm2/sr). We found a suggestive association between LAN and ER-breast cancer. Conclusion: This large cohort study of Danish female nurses suggests weak evidence of the association between LAN and breast cancer incidence.

Background: There is a high and growing prevalence of childhood obesity which increases the risk of adult obesity and adverse physical and mental health outcomes in adulthood. Experimental and clinical data suggest that the early life environment, particularly prenatal stress, may program development of obesity in the offspring. But few studies have assessed the associations between prenatal maternal stress and rapid (ascending) weight gain, which is the strongest predictor of adult obesity and metabolic disease. Experimental data indicate that the associations may be sex dependent, but the sex-dependent association between prenatal stress and growth in the human offspring during childhood and adolescence is largely unexplored. The aim of this study is to investigate the association between prenatal exposure to stressful life events and childhood obesity in the offspring and whether maternal smoking during pregnancy and breastfeeding mediate this.Method: Participants from a large prospective population-based Australian pregnancy cohort study (The Raine Study, n=2868) were closely and frequently followed from prenatal life (18 weeks gestation) through to adolescence. Maternal stressful life events were prospectively recorded at 18 and 34 weeks and childhood BMI (categorized into six z-score trajectories) was measured from 3 to age 14 years. We studied the prospective association between maternal exposure to stressful life events and BMI z-score trajectories in 2056 offspring (1082 boys). Mothers prospectively reported stressful life events at 18- and 34-weeks' gestation using a standardized and validated 10-point questionnaire. Age- and gender-specific z-scores for BMI were obtained from height and weight at age 3, 5, 8, 10 and 14 years using standardized methods. Latent class group analysis identified six distinct trajectory classes of BMI z-score. Multinomial logistic regression was used to examine the associations between maternal stressful life events and gender-specific BMI z-score trajectories as well as risk of overweight/obesity at each age point. Mediation analyses were also conducted to model the indirect associations through maternal smoking during pregnancy and breastfeeding. Results: Of the 2056-included offspring, 1322 (64.3%) were exposed to at least one maternal stressful life event during early gestation and 1203 (58.5%) were exposed in late gestation. In boys, exposure to stressful life events in early but not late gestation was significantly associated with ascending (accelerated) weight-gain (ages 3-14 years) (adjusted odds ratio (aOR): 1.25, 95% CI: 1.02, 1.52) and increased risk of overweight (aOR: 1.18, 95% CI: 1.00, 1.39) aged 10 years. No similar associations were observed in girls. We observed that 29.2% of the association between more maternal stressful life events and obesity in male offspring was mediated by breastfeeding for less than 6 months. Likewise, up to 35% of the association between more maternal stressful life events and obesity in male offspring was mediated by maternal smoking during the index pregnancy.Conclusion: Prenatal stress in early gestation is directly associated with accelerated childhood weight gain (assessed by childhood BMI z-score trajectories) and risk of obesity in adolescent boys, but not girls and breastfeeding and maternal smoking significantly mediates this association.

BackgroundWhile air pollution has been linked to the development of chronic obstructive pulmonary disease (COPD), evidence on the role of environmental noise is just emerging. We examined the associations of long-term exposure to air pollution and road traffic noise with COPD incidence.MethodsWe defined COPD incidence for 24 538 female nurses from the Danish Nurse Cohort (age >44 years) as the first hospital contact between baseline (1993 or 1999) and 2015. We estimated residential annual mean concentrations of particulate matter with an aerodynamic diameter 2.5) since 1990 and nitrogen dioxide (NO2) since 1970 using the Danish Eulerian Hemispheric Model/Urban Background Model/Air Geographic Information System modelling system, and road traffic noise (Lden) since 1970 using the Nord2000 model. Time-varying Cox regression models were applied to assess the associations of air pollution and road traffic noise with COPD incidence.Results977 nurses developed COPD during a mean of 18.6 years’ follow-up. We observed associations with COPD for all three exposures with HRs and 95% CIs of 1.19 (1.01–1.41) per 6.26 µg·m−3 for PM2.5, 1.13 (1.05–1.20) per 8.19 µg·m−3 for NO2 and 1.15 (1.06–1.25) per 10 dB for Lden. Associations with NO2 and Lden attenuated slightly after mutual adjustment, but were robust to adjustment for PM2.5. Associations with PM2.5 were attenuated to null after adjustment for either NO2 or Lden. No potential interaction effect was observed between air pollutants and noise.ConclusionLong-term exposure to air pollution, especially traffic-related NO2, and to road traffic noise were independently associated with COPD.

While exposure to sunlight is a well-documented primary source of vitamin D supply, factors leading to vitamin D deficiency vary according to population characteristics. Using nationwide data from the Korea National Health and Nutrition Examination Survey (KNHANES), we aimed to investigate a diverse range of potential factors in association with vitamin D deficiency. Overall, 21,208 participants aged &ge, 20 years were selected from KNHANES conducted between 2010 and 2014. The associations between various environmental and occupational factors and vitamin D deficiency (defined as serum 25-hydroxyvitamin D [25(OH)D] &lt, 20 ng/mL) were evaluated in logistic regression models after controlling for potential covariates and also after stratification for age and sex. Under given criteria, 15,138 (71.4%) participants were vitamin D deficient. Significant associations were observed between vitamin D deficiency and average environmental temperature and radiation, weekly walking frequency, type of occupation, and shift work. When participants were stratified by age and sex, we observed greater associations of vitamin D deficiency with walking frequency among young males (odds ratio [OR] and 95% confidence interval [95% CI]: 1.24 [1.05&ndash, 1.47] for those walking &lt, 5 times per week compared to those walking &ge, 5 times per week) and shift work (OR [95% CI]: 1.40 [1.10&ndash, 1.78] for those working at night compared to those working during the day). We also observed a significant association of vitamin D deficiency with educational attainment (OR [95% CI]: 1.43 [1.09&ndash, 1.89] for those with &le, middle school compared to those with &ge, high school) among older group of females. This study suggests that vitamin D deficiency is related to geographical conditions and subpopulation characteristics. The age and sex-specific associations may urge the effective promotion of vitamin D supply recommendations.

