Environmental Health Perspectives最新文献

Background: Toenails are promising biomarkers of long-term metal exposure in epidemiologic studies, but their accuracy may be compromised by systematic and random errors associated with heterogeneous toenail sample masses, as well as by substantial variability across laboratory batches.

Objectives: We propose a novel modeling approach to calibrate toenail metal concentrations for the heterogeneity in sample masses and the variability between batches.

Methods: We developed a heteroscedastic spline mixed model relating sample mass and laboratory batch with measured concentrations, allowing for an average bias in measurements over all batches as a smooth function of sample mass, random variation in mass-related biases across batches, and mass-related heterogeneity in within-batch error variance. The model allowed partitioning the total variance of measured concentrations into the extraneous variances (due to different sample masses and laboratory batches) and the intrinsic variance (resulting from distinct metal exposures). We derived calibrated metal concentrations from the model by removing both sources of extraneous variation and estimating the predicted concentrations had all toenail samples been analyzed in a single batch and of the same mass. We provide the R script COMET (COrrected METals) to fit the proposed model, extract variance components, and calibrate metal concentrations.

Results: In a multicase-control study in Spain (MCC-Spain) with toenail determinations for 16 metals in 4,473 incident cases of five common cancers and 3,450 population controls, sample mass and batch accounted for 26-60% of the total variance of measured concentrations for most metals. Compared with calibrated concentrations, odds ratios for measured concentrations were biased by > 10% toward or away from the null in one-quarter of the estimated metal-cancer associations.

Discussion: The proposed model allows correcting toenail metal concentrations for sample mass heterogeneity and between-batch variability, and could be applied to other biological specimens of heterogeneous size, distinct laboratory techniques, and different study designs. https://doi.org/10.1289/EHP14784.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, and increasing evidence suggests that exposure to environmental pollutants is associated with the increased incidence of MASLD. The farnesoid X receptor (FXR) plays an important role in the development of MASLD by regulating bile acids (BAs) and lipid metabolism. However, whether FXR-active pollutants are the environmental drivers of MASLD remains unclear.

Objectives: This study aimed to determine whether FXR-active pollutants exist in the environment and evaluate their ability to trigger MASLD development in mice.

Methods: An FXR protein affinity pull-down assay and nontargeted mass spectrometry analysis were used to identify environmental FXR ligands in sewage sludge. A homogeneous time-resolved fluorescence coactivator recruitment assay and cell-based dual-luciferase reporter assay were used to determine the FXR activities of the identified pollutants. Targeted analysis of BAs, mass spectrometry imaging, lipidomic analysis, 16S rRNA sequencing, and quantitative polymerase chain reaction were conducted to assess the ability of FXR-active pollutants to induce metabolic disorders of BAs and lipids and to contribute to MASLD development in C57BL/6N mice.

Results: We identified 19 compounds in the sewage sludge that had FXR-antagonistic activity, and triphenyl phosphate (TPHP) was the FXR antagonist with the highest efficacy. Mice exposed to either 10 or 50 mg/kg TPHP for 30 days had higher levels of conjugated primary BAs in enterohepatic circulation, and the BA pool showed FXR antagonistic activities. The exposed mice also had greater lipogenesis (more Oil Red O staining and high triglyceride levels) in liver.

Conclusions: 19 FXR-antagonistic pollutants were identified in sewage sludge. FXR inhibition by the strongest antagonist TPHP may have a role in promoting MASLD development in mice by inducing a positive feedback loop between the FXR and BAs. https://doi.org/10.1289/EHP15435.

Background: Environmental epidemiologists strive to conduct research that will lead to actions that improve public health outcomes. The risk assessment process is the bridge between scientific research and policies that can impact public health. Historically, epidemiologic studies have not frequently been used to inform U.S. Environmental Protection Agency (EPA) assessments outside of the context of air pollution. There are certain practices that can be adopted by the epidemiology community to facilitate the integration of epidemiologic studies into policy-relevant assessments.

Objectives: The central objective of this commentary is to provide guidance to epidemiologists that will enhance the value of their studies for EPA assessments. First, we provide an overview of EPA dose-response and toxicity value derivation to increase literacy about these processes across the environmental epidemiology community. Second, we provide suggestions for modeling and reporting to facilitate the use of epidemiologic studies in EPA dose-response assessments that form the basis for decision-making.

Discussion: Epidemiologic research can be utilized in all aspects of dose-response assessment, which involves identifying a point of departure followed by specific adjustments and/or extrapolations to identify a toxicity value intended to prevent adverse effects across the population. To facilitate integration of epidemiologic research into the dose-response assessment process, we provide specific recommendations for additional modeling (e.g., modeling in the low exposure range; exploring non-linearity) and reporting (e.g., sufficient information to conduct study evaluation; details on exposure levels in the population) in published epidemiologic research. Many of these suggestions require only additional reporting in the final manuscript or associated appendices but would have substantial impact on the contribution of the published work to the assessment process. https://doi.org/10.1289/EHP15203.

