Predicting Lung Cancer in Korean Never-Smokers With Polygenic Risk Scores.

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer and these loci have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs); PRSs were calculated using a pruning-thresholding-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31-2.23) using the 40%-60% percentile group as the reference, and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747-0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLong's test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.

Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk.

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Prenatal and childhood exposure to endocrine-disrupting chemicals and early thelarche in 8-year-old girls: A prospective study using Bayesian kernel regression.

BACKGROUND: Studies on the combined effects of persistent and non-persistent endocrine-disrupting chemicals (EDCs) on puberty are insufficient. To date, no studies have analyzed breast development at age 8 years, a key criterion for determining precocious puberty. We investigated the relationship between prenatal or childhood exposure to EDC mixtures and early thelarche, defined as breast development before age 8 years in girls. METHODS: This prospective study included 211 girls with data on prenatal and 8-year-old exposure of cadmium (Cd), lead, mercury, bisphenol-A (BPA), 3-phenoxybenzoic acid, and three phthalate metabolites from the Environment and Development of Children cohort. Prenatal exposure was assessed through samples from pregnant women at 14-27th weeks of gestation. Tanner staging was assessed by a pediatric endocrinologist. The relationship between single and mixed chemical exposures and outcomes was assessed using logistic regression, generalized additive models (GAM), and Bayesian kernel machine regression (BKMR) models. RESULTS: Early thelarche was observed in 42 (19.9%) girls at age 8 years. In the logistic regression models, the risk of early thelarche increased with increased exposure to Cd in their mothers (adjusted odds ratio [aOR] per interquartile range [IQR] = 1.80, 95% confidence interval [CI] 1.23-2.65) but decreased with prenatal BPA exposure (aOR per IQR = 0.57, 95% CI 0.35-0.92). None of the 8-year-old chemical exposures was associated with early thelarche. In the GAM, early thelarche was positively correlated with prenatal Cd and inversely associated with prenatal BPA exposure (p = 0.004 for Cd and p = 0.036 for BPA). In the BKMR models, an increase in log-transformed prenatal Cd concentrations from the 25th to 75th percentile was associated with an increase in the estimated probability of early thelarche at age 8 years (risk difference: 0.46 [95% credible interval: 0.04-0.88]) when other chemicals were set at their median values. CONCLUSIONS: Considering the combined effects of persistent and non-persistent chemical mixtures, maternal Cd exposure during the second trimester may be associated with early thelarche in 8-year-old girls.

Infantile allergic diseases: a cohort study prenatal fish intake and mercury exposure context.

BACKGROUND: Allergic diseases (ADs) have been increasingly reported in infants and children over the last decade. Diet, especially the inclusion of fish intake, may help to lower the risk of ADs. However, fish also, can bioaccumulate environmental contaminants such as mercury. Hence, our study aims to determine what effects the type and frequency of fish intake have on ADs in six-month-old infants, independently and jointly with mercury exposure. METHODS: This study is part of the prospective birth cohort: Mothers and Children's Environmental Health (MOCEH) study in South Korea. Data was collected on prenatal fish intake, prenatal mercury concentration and ADs for infants aged six months for 590 eligible mother-infant pairs. Logistic regression analysis was conducted to evaluate the risk of prenatal fish intake and mercury concentration on ADs in infants. Finally, interaction between fish intake and mercury concentration affecting ADs in infants was evaluated. Hazard ratios of prenatal fish intake on ADs in 6 month old infants were calculated by prenatal mercury exposure. RESULTS: Logistic regression analysis showed that white fish (OR: 0.53; 95% CI 0.30-0.94; P < 0.05) intake frequency, once a week significantly decreased the risk of ADs in infants. Stratification analysis showed that consuming white fish once a week significantly reduced the hazard of ADs (HR: 0.44; 95% CI 0.21-0.92; P < 0.05) in infants in the high-mercury (≥ 50th percentile) exposure group. CONCLUSION: The result indicates that prenatal white fish intake at least once a week reduces the risk of ADs in infants, especially in the group with high prenatal mercury exposure.

