Bayesian Kernel Machine Regression Research Articles

Exploring Prenatal Exposure to Halogenated Compounds and Its Relationship with Birth Outcomes Using Nontarget Analysis.

Halogenated organic compounds (HOCs) are a class of contaminants showing high toxicity, low biodegradability, and high bioaccumulation potential, especially chlorinated and brominated HOCs (Cl/Br-HOCs). Knowledge gaps exist on whether novel Cl/Br-HOCs could penetrate the placental barrier and cause adverse birth outcomes. Herein, 326 cord blood samples were collected in a hospital in Jinan, Shandong Province from February 2017 to January 2022, and 44 Cl/Br-HOCs were identified with communicating confidence level above 4 based on a nontarget approach, covering veterinary drugs, pesticides, and their transformation products, pharmaceutical and personal care products, disinfection byproducts, and so on. To our knowledge, the presence of closantel, bromoxynil, 4-hydroxy-2,5,6-trichloroisophthalonitrile, 2,6-dibromo-4-nitrophenol, and related components in cord blood samples was reported for the first time. Both multiple linear regression (MLR) and Bayesian kernel machine regression (BKMR) models were applied to evaluate the relationships of newborn birth outcomes (birth weight, length, and ponderal index) with individual Cl/Br-HOC and Cl/Br-HOCs mixture exposure, respectively. A significantly negative association was observed between pentachlorophenol exposure and newborn birth length, but the significance vanished after the false discovery rate correction. The BKMR analysis showed that Cl/Br-HOCs mixture exposure was significantly associated with reduced newborn birth length, indicating higher risks of fetal growth restriction. Our findings offer an overview of Cl/Br-HOCs exposome during the early life stage and enhance the understanding of its exposure risks.

Association of Combined Per- and Polyfluoroalkyl Substances and Metals with Chronic Kidney Disease

Background: Exposure to environmental pollutants such as metals and Per- and Polyfluoroalkyl Substances (PFAS) has become common and increasingly associated with a decrease in the estimated Glomerular Filtration Rate (eGFR), which is a marker often used to measure chronic kidney disease (CKD). However, there are limited studies involving the use of both eGFR and the urine albumin creatinine ratio (uACR), which are more comprehensive markers to determine the presence of CKD and the complexity of pollutant exposures and response interactions, especially for combined metals and PFAS, which has not been comprehensively elucidated. Objective: This study aims to assess the individual and combined effects of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), Cadmium (Cd), Mercury (Hg), and Lead (Pb) exposure on CKD using data from the National Health and Nutritional Examination Survey (NHANES) 2017–2018. Methods: We employed the use of bivariate logistic regression and Bayesian Kernel Machine Regression (BKMR) in our analysis of the data. Results: Logistic regression results revealed a positive association between PFOA and CKD. Our BKMR analysis revealed a non-linear and bi-phasic relationship between the metal exposures and CKD. In our univariate exposure–response function plot, Cd and Hg exhibited a U and N-shaped interaction, which indicated a non-linear and non-additive relationship with both low and high exposures associated with CKD. In addition, the bivariate exposure–response function between two exposures in a mixture revealed that Cd had a U-shaped relationship with CKD at different quantiles of Pb, Hg, PFOA, and PFOS, indicating that both low and high levels of Cd is associated with CKD, implying a non-linear and complex biological interaction. Hg’s interaction plot demonstrated a N-shaped association across all quantiles of Cd, with the 75th quantile of Pb and the 50th and 75th quantiles of PFOA and PFOS. Furthermore, the PIP results underscored Cd’s consistent association with CKD (PIP = 1.000) followed by Hg’s (PIP = 0.9984), then PFOA and PFOS with a closely related PIP of 0.7880 and 0.7604, respectively, and finally Pb (PIP = 0.6940), contributing the least among the five environmental pollutants on CKD, though significant. Conclusions: Our findings revealed that exposure to environmental pollutants, particularly Hg and Cd, are associated with CKD. These findings highlight the need for public health interventions and strategies to mitigate the cumulative effect of PFAS and metal exposure and elucidate the significance of utilizing advanced statistical methods and tools to understand the impact of environmental pollutants on human health. Further research is needed to understand the mechanistic pathways of PFAS and metal-induced kidney injury and CKD, and longitudinal studies are required to ascertain the long-term impact of these environmental exposures.