Background: Ambient air pollution is likely a risk factor for asthma, and recent evidence suggests the possible relevance of road traffic noise. Objectives: We examined the associations of long-term exposure to air pollution and road traffic noise with adult-asthma incidence. Methods: We followed 28,731 female nurses (age > 44 years) from the Danish Nurse Cohort, recruited in 1993 and 1999, for first hospital contact for asthma from 1977 until 2015. We estimated residential annual mean concentrations of particulate matter with diameter < 2.5 µm (PM2.5) since 1990 and nitrogen dioxide (NO2) since 1970 with the Danish DEHM/UBM/AirGIS modeling system, and road traffic noise (Lden) since 1970 with the Nord2000 model. Time-varying Cox regression models were used to associate air pollution and road traffic noise exposure with asthma incidence. Results: During 18.6 years’ mean follow-up, 528 out of 23,093 participants had hospital contact for asthma. The hazard ratios (HR) and 95% confidence intervals for asthma incidence associated with 3-year moving average exposures were 1.29 (1.03, 1.61) per 6.3 µg/m3 for PM2.5, 1.16 (1.07, 1.27) per 8.2 µg/m3 for NO2, and 1.12 (1.00, 1.25) per 10 dB for Lden. The HR for NO2 remained unchanged after adjustment for either PM2.5 or Lden, while the HRs for PM2.5 and Lden attenuated to unity after adjustment for NO2. Conclusions: Long-term exposure to air pollution was associated with adult-asthma incidence independently of road traffic noise, with NO2 most relevant. Road traffic noise was not independently associated with adult-asthma incidence.

Although many studies have evaluated the effects of ambient particulate matter with diameters of less than 2.5 μm (PM2.5) on stroke mortality in the general population, little is known about the mortality effects of PM2.5 in post-stroke populations. Therefore, a retrospective cohort was constructed using information from the health insurance database to evaluate whether exposure to PM2.5 is associated with increased mortality in aged stroke survivors residing in seven Korean metropolitan cities. A total of 45,513 older adults (≥65 years) who visited emergency rooms due to stroke and who were discharged alive between 2008 and 2016 were followed up. By using district-level modeled PM2.5 concentrations and a time-varying Cox proportional hazard model, associations between 1-month and 2-month moving average PM2.5 exposures and mortality in stroke survivors were evaluated. The annual average concentration of PM2.5 was 27.9 μg/m3 in the seven metropolitan cities, and 14,880 subjects died during the follow-up period. A 10 μg/m3 increase in the 1-month and 2-month moving average PM2.5 exposures was associated with mortality hazard ratios of 1.07 (95% confidence interval: 1.05, 1.09) and 1.06 (95% confidence interval: 1.03, 1.08), respectively. The effects of PM2.5 were similar across types of stroke (ischemic and hemorrhagic), age groups (65–74, 75–84, and ≥85), and income groups (low and high) but were greater in women than in men. This study highlights the adverse health effects of ambient PM2.5 in post-stroke populations. Active avoidance behaviors against PM2.5 are recommended for aged stroke survivors.

Although several studies have evaluated the association between fine particulate matter (PM2.5) and acute lower respiratory infection (ALRI) in children, their results were inconsistent Therefore, we aimed to evaluate the association between short-term exposure to PM2.5 and ALRI hospitalizations in children (0&ndash, 5 years) living in seven metropolitan cities of Korea. The ALRI hospitalization data of children living in seven metropolitan cities of Korea from 2008 to 2016 was acquired from a customized database constructed based on National Health Insurance data. The time-series data in a generalized additive model were used to evaluate the relationship between ALRI hospitalization and 7-day moving average PM2.5 exposure after adjusting for apparent temperature, day of the week, and time trends. We performed a meta-analysis using a two-stage design method. The estimates for each city were pooled to generate an average estimate of the associations. The average PM2.5 concentration in 7 metropolitan cities was 29.0 &mu, g/m3 and a total of 713,588 ALRI hospitalizations were observed during the 9-year study period. A strong linear association was observed between PM2.5 and ALRI hospitalization. A 10 &mu, g/m3 increase in the 7-day moving average of PM2.5 was associated with a 1.20% (95% CI: 0.71, 1.71) increase in ALRI hospitalization. While we found similar estimates in a stratified analysis by sex, we observed stronger estimates of the association in the warm season (1.71%, 95% CI: 0.94, 2.48) compared to the cold season (0.31%, 95% CI: &minus, 0.51, 1.13). In the two-pollutant models, the PM2.5 effect adjusted by SO2 was attenuated more than in the single pollutant model. Our results suggest a positive association between PM2.5 exposure and ALRI hospitalizations in Korean children, particularly in the warm season. The children need to refrain from going out on days when PM2.5 is high.

Background: Long-term exposure to air pollution has been linked to coronary cardiovascular disease andcerebrovascular disease mor, yet litearture on heart failure (HF) is rather new and limited. We...

BACKGROUND: Epigenetic mechanisms have been suggested to play a role in the link between in utero exposure to bisphenol A (BPA) and pediatric obesity; however, there is little evidence regarding th...