Prenatal and early-life air pollutant exposure and epigenetic aging acceleration.

BACKGROUND: This study investigated the association of prenatal and early childhood exposure to air pollution with epigenetic age acceleration (EAA) at six years of age using the Environment and Development of Children Cohort (EDC Cohort) MATERIALS & METHODS: Air pollution, including particulate matter [< 2.5 µm (PM2.5) and < 10 µm (PM10) in an aerodynamic diameter], nitrogen dioxide (NO2), ozone (O3), carbon monoxide (CO), and sulfur dioxide (SO2) were estimated based on the residential address for two periods: 1) during the whole pregnancy, and 2) for one year before the follow-up in children at six years of age. The methylation levels in whole blood at six years of age were measured, and the methylation clocks, including Horvath's clock, Horvath's skin and blood clock, PedBE, and Wu's clock, were estimated. Multivariate linear regression models were constructed to analyze the association between EAA and air pollutants. RESULTS: A total of 76 children in EDC cohort were enrolled in this study. During the whole pregnancy, interquartile range (IQR) increases in exposure to PM2.5 (4.56 µg/m3) and CO (0.156 ppm) were associated with 0.406 years and 0.799 years of EAA (Horvath's clock), respectively. An IQR increase in PM2.5 (4.76 µg/m3) for one year before the child was six years of age was associated with 0.509 years of EAA (Horvath's clock) and 0.289 years of EAA (Wu's clock). PM10 (4.30 µg/m3) and O3 (0.003 ppm) exposure in the period were also associated with EAA in Horvath's clock (0.280 years) and EAA in Horvath's skin and blood clock (0.163 years), respectively. CONCLUSION: We found that prenatal and childhood exposure to ambient air pollutants is associated with EAA among children. The results suggest that air pollution could induce excess biological aging even in prenatal and early life.

Association of long-term exposure to PM2.5 and survival following ischemic heart disease.

BACKGROUND: Numerous studies have suggested that long-term exposure to particulate matter ≤2.5 µm (PM2.5) 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 PM2.5 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 PM2.5 data corresponding to each patient's administrative districts and estimated hazard ratios (HRs) of cause-specific mortality associated with the long-term exposure to PM2.5 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/m3 increase in a 12-month moving average PM2.5. 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 PM2.5 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 PM2.5 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.

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

Pre- and postnatal exposure to multiple ambient air pollutants and child behavioral problems at five years of age.

Ambient air pollution is emerging as a risk factor for adverse neurological symptoms and early childhood diseases. This study aimed to evaluate the association between pre- and postnatal exposure to air pollutants and childhood behavior by using MOCEH prospective birth cohort data. In total, 353 mother-child pairs at birth, who completed child behavioral assessments using the Korean version of the Child Behavior Checklist at five years of age, were included in the study. Multivariate linear regression (MLR) for single pollutant and Bayesian kernel machine regression (BKMR) for multiple pollutants were conducted. MLR analysis showed that air pollutant exposures during the first trimester were significantly associated with the internalizing problems score after adjusting for covariates. The estimates were 0.19 (0.05-0.32) per 1 µg/m3 increase in PM2.5, 0.13 (0.04-0.22) per 1 µg/m3 increase in PM10, and 0.20 (0.02-0.37) per 1 ppb increase in NO2. The BKMR model analysis revealed that the overall effects of multiple air pollutants during the first trimester of pregnancy and 0-6 months of the infantile period were significantly associated with behavioral problems. Boys showed a stronger associations than girls. Taken together, these results showed that the first trimester of pregnancy and 0-6 months of the infantile period were important for air pollutant exposure because exposure at these periods was associated with behavioral problems in 5-year-old children. Future efforts are required to control air pollution levels and reduce the health burden of vulnerable populations, including pregnant women and children.

Dietary patterns are associated with attention-deficit hyperactivity disorder (ADHD) symptoms among preschoolers in South Korea: a prospective cohort study.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: These findings can be useful to further understand the roles of dietary factors in ADHD.

Association Between Sleep Duration and Intelligence Quotient in 6-Year-Old Children.