Gender-specific abdominal fat distribution and insulin resistance associated with organophosphate esters and phthalate metabolites exposure

The worldwide prevalence of obesity highlights the potential contribution of endocrine-disrupting chemicals (EDCs). However, common epidemiological measures such as body mass index and waist circumference may misrepresent the intricate obesity risks these chemicals pose across genders. This study delves deeper into abdominal fat by differentiating between subcutaneous and visceral regions by analyzing data from National Health and Nutrition Examination Surveys (NHANES). We particularly investigated the gender-specific associations between organophosphorus flame-retardant metabolites (mOPFRs), phthalates (mPAEs) and accumulated fat indexes from 2536 people. Aiding by Bayesian Kernel Machine Regression (BKMR), we found while co-exposure to mOPFRs and mPAEs was linked to general and abdominal obesity across the entire and gender-specific populations, a gender-specific fat distribution emerged. For women, urinary BDCPP and MBzP were linked to an increased subcutaneous fat index (SFI) [BDCPP OR: 1.12 (95% CI: 1.03–1.21), MBzP OR: 1.09 (95% CI: 1.01–1.18)], but not to visceral fat index (VFI). These metabolites had a combined linkage with SFI, with BDCPP (weighting 22.0%) and DPHP (weighting 31.0%) being the most influential in Quantile g-computation model (qgcomp) model. In men, BCEP exposure exclusively associated with the elevated VFI [OR: 1.14 (95% CI: 1.03–1.26)], a trend further highlighted in mixture models with BCEP as the predominant association. Intriguingly, only males displayed a marked correlation between these metabolites and insulin resistance in subpopulation. An attempted mediation analysis revealed that elevated C-reactive protein mediated 12.1% of the association between urinary BCEP and insulin resistance, suggesting a potential role of inflammation. In conclusion, the gender-specific fat distribution and insulin resistance that associated with mOPFRs represented the potential risk of these chemicals to man.

Associations between single and multiple dietary vitamins and the risk of periodontitis: results from NHANES 2009–2014

BackgroundPeriodontitis is a prevalent inflammatory periodontal disease that has an impact on the overall quality of life. Although several studies have indicated an association between individual vitamin intake and periodontitis risk, the associations of the multivitamins with periodontitis risk remain unclear.AimThis study aimed to explore the joint effect of multivitamins (including vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, and vitamin K) on periodontitis.MethodsFor this cross-sectional study, data were collected from participants aged ≥ 30 years in the National Health and Nutrition Examination Surveys 2009–2014 (n = 9,820). We employed weighted multivariate logistic regression models to evaluate the single association between individual vitamin intakes and periodontitis, and Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression, and quantile g-computation (qgcomp) models to assess the joint effect of nine vitamins on periodontitis.ResultsThe overall prevalence of periodontitis was approximately 35.97%. After adjustment of covariates, vitamin B6 [odds ratio (OR) = 0.82, 95% confidence interval (CI): 0.72–0.94] and vitamin E (OR = 0.79, 95%CI: 0.69–0.92) were negatively related to the likelihood of developing periodontitis, respectively. The result of three models indicated that, mixture of vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, and vitamin K had a significant negative combined effect on the risk of periodontitis. In the BKMR model, when all remaining vitamins were at their median levels, the periodontitis risk decreased with increased concentration levels of vitamin E and vitamin B2. WQS analysis indicated the highest weighted chemical was vitamin E, followed by vitamin B12 and vitamin D. In the qgcomp model, vitamin E received the highest negative weights for the periodontitis risk, followed by vitamin B2 and vitamin D, respectively.ConclusionBoth dietary vitamin B6 and vitamin E were associated with decreased odds of periodontitis. Additionally, the mixture-exposed analyses consistently showed the negative correlations between nine dietary vitamins mixtures and periodontitis.

Association between exposure to multiple metals and stress urinary incontinence in women: a mixture approach.

There is limited evidence linking exposure to heavy metals, especially mixed metals, to stress urinary incontinence (SUI). This study aimed to explore the relationship between multiple metals exposure and SUI in women. The data were derived from the National Health and Nutrition Examination Survey (NHANES), 2007-2020. In the study, a total of 13 metals were analyzed in blood and urine. In addition, 5155 adult women were included, of whom 2123 (41.2%) suffered from SUI. The logistic regression model and restricted cubic spline (RCS) were conducted to assess the association of single metal exposure with SUI risk. The Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) were used to estimate the combined effect of multiple metals exposure on SUI. First, we observed that blood Pb, Hg and urinary Pb, Cd were positively related to SUI risk, whereas urinary W was inversely related by multivariate logistic regression (all p-FDR < 0.05). Additionally, a significant non-linear relationship between blood Hg and SUI risk was observed by RCS analysis. In the co-exposure models, WQS model showed that exposure to metal mixtures in blood [OR (95%CI) = 1.18 (1.06, 1.31)] and urine [OR (95%CI) = 1.18 (1.03, 1.34)] was positively associated with SUI risk, which was consistent with the results of BKMR model. A potential interaction was identified between Hg and Cd in urine. Hg and Cd were the main contributors to the combined effects. In summary, our study indicates that exposure to heavy metal mixtures may increase SUI risk in women.