BACKGROUND: Sufficient sleep during childhood is important for cognitive functions such as learning and successful school performance. This study aimed to investigate the effects of sleep duration on the intelligence quotient (IQ) of 6-year-old children and aimed to analyze whether these effects differed by sex. METHODS: The IQ of 538 6-year-old Korean participants from the cohort study, "The Environment and Development of Children," was measured during follow-up using the Korean Educational Developmental Institute's Wechsler Intelligence Scale for Children. The total, verbal, and performance IQ scores were evaluated. The relationship between sleep duration and IQ scores after adjusting for maternal age, maternal educational level, maternal occupation, maternal IQ, exposure to secondhand smoking, gestational age, and monthly age and birth season was also assessed. RESULTS: Longer sleep duration was significantly associated with improved verbal IQ measures (ß 0.55; p value 0.030). After stratifying participants by sex, a significant association was observed between sleep duration and total, verbal, and performance IQ scores in boys (total IQ 2.49, p value 0.012; verbal IQ 0.75, p value: 0.037; performance IQ 0.73, p value 0.048), but not in girls. CONCLUSIONS: The results indicated that only boys show a significant association between IQ scores and sleep duration. These findings support the hypothesis that sleep duration is associated with IQ, in a sex dependent manner. Future studies are needed for a thorough evaluation of the connection between sleep duration and health outcome in young children.

Particulate air pollution and survival after stroke in older adults: A retrospective cohort study in Korea.

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.

Prenatal heavy metal exposures and atopic dermatitis with gender difference in 6-month-old infants using multipollutant analysis.

BACKGROUND: Prenatal exposure to heavy metals during critical developmental phases has been implicated in allergic phenotypes. However, few studies have been conducted on the gender-specific association of prenatal heavy metal exposure with atopic dermatitis (AD) in infants. OBJECTIVE: To examine the gender-specific association of prenatal exposure to multiple heavy metals with AD incidence in 6-month-old infants using data from the Mothers and Children's Environmental Health (MOCEH). METHODS: We evaluated 738 mother-child pairs from the MOCEH study, an ongoing prospective birth cohort. The concentrations of three heavy metals (lead, mercury and cadmium) in maternal blood samples were measured during early and late pregnancy. Each quartile of heavy metal concentration was used to consider the possible nonlinear association with AD. For assessing the multi-pollutant model, we constructed the multivariate regression model including all three heavy metals at both early and late pregnancy. Further, the group Lasso model was used to perform the variable selection with categorized exposures and assess the effect of multiple pollutants including their pairwise interactions. RESULTS: A total of 200 incident cases of AD were diagnosed in 6-month-old infants. In the multivariate regression model of the boy group, adjusted odds ratios comparing the second, third and fourth quartile of lead exposure in boys with the first quartile were 1.83 (95% CI: 1.00, 3.38), 1.04 (0.91, 3.32) and 2.40 (1.18, 4.90), respectively. However, the only second quartile of lead exposure compared to first quartile was significantly associated with AD in girls. In addition, the results of the group Lasso model were similar with the results of multivariate regression model. CONCLUSION: The results suggest that lead exposure in late pregnancy increases risk of AD in 6-month-old boys although the strength of association is weak. Further studies are needed to confirm the susceptibility window and gender differences in lead-induced AD.

Short-term exposure to air pollution and hospital admission for heart failure among older adults in metropolitan cities: a time-series study.

PURPOSE: We aimed to investigate the association between air pollution concentration levels and hospital admissions for heart failure (HF) among older adults in metropolitan cities in South Korea. METHODS: We used hospital admission data of 1.8 million older adults in seven metropolitan cities from 2008 to 2016, derived from the National Health Insurance Service of South Korea. Daily HF admission data were linked to air pollutants concentrations for the respective dates, including particulate matter less than 2.5 µm in size (PM2.5), 10 µm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone. We estimated the association between air pollutants and daily HF admissions using quasi-Poisson generalized additive models for each city. RESULTS: During the study period, 142,490 hospital admissions for HF were noted. Increases of 10 µg/m3 of PM2.5 and PM10, and 10 ppb of SO2, NO2, and CO were associated with an increased risk of HF admission by 0.93% ([95% confidence intervals 0.51-1.36], 0.55% [0.31-0.80], 6.04% [2.15-10.08], 1.10% [0.38-1.82], and 0.05% [0.01-0.09]), respectively, on the same day. Increases in mean exposure to PM2.5, PM10, and SO2 for 8 days from the concurrent day were also significantly associated with HF admissions. During the warm season, the risk of HF admissions increased shortly after an increase in PM2.5, whereas prolonged effects were observed during the cold season. CONCLUSION: Our study suggests the adverse effects of air pollution on HF. Moreover, the evidence of seasonality may help tailor protection guidelines for older adults.

Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses.

BACKGROUND: The prevalence of congenital anomalies in newborns in South Korea was 272.9 per 100,000 in 2005, and 314.7 per 100,000 in 2006. In other studies, the prevalence of congenital anomalies in South Korea was equivalent to 286.9 per 10,000 livebirths in 2006, while it was estimated 446.3 per 10,000 births during the period from 2008 to 2014. Several systematic reviews and meta-analyses analyzing the factors contributing to congenital anomalies have been reported, but comprehensive umbrella reviews are lacking. METHODS: We searched PubMed, Google Scholar, Cochrane, and EMBASE databases up to July 1, 2019, for systematic reviews and meta-analyses that investigated the effects of environmental and genetic factors on any type of congenital anomalies. We categorized 8 subgroups of congenital anomalies classified according to the 10th revision of the International Statistical Classification of Diseases (ICD-10). Two researchers independently searched the literature, retrieved the data, and evaluated the quality of each study. RESULTS: We reviewed 66 systematic reviews and meta-analyses that investigated the association between non-genetic or genetic risk factors and congenital anomalies. Overall, 269 associations and 128 associations were considered for environmental and genetic risk factors, respectively. Congenital anomalies based on congenital heart diseases, cleft lip and palate, and others were associated with environmental risk factors based on maternal exposure to environmental exposures (air pollution, toxic chemicals), parental smoking, maternal history (infectious diseases during pregnancy, pregestational and gestational diabetes mellitus, and gestational diabetes mellitus), maternal obesity, maternal drug intake, pregnancy through artificial reproductive technologies, and socioeconomic factors. The association of maternal alcohol or coffee consumption with congenital anomalies was not significant, and maternal folic acid supplementation had a preventive effect on congenital heart defects. Genes or genetic loci associated with congenital anomalies included MTHFR, MTRR and MTR, GATA4, NKX2-5, SRD5A2, CFTR, and 1p22 and 20q12 anomalies. CONCLUSION: This study provides a wide perspective on the distribution of environmental and genetic risk factors of congenital anomalies, thus suggesting future studies and providing health policy implications.

Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Causal association between ambient ozone concentration and mortality in Seoul, Korea.

BACKGROUND: The linearity of concentration-response (C-R) curve between ambient ozone (O3) concentration and mortality has been controversial. The aim of the present analysis was to examine the C-R curve between O3 concentration and mortality with a causal framework approach. METHODS: We extracted data of hourly meteorology, hourly O3 concentration and daily non-accidental mortality in Seoul from 2001 to 2009. We divided the dataset into two, odd-number (training set) and even-number years (testing set). Using the training set, we constructed a prediction model from hourly O3 concentration with support vector regression estimating the daily variations of mean O3 concentration caused by sun irradiation, wind speed and direction, controlling temperature, barometric pressure and temporal trend. With this model we predicted variance of daily O3 from the testing set, thus creating an instrumental variable. We analyzed the association between the instrumental variable and daily mortality. We also analyzed the association according to the quartiles of daily mean O3 concentration to examine the linearity of the association. RESULTS: The instrumental variable was significantly and negatively associated with daily mortality in the linear model. In the stratified analysis, the negative slope was observed in the lowest quartile and the negative slope of the association diminished as the quartile increased, and the slope became positive over the 3rd quartile (O3 > 23.3 ppb). The interaction between quartiles and instrumental variable was significant (P = 0.0108). CONCLUSION: We observed unequal effect of exposure to ambient O3 concentration on mortality according to the different ranges of daily mean O3 concentration with a causal framework approach.