Associations of metals and metal mixtures with glucose homeostasis: A combined bibliometric and epidemiological study

This study employs a combination of bibliometric and epidemiological methodologies to investigate the relationship between metal exposure and glucose homeostasis. The bibliometric analysis quantitatively assessed this field, focusing on study design, predominant metals, analytical techniques, and citation trends. Furthermore, we analyzed cross-sectional data from Beijing, examining the correlations between 14 blood metals and 6 glucose homeostasis markers using generalized linear models (GLM). Key metals were identified using LASSO-PIPs criteria, and Bayesian kernel machine regression (BKMR) was applied to assess metal mixtures, introducing an "Overall Positive/Negative Effect" concept for deeper analysis. Our findings reveal an increasing research interest, particularly in selenium, zinc, cadmium, lead, and manganese. Urine (27.6%), serum (19.0%), and whole blood (19.0%) were the primary sample types, with cross-sectional studies (49.5%) as the dominant design. Epidemiologically, significant associations were found between 9 metals—cobalt, copper, lithium, manganese, nickel, lead, selenium, vanadium, zinc—and glucose homeostasis. Notably, positive-metal mixtures exhibited a significant overall positive effect on insulin levels, and notable interactions involving nickel were identified. These finding not only map the knowlege landscape of research in this domain but also introduces a novel perspective on the analysis strategies for metal mixtures.

Long-term exposure to PM2.5 compositions and O3 and their interactive effects on DNA methylation of peripheral brain-derived neurotrophic factor promoter

ABSTRACT This study examined the associations of long-term exposure to ambient fine particulate matter (PM2.5) compositions/ozone with methylation of peripheral brain-derived neurotrophic factor (BDNF) promoters. A total of 101 participants were recruited from a cohort in Shijiazhuang, Hebei province, China. They underwent baseline and follow-up surveys in 2011 and 2015. DNA methylation levels were detected by bisulfite-PCR amplification and pyrosequencing. Participants‘ three-year average levels of PM2.5 compositions and ozone were estimated. Bayesian kernel machine regression (BKMR) models were used to examine the joint effects of pollutants on methylation levels. Exposure to PM2.5 compositions and ozone mixtures at the 75th percentile was associated with increased methylation levels at CpG2 of BDNF promoter (203%, 95% CI: 89, 316) than the lowest level of exposure, and sulfate dominated the effect in the BKMR models.Our findings provide clues to the epigenetic mechanisms for the associations of PM2.5 compositions and ozone with BDNF.

Pre-pregnancy ozone and ultrafine particulate matter exposure during second year of life associated with decreased cognitive and adaptive functioning at aged 2–5 years

BackgroundThis study sought to investigate the association of prenatal and early life exposure to a mixture of air pollutants on cognitive and adaptive outcomes separately in children with or without autism spectrum disorder (ASD). MethodsUtilizing data from the CHARGE case-control study (birth years: 2000–2016), we predicted daily air concentrations of NO2, O3, and particulate matter <0.1 μm (PM0.1), between 0.1 and 2.5 μm (PM0.1-2.5), and between 2.5 and 10 μm (PM2.5-10) using chemical transport models with ground-based monitor adjustments. Exposures were evaluated for pre-pregnancy, each trimester, and the first two years of life. Individual and combined effects of pollutants were assessed with Vineland Adaptive Behavior Scales (VABS) and Mullen Scales of Early Learning (MSEL), separately for children with ASD (n = 660) and children without ASD (typically developing (TD) and developmentally delayed (DD) combined; n = 753) using hierarchical Bayesian Kernel Machine Regression (BKMR) models with three groups: PM size fractions (PM0.1, PM0.1-2.5, PM2.5-10), NO2, and O3. ResultsPre-pregnancy Ozone was strongly negatively associated with all scores in the non-ASD group (group posterior inclusion probability (gPIP) = 0.83–1.00). The PM group during year 2 was also strongly negatively associated with all scores in the non-ASD group (gPIP = 0.59–0.93), with PM0.1 driving the group association (conditional PIP (cPIP) = 0.73–0.96). Weaker and less consistent associations were observed between PM0.1-2.5 during pre-pregnancy and ozone during year 1 and VABS scores in the ASD group. ConclusionsThese findings prompt further investigation into ozone and ultrafine PM as potential environmental risk factors for neurodevelopment.