Combined effects of multiple prenatal exposure to pollutants on birth weight: The Mothers and Children's Environmental Health (MOCEH) study.

BACKGROUND: Increasing evidence shows that prenatal environmental exposures is a risk factor for restricted intrauterine growth. However, only a few studies have examined the effects of multiple environmental exposures on fetal growth. OBJECTIVE: To investigate the effects of prenatal exposure on multiple environmental pollutants (heavy metals, bisphenol, phthalates, and air pollutants) on birth weight. METHODS: The Mothers and Children's Environmental Health study is a prospective birth cohort comprising a total of 719 mother-child pairs, including 466 pairs undergoing early pregnancy exposure and 542 pairs of late pregnancy exposure. The concentrations of three heavy metals (mercury, lead, and cadmium) in the maternal blood samples were measured. The concentrations of three phthalate metabolites [mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono-n-butyl phthalate] and bisphenol A in maternal urine samples were measured. Daily exposure to ambient particulate matter (PM10) and nitrogen dioxide (NO2) exposure was estimated based on residence and averaged by gestational age. To assess the combined effect of multiple pollutants, principal components analysis (PCA) and supervised principal components analysis (SCPA) were conducted. RESULTS: Based on PCA, the components representing PM10 and NO2 exposure during early pregnancy were significantly associated with birth weight of -32.68 g (95% CI: -64.45 g to -0.91 g) per unit increase of the corresponding component. In SCPA model, the components representing NO2 exposure during early pregnancy and the combined exposure to mercury and lead during late pregnancy were negatively associated with birth weight of -46.63 g (95% CI: -90.65 g to -2.62 g) and -55.32 g (95% CI: -99.01 g to -11.64 g), respectively, per unit increase of the corresponding component. CONCLUSION: Based on our multi-pollutant model, PM10 and NO2 exposure in early pregnancy and the combined effect of Pb and Hg in late pregnancy were associated with reduced birth weight. Our results suggest that exposure to various pollutants during pregnancy has a significant cumulative effect on birth weight, even if each pollutant is at a level below the concentration required for direct effect.

Source country-specific burden on health due to high concentrations of PM2.5.

Asian countries face frequent spikes in concentrations of particulate matter smaller than 2.5 µm (PM2.5), which may consist of domestic emissions, transported pollutants from neighboring countries, and secondary aerosol formation (SAF). We aimed to estimate the burden on health in South Korea due to PM2.5 exposure from source countries. We computed the health benefits of meeting air quality guidelines during high pollution periods or spike periods. We used daily mortality counts, PM2.5 concentrations, and primary and secondary contributions to pollutant levels in seven cities and nine provinces in South Korea during 2006-2016. Generalized additive mixed modeling with a Poisson distribution and random effects in 16 regions was used to examine the short-term effects of PM2.5 on mortality. We computed attributable burden due to PM2.5 exposure and the potential benefits of meeting the air quality guidelines set by the World Health Organization (WHO, 25 µg/m3) and the Korea Ministry of Environment (50 and 35 µg/m3 before and after 2015, respectively). A concentration-response curve showed a non-linear relationship between daily mortality counts and PM2.5 levels. The short-term health impacts of PM2.5 were suggested to be 1638 non-accidental deaths in 2016 in South Korea due to daily domestic emissions and pollutants transported from neighboring countries. Of these, 1509, 995, or 238 deaths could have been prevented if the daily mean PM2.5 concentration had been kept below 25, 35, or 50 µg/m3. After accounting for the contribution of SAF to PM2.5, primary sources of PM2.5 resulted in 258-860 and 26-88 deaths due to pollution transported from China and North Korea, respectively, and 162-538 deaths were due to domestic emissions. Meeting the air quality guidelines of the WHO could have prevented most of these deaths.

Prenatal exposure to di-(2-ethylhexyl) phthalate and decreased skeletal muscle mass in 6-year-old children: A prospective birth cohort study.

BACKGROUND/AIM: Phthalate is a well-known endocrine-disrupting chemical that has anti-androgenic effects. Although there are several studies on the relationship between body composition and phthalate, studies that investigated the effects of phthalate on skeletal muscle during childhood are lacking. METHODS: We analyzed data from 481 mother-and-child pairs enrolled in the Environment and Development of Children cohort in South Korea. We examined the association between phthalate metabolites (mono [2-ethyl-5-hydroxyhexyl] phthalate [MEHHP], mono [2-ethyl-5-oxohexyl] phthalate [MEOHP], molar sum of MEHHP and MEOHP [Σ DEHP], and mono-n-butyl phthalate [MnBP]) in prenatal maternal urine and children's urine at the age of 6, and body composition indices (body mass index [BMI] z-score, percentage of fat mass, fat mass index, percentage of skeletal muscle, and the skeletal muscle index [SMI]) measured when the child was 6 years using a bioelectrical impedance analyzer. RESULTS: A 2-fold increase in Σ DEHP and MnBP in the prenatal maternal urine was significantly associated with a -0.07 unit (95% CI: -0.11, -0.03) and -0.09 unit (95% CI: -0.14, -0.03) change in SMI, respectively, in 6-year old girls alone. BMI z-score was also negatively associated with a 2-fold increase in MEHHP and MnBP in prenatal maternal urine as -0.11 unit (95% CI: -0.22, -0.01) and -0.15 unit (95% CI: -0.28, -0.02) change, respectively, only among girls. Among boys, phthalate metabolites in the prenatal and children's urine were not significantly associated with any body composition indices. CONCLUSIONS: Our longitudinal study shows that high levels of prenatal exposure to phthalates are significantly associated with decreased SMI among girls. We can postulate that anti-androgenic effects of phthalates during pregnancy may affect girl offspring's muscle growth.

Prenatal exposure to mixtures of heavy metals and neurodevelopment in infants at 6 months.

BACKGROUND: Exposure to mixture of neurotoxic metals such as lead, mercury and cadmium occurs at a specific point of time. When exposed to metal mixtures, one metal may act as an agonist or antagonist to another metal. Thus, it is important to study the effects of exposure to a combination of metals on children's development using advance statistical methods. OBJECTIVES: In this study, we explored the effects of prenatal metal exposure including lead, mercury and cadmium in early pregnancy (12-20 weeks), late pregnancy (>28 weeks), and at birth on neurodevelopment of infants at 6 months of age. METHODS: We included 523 eligible mother-child pairs from the mothers and children environmental health (MOCEH) study, a prospective birth cohort study in Korea. We used linear regression, Bayesian kernel machine regression (BKMR) and generalized additive models (GAM), to evaluate the effects of exposure to metal mixtures on neurodevelopment of infants aged 6 months. The Korean version of Bayley scale of infant and toddler development-II was used to measure the child's neurodevelopment. RESULTS: Linear regression models showed a significant negative effect of lead exposure during late pregnancy on the mental development index (MDI) [ß = -2.51 (-4.92, -0.10)] scores of infants aged 6 months following co-exposure to mercury. Further, linear regression analysis showed a significant interaction between late pregnancy lead and mercury concentrations. BKMR analysis showed similar results as those obtained in linear regression models. These results were also replicated in the GAM. Stratification analysis showed that greater than 50 percentile concentration of mercury in late pregnancy potentiated the adverse effects of lead in late pregnancy on MDI [ß = -4.33 (-7.66, -1.00)] and psychomotor development index (PDI) [ß = -5.30 (-9.13, -1.46)] at 6 months of age. Prenatal cadmium exposure did not show a significant association with MDI and PDI at 6 months in the linear regression or BKMR analysis. CONCLUSION: Based on all the statistical methods used, we demonstrated the effect of combined exposure to metals on the neurodevelopment of infants aged 6 months, with significant interaction between lead and mercury.