First trimester plasma PER- AND Polyfluoroalkyl Substances (PFAS) and blood pressure trajectories across the second and third trimesters of pregnanacy

BackgroundEvidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) increases risk of high blood pressure (BP) during pregnancy. Prior studies did not examine associations with BP trajectory parameters (i.e., overall magnitude and velocity) during pregnancy, which is linked to adverse pregnancy outcomes. ObjectivesTo estimate associations of multiple plasma PFAS in early pregnancy with BP trajectory parameters across the second and third trimesters. To assess potential effect modification by maternal age and parity. MethodsIn 1297 individuals, we quantified six PFAS in plasma collected during early pregnancy (median gestational age: 9.4 weeks). We abstracted from medical records systolic BP (SBP) and diastolic BP (DBP) measurements, recorded from 12 weeks gestation until delivery. BP trajectory parameters were estimated via Super Imposition by Translation and Rotation modeling. Subsequently, Bayesian Kernel Machine Regression (BKMR) was employed to estimate individual and joint associations of PFAS concentrations with trajectory parameters – adjusting for maternal age, race/ethnicity, pre-pregnancy body mass index, income, parity, smoking status, and seafood intake. We evaluated effect modification by age at enrollment and parity. ResultsWe collected a median of 13 BP measurements per participant. In BKMR, higher concentration of perfluorooctane sulfonate (PFOS) was independently associated with higher magnitude of overall SBP and DBP trajectories (i.e., upward shift of trajectories) and faster SBP trajectory velocity, holding all other PFAS at their medians. In stratified BKMR analyses, participants with ≥ 1 live birth had more pronounced positive associations between PFOS and SBP velocity, DBP magnitude, and DBP velocity – compared to nulliparous participants. We did not observe significant associations between concentrations of the overall PFAS mixture and either magnitude or velocity of the BP trajectories. ConclusionEarly pregnancy plasma PFOS concentrations were associated with altered BP trajectory in pregnancy, which may impact future cardiovascular health of the mother.

Association between Per- and poly-fluoroalkyl substances and nonalcoholic fatty liver disease: a nested case-control study in northwest China

Per- and poly-fluoroalkyl substances (PFAS) have been reported to have hepatotoxic effects. However, it is unclear whether they are linked to non-alcoholic fatty liver disease (NAFLD). This nested case-control study focused on the epidemiological links between PFAS and the prevalence of NAFLD. We selected 476 new cases of NAFLD and 952 age- and sex-matched controls from the Jinchang cohort population between 2014 and 2019. Serum concentrations of PFAS were measured using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Only PFAS with a detection rate of ≥ 90 % were included for analysis, which included PFPeA, PFOA, PFNA, PFHxS, PFOS, and 9Cl-PF3ONS. The relationship between single and co-exposure to PFAS and the occurrence of NAFLD was evaluated using conditional logistic regression, Quantile g-computation (QgC), and Bayesian kernel machine regression (BKMR) model. Logistic regression indicated that PFPeA, PFOA, and 9Cl-PF3ONS were positive correlation with the incidence of NAFLD after adjusting for confounders, with odds ratios (OR) and 95 % confidence interval (CI) of 3.13 (95 % CI: 2.53, 3.86), 1.39 (95 % CI: 1.12, 1.73), and 1.41 (95 % CI: 1.20, 1.66), respectively. PFNA, PFHxS, and PFOS were nonlinearly and negatively associated with the incidence of NAFLD, with OR (95 % CI) of 0.53 (0.46, 0.62), 0.83 (0.73, 0.95), and 0.52 (0.44, 0.61), respectively. QgC showed a significant joint effect of PFAS on NAFLD onset (OR: 1.52, 95 % CI: 1.24, 1.88). BKMR showed a weak positive trend between PFAS mixtures and NAFLD incidence. Positive correlations were primarily driven by PFPeA and 9Cl-PF3ONS, while negative correlations were mainly influenced by PFNA and PFOS. The BKMR model also suggested that there was an interaction between PFOS and PFNA and other four PFAS compounds. In conclusion, our findings suggest that individual and co-exposure to PFAS is associated with a risk of NAFLD onset.

Association between phthalate metabolite mixture in neonatal cord serum and birth outcomes

Prenatal exposure to phthalates (PAEs) is ubiquitous among Chinese neonates. PAEs entering the body will be transformed to various hydrolyzed and oxidated PAE metabolites (mPAEs). PAEs and mPAEs exposure may lead to adverse birth outcomes through disruption of multiple hormone signaling pathways, induction of oxidative stress, and alterations in intracellular signaling processes. In this study, the concentrations of 11 mPAEs in 318 umbilical cord serum samples from neonates in Jinan were quantified with HPLC-ESI-MS. Multiple linear regression, Bayesian kernel machine regression, and quantile g-computation models were utilized to investigate the effects of both individual mPAE and mPAE mixture on birth outcomes. Stratified analysis was performed to explore whether these effects were gender-specific. mPAE mixture was negatively associated with birth length (BL) z-score, birth weight (BW) z-score, head circumference (HC) z-score, and ponderal index (PI). Mono(2-ethylhexyl) phthalate (MEHP) manifested negative associations with BL(z-score), BW(z-score), HC(z-score), and PI, whereas mono(2-carboxymethylhexyl) phthalate (MCMHP) was negatively associated with BW(z-score) and PI within the mPAE mixture. Stratified analysis revealed that the negative associations between mPAE mixture and four birth outcomes were attenuated in female infants, while the positive impact of mono(2-ethyl-5carboxypentyl) phthalate (MECPP) on BL(z-score) and BW(z-score) could be detected only in females. In summary, our findings suggest that prenatal exposure to phthalates may be associated with intrauterine growth restriction, and these effects vary according to the gender of the infant.

Exposure to heavy metallic and trace essential elements and risk of diminished ovarian reserve in reproductive age women: A case-control study

The associations between metallic elements and ovarian reserve function have remained uncertain yet. In this case-control study, we involved 149 women with diminished ovarian reserve (DOR) and 151 women with normal ovarian reserve, and assessed the levels of six heavy metallic (Cr, Cd, As, Hg, Pb, and Mn) and seven trace essential (Se, Fe, Zn, Co, Mo, Cu, I) elements in their follicular fluid with inductively coupled plasma mass spectrometry. Associations were examined with logistic regressions and Bayesian kernel machine regression (BKMR). As a result, we found that the medium and the highest tertiles of Pb were significantly associated with an increased likelihood of DOR compared to the lowest tertile, while the medium or/an the highest tertiles of Cu, I, and Fe showed significantly lower likelihoods of DOR compared to the lowest tertiles. Cu and Pb showed significantly non-linear associations with ovarian reserve markers such as follicle-stimulating, anti-mullerian hormone levels, and antral follicle count. With the rising overall concentrations of heavy metals, the likelihood of DOR increased although not significant. There was a trend of a "U-shaped" association across the whole concentration range of trace essential elements and the likelihood of DOR. Our study revealed that avoiding heavy metallic elements and properly supplementing trace essential elements are conducive to ovarian function.

Urinary phthalate/DINCH metabolites associations with kisspeptin and reproductive hormones in teenagers: A cross-sectional study from the HBM4EU aligned studies

BackgroundExposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated. ObjectiveTo investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies. MethodsIn 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed. ResultsThe LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): −2.8 (−4.2;-0.4); MEHP: −1.4 (−3.4,0.2)] and higher FSH [∑DINP: 11.8 (−0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [−4.28 (−8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: −12.22 (−21.09;-1.18); oxo-MEHP: −12.73 (−22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males. ConclusionWe observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH.

An association between PM2.5-related components and respiratory infectious diseases: A China's mainland-based study

The particulate matter with diameter of less than 2.5 µm (PM2.5) is an important risk factor for respiratory infectious diseases, such as scarlet fever, tuberculosis, and similar diseases. However, it is not clear which component of PM2.5 is more important for respiratory infectious diseases. Based on data from 31 provinces in mainland China obtained between 2013 and 2019, this study investigated the effects of different PM2.5 components, i.e., sulfate (SO42−), nitrate (NO3−), ammonium (NH4+), and organic matter (OM), and black carbon (BC), on respiratory infectious diseases incidence [pulmonary tuberculosis (PTB), scarlet fever (SF), influenza, hand, foot, and mouth disease (HFMD), and mumps]. Geographical probes and the Bayesian kernel machine regression (BKMR) model were used to investigate correlations, single-component effects, joint effects, and interactions between components, and subgroup analysis was used to assess regional and temporal heterogeneity. The results of geographical probes showed that the chemical components of PM2.5 were associated with the incidence of respiratory infectious diseases. BKMR results showed that the five components of PM2.5 were the main factors affecting the incidence of respiratory infectious diseases (PIP>0.5). The joint effect of influenza and mumps by co-exposure to the components showed a significant positive correlation, and the exposure-response curve for a single component was approximately linear. And single-component modelling revealed that OM and BC may be the most important factors influencing the high incidence of respiratory infections. Moreover, respiratory infectious diseases in southern and southwestern China may be less affected by the PM2.5 component. This study is the first to explore the relationship between different components of PM2.5 and the incidence of five common respiratory infectious diseases in 31 provinces of China, which provides a certain theoretical basis for future research.

Associations of multiple metals exposure with immunoglobulin levels in pregnant women: Hangzhou Birth Cohort Study

Metal may affect maternal immune function, but few epidemiological studies have reported the associations between multiple-metal exposure and maternal immunoglobulin (Ig) levels. Based on the Hangzhou Birth Cohort Study, 1059 participants were included, and eleven metals in whole blood samples and serum IgA, IgG, IgE and IgM levels were measured. Linear regression, quantile-based g-computation (QGC), and Bayesian kernel machine regression (BKMR) models were used to evaluate the associations. Compared with the first tertile of metal levels, arsenic (As) was negatively associated with IgE (β = -0.25, 95% confidence interval (CI) = -0.48 to -0.02). Moreover, significant associations of manganese (Mn) with IgA, IgG and IgM were demonstrated (β = 0.10, 95% CI = 0.04 to 0.18; β = 0.07, 95% CI = 0.03 to 0.12; β = 0.10, 95% CI = 0.03 to 0.18, respectively). Cadmium (Cd) were associated with higher levels of IgM. QGC models showed the positive association of the metal mixtures with IgA and IgG, with Mn playing a major role. Mn and Cd had positive contributions to IgM, while As had negative contributions to IgE. In the BKMR models, the latent continuous outcomes of IgA and IgG showed a significant increase when all the metals were at their 60th percentile or above compared to those at their 50th percentile. Therefore, exposure to metals was associated with maternal Igs, and mainly showed that Mn was associated with increased levels of IgA, IgG and IgM, and As was associated with low IgE levels.

Associations between synthetic phenols, phthalates, and placental growth/function: a longitudinal cohort with exposure assessment in early pregnancy

Abstract STUDY QUESTION Is exposure to environmental chemicals associated with modification of placental morphology and function? SUMMARY ANSWER Phthalates, a class of ubiquitous chemicals, showed an association with altered placental weight, placental vascular resistance and placental efficiency. WHAT IS KNOWN ALREADY Only a few epidemiological studies have assessed the effects of phenols and phthalates on placental health. Their results were affected by exposure measurement errors linked to the rapid excretion of these compounds and the reliance on a limited number of spot urine samples to assess exposure. STUDY DESIGN, SIZE, DURATION A prospective mother-child cohort with improved exposure assessment for non-persistent chemicals, recruited participants between 2014 and 2017. Sample size ranged between 355 (placental parameters measured at birth: placental weight and placental-to-fetal weight ratio: a proxy for placental efficiency) and 426 (placental parameters measured during pregnancy: placental thickness and vascular resistance). PARTICIPANTS/MATERIALS, SETTING, METHODS Phenols (four parabens, two bisphenols, triclosan and benzophenone-3), 13 phthalate metabolites, and two non-phthalate plasticizer metabolites were measured in within-subject pools of repeated urine samples collected during the 2nd and 3rd trimesters of pregnancy (median = 21 samples/trimester/woman). Placental thickness and placental vascular resistance (PVR) were measured during pregnancy. The placenta was weighed at birth and the placental-to-fetal-weight ratio (PFR) was computed. Both adjusted linear regression and Bayesian Kernel Machine Regression were used to evaluate associations between phenols and phthalates (alone or as mixture) and placental parameters. Effect modification by child sex was also investigated. MAIN RESULTS AND THE ROLE OF CHANCE Several phthalate metabolites were negatively associated with placental outcomes. Monobenzyl phthalate (MBzP) concentrations, during the 2nd and 3rd trimesters of pregnancy, were associated with a decrease in both placental weight at birth (β= -20.1 g [95% CI: -37.8; -2.5] and β= -17.4 g [95% CI: -33.2; -1.6], for 2nd and 3rd trimester, respectively) and PFR (β= -0.5 [95% CI: -1, -0.1] and β=-0.5 [95% CI: -0.9, -0.1], for 2nd and 3rd trimester, respectively). Additionally, MBzP was negatively associated with PVR during the 3rd trimester (β= -0.9 [95% CI: -1.8; 0.1]). Mono-n-butyl phthalate (MnBP), was negatively associated with PVR in both trimesters (β=-1.3, 95%IC: [-2.3, -0.2], and β=-1.2, 95%IC: [-2.4, -0.03], for 2nd and 3rd trimester, respectively). After stratification for child sex, ∑ diisononyl phthalate (DiNP) (either 2nd or 3rd trimester exposures, depending on the outcomes considered) was associated with decreased PVR in the 3rd trimester, as well as decreased placental weight and PFR in males. No associations were observed for phenol biomarkers. LIMITATIONS, REASONS FOR CAUTION False positives cannot be ruled out. Therefore, chemicals that were associated with multiple outcomes (MnBP and DiNP) or reported in existing literature as associated with placental outcomes (MBzP) should be considered as the main results. WIDER IMPLICATIONS OF THE FINDINGS Our results are consistent with in vitro studies showing that phthalates target peroxisome proliferator-activated receptor γ, in the family of nuclear receptors involved in key placental development processes such as trophoblast proliferation, migration, and invasion. In addition to placental weight at birth, we studied placental parameters during pregnancy, which could provide a broader view of how environmental chemicals affect maternal-fetal exchanges over the course of pregnancy. Our findings contribute to the increasing evidence indicating adverse impacts of phthalate exposure on placental health. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the French Research Agency—ANR (MEMORI project ANR-21-CE34-0022). The SEPAGES cohort was supported by the European Research Council (N°311765-E-DOHaD), the European Community’s Seventh Framework Programme (FP7/2007-206—N°308333-892 HELIX), the European Union’s Horizon 2020 research and innovation programme (N° 874583 ATHLETE Project, N°825712 OBERON Project), the French Research Agency—ANR (PAPER project ANR-12-PDOC-0029-01, SHALCOH project ANR-14-CE21-0007, ANR-15-IDEX-02 and ANR-15-IDEX5, GUMME project ANR-18-CE36-005, ETAPE project ANR-18-CE36-0005—EDeN project ANR-19-CE36-0003-01), the French Agency for Food, Environmental and Occupational Health &amp; Safety—ANSES (CNAP project EST-2016-121, PENDORE project EST-2016-121, HyPAxE project EST-2019/1/039, PENDALIRE project EST-2022-169), the Plan Cancer (Canc’Air project), the French Cancer Research Foundation Association de Recherche sur le Cancer—ARC, the French Endowment Fund AGIR for chronic diseases—APMC (projects PRENAPAR, LCI-FOT, DysCard), the French Endowment Fund for Respiratory Health, the French Fund—Fondation de France (CLIMATHES—00081169, SEPAGES 5–00099903, ELEMENTUM - 00124527). Nicolas Jovanovic was supported by a doctoral fellowship from University Grenoble Alpes. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT02852499.

Non-persistent Endocrine Disrupting Chemical Mixtures and Uterine Leiomyomata in the Study of Environment, Lifestyle and Fibroids (SELF)

BackgroundResults of studies investigating associations between individual endocrine-disrupting chemicals (EDCs) and incidence of uterine leiomyomata (UL), a hormone-dependent gynecological condition, have been inconsistent. However, few studies have evaluated simultaneous exposure to a mixture of EDCs with UL incidence. MethodsWe conducted a case-cohort analysis (n=708) of data from the Study of the Environment, Lifestyle and Fibroids (SELF), a prospective cohort study. Participants were aged 23-35 years at enrollment, had an intact uterus, and identified as Black or African American. We measured biomarker concentrations of 21 non-persistent EDCs, including phthalates, phenols, parabens, and triclocarban, in urine collected at baseline, 20-month, and 40-month clinic visits. We ascertained UL incidence and characteristics using ultrasounds at baseline and approximately every 20 months through 60 months. We used probit Bayesian Kernel Machine Regression (BKMR-P) to evaluate joint associations between EDC mixtures with cumulative UL incidence. We estimated the mean difference in the probit of UL incidence over the study period, adjusting for baseline age, education, years since last birth, parity, smoking status and body mass index. We converted probit estimates to odds ratios for ease of interpretation. ResultsWe observed that urinary concentrations of the overall EDC mixture were inversely associated with UL incidence in the overall mixtures model, with the strongest inverse associations at the 70th percentile of all biomarkers compared with their 50th percentile (odds ratio =0.59; 95% confidence interval: 0.36, 0.96). Strongest contributors to the joint association for the mixture were bisphenol S (BPS), ethyl paraben (EPB), bisphenol F (BPF) and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), which each demonstrated inverse associations except for MECPP. There was suggestive evidence of an interaction between MECPP and EPB. ConclusionIn this prospective ultrasound study, we observed evidence of an inverse association between the overall mixture of urinary biomarker concentrations of non-persistent EDCs with UL incidence.

Association between Multiple Trace Elements, Executive Function, and Cognitive Impairment with No Dementia in Older Adults.

Many studies suggest a significant association between individual essential trace elements (ETEs) and cognitive impairment in older adults, but evidence of the synchronized effect of multiple ETEs on cognitive function is lacking. We investigated the association between multiple ETEs, cognitive impairment with no dementia (CIND), and executive function in older Korean adults, using the Bayesian kernel machine regression (BKMR) model. Three hundred and thirty-six older adults were included as the study population and classified as the CIND and control groups. Blood manganese (Mn), copper (Cu), zinc (Zn), selenium (Se), and molybdenum (Mo) were measured as relevant ETEs. The frontal/executive tests included digit symbol coding (DSC), the Korean color word Stroop test (K-CWST), a controlled oral word association test (COWAT), and a trial-making test (TMT). Overall, the BKMR showed a negative association between multiple ETEs and the odds of CIND. Mn was designated as the most dominant element associated with the CIND (PIP = 0.6184), with a U-shaped relationship. Cu and Se levels were positively associated with the K-CWST percentiles (β = 31.78; 95% CI: 13.51, 50.06) and DSC percentiles (β = 25.10; 95% CI: 7.66, 42.53), respectively. Our results suggest that exposure to multiple ETEs may be linked to a protective mechanism against cognitive impairment in older adults.

Association of mixed polycyclic aromatic hydrocarbons exposure with oxidative stress in Korean adults

Polycyclic aromatic hydrocarbons (PAHs) are widespread pollutants associated with several adverse health effects and PAH-induced oxidative stress has been proposed as a potential mechanism. This study evaluated the associations of single and multiple PAHs exposure with oxidative stress within the Korean adult population, using serum gamma glutamyltransferase (GGT) as an oxidative stress marker. Data from the Second Korean National Environmental Health Survey (2012–2014) were analyzed. For analysis, 5225 individuals were included. PAH exposure was assessed with four urinary PAH metabolites: 1-hydroxyphenanthrene, 1-hydroxypyrene, 2-hydroxyfluorene, and 2-naphthol. After adjusting for age, sex, body mass index, drinking, passive smoking, and current smoking (model 1), as well as the presence of diabetes and hepatobiliary diseases (model 2), complex samples general linear model regression analyses for each metabolite revealed a significant positive association between Ln(1-hydroxyphenanthrene) and Ln(GGT) (model 1: β = 0.040, p < 0.01 and model 2: β = 0.044, p < 0.05). For the complete dataset (n = 4378), a significant positive association was observed between mixture of four urinary PAH metabolites and serum GGT in both the quantile g-computation and the Bayesian kernel machine regression analysis. Our study provides evidence for the association between mixed PAH exposure and oxidative stress.

The association of urinary heavy metal exposure with frailty susceptibility and mortality in middle-aged and older adults: a population-based study

Heavy metals’ presence as environmental pollutants has a close link to adverse health effects. Frailty, a clinical syndrome hallmarked by elevated vulnerability to stressors, presents a substantial challenge in healthcare. However, the association between exposure to heavy metals and frailty largely remains unexplored. Utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 2003–2018 and correlated with the U.S. National Death Index (NDI) from 2019, we investigated mortality outcomes. Logistic regression, Cox regression, Kaplan-Meier survival curves, weighted quantile-sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were employed to assess the association between heavy metal exposure and frailty incidence and mortality in the frail population. Eight metals were measured in urine using inductively coupled plasma mass spectrometry with values adjusted for urinary creatinine, which was used to reflect heavy metal exposure. The cohort incorporated 5370 female participants aged 45 and above, with 1518 diagnosed with frailty. The findings indicated a substantial correlation between exposure to specific heavy metals, namely tungsten (odds ratio [OR]: 1.94, 95% confidence interval [CI]: 1.31–2.89), cobalt (OR: 1.64, 95% CI: 1.40–1.93), cadmium (OR: 1.93, 95% CI: 1.52–2.43), and uranium (OR: 7.36, 95% CI: 1.53–35.28), and an elevated risk of frailty. WQS and BKMR regression models identified cadmium, cobalt, and tungsten as main contributors to frailty. Cox regression analysis, after adjustment for covariates, suggested that the higher the exposure levels to cadmium and lead, the higher the risk of death in frail patients, with associated hazard ratios (HR) of 95% CI: 1.96 (1.53, 2.52) and 1.30 (1.13, 1.49), respectively. Our study revealed a significant positive correlation between exposure to heavy metal mixtures and frailty onset in middle-aged and older adults, along with increased mortality in frail patients. Cobalt, cadmium, and tungsten emerged as prominent contributors to frailty, with cobalt and cadmium directly impacting the long-term life expectancy of frail patients.