Background: Fine particulate matter (PM_2.5) is considered a major component of ambient particulate matter (PM). Exposure to PM_2.5 was shown to be related to male reproductive system injury. Ferroptosis is regarded as an iron-dependent programmed cell death, that is associated with the pathological process. It has been reported that SIRT1 has protective effects on the male reproductive system. However, the underlying mechanisms of exposure to PM_2.5 induced-testicular injury are still unexplored.

Objectives: In this study, we investigated the relationship between ferroptosis and male reproductive injury, after exposure to PM_2.5 and the role of SIRT1/HIF-1α signaling pathway in this process.

Methods: We established PM_2.5 exposure model in vivo and in vitro using Sertoli cell Sirt1 conditional knockout C57BL/6 (cKO) mice testes and primary Sertoli cells. Hematoxylin and eosin (H&E) staining were conducted to examine the histology of the mice testes. Sperm parameters and biotin tracer assay were conducted to evaluate the effects of exposure to PM_2.5 on the mice testes. Related markers and genes related to the blood-testis barrier (BTB) and ferroptosis were measured by real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and immunofluorescence assay. siRNA transfection was used to evaluate the potential mechanism.

Results: Significant pathological damage and lower sperm quality were detected in mice testes exposed to PM_2.5. We found that exposure to PM_2.5 damaged the blood-testis barrier (BTB) and inhibited the expression level of the BTB-related proteins (including Connexin 43, Occludin, Claudin 11, N-Cadherin and ZO-1). According to the enrichment analysis results, ferroptosis and HIF-1α signaling pathway were significantly enriched in mice testes and primary Sertoli cells exposed to PM_2.5. Subsequent experiments were conducted to verify the results of enrichment analysis and revealed differences in the expression levels of HIF-1α, ferroptosis-related genes (including GPX4, SLC7A11, ACSL4 and HO-1) and ferroptosis-related markers (including MDA, GSH and Fe²⁺), associated with lower expression of SIRT1 after exposure to PM_2.5. These results suggest that PM_2.5 exposure may be associated with ferroptosis and HIF-1α signaling pathway in male reproductive dysfunction.

Conclusions: Taken together, in vivo and in vitro experiments verified that PM_2.5 exposure in mice may lead to testicular dysfunction through new pathways. https://doi.org/10.1289/EHP14447.

Background: Plastic cutting boards are commonly used in food preparation, increasing human exposure to microplastics (MPs). However, the health implications are still not well understood.

Objectives: The objective of this study was to assess the impacts of long-term exposure to MPs released from cutting boards on intestinal inflammation and gut microbiota.

Methods: MPs were incorporated into mouse diets by cutting the food on polypropylene, polyethylene, and willow wooden cutting boards; diets were fed to mice over periods of 4 and 12 weeks. Serum levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), lipopolysaccharide (LPS, an endotoxin), and carcinoembryonic antigen (CEA), along with ileum and colon levels of IL-1β, TNF-α, malondialdehyde (MDA), superoxide dismutase (SOD), secretory immunoglobulin A (sIgA), and myosin light chain kinase (MLCK), were measured using mouse ELISA kits. The mRNA expression of mucin 2 and intestinal tight junction proteins in mouse ileum and colon tissues was quantified using real-time quantitative RT-PCR. Fecal microbiota, fecal metabolomics, and liver metabolomics were characterized.

Results: Polypropylene and polyethylene cutting boards released MPs, with concentrations reaching 1088 ± 95.0 and 1211 ± 322 µg g^-1 in diets, respectively, and displaying mean particle sizes of 10.4 ± 0.96 vs 27.4 ± 1.45 µm. Mice fed diets prepared on polypropylene cutting boards for 12 weeks exhibited significantly higher serum levels of LPS, CRP, TNF-α, IL-10, and CEA, as well as higher levels of IL-β, TNF-α, MDA, SOD, and MLCK in the ileum and colon compared to mice fed diets prepared on willow wooden cutting boards. These mice also showed lower relative expression of Occludin and Zonula occludens-1 in the ileum and colon. In contrast, mice exposed to diets prepared on polyethylene cutting boards for 12 weeks did not show evident inflammation; however, there was a significant decrease in the relative abundance of Firmicutes and an increase in Desulfobacterota compared to those fed diets prepared on willow wooden cutting boards, while exposure to diets prepared on polyethylene cutting boards over 12 weeks also altered mouse fecal and liver metabolites compared to those fed diets prepared on willow wooden cutting boards.

Discussion: The findings suggest that MPs from polypropylene cutting boards impaired intestinal barrier function and induced inflammation, whereas those from polyethylene cutting boards affected the gut microbiota, gut metabolism, and liver metabolism in the mouse model. These findings offer crucial insights into the safe use of plastic cutting boards. https://doi.org/10.1289/EHP15472.

Background: There are indications that fluoride exposure considered to be beneficial for dental health may not be safe from a neurodevelopmental perspective.

Objectives: To assess the impact of prenatal and childhood fluoride exposure on cognitive abilities at 5 and 10 years of age.

Methods: We studied 500 mother-child pairs from the MINIMat (Maternal and Infant Nutrition Interventions in Matlab) birth cohort in rural Bangladesh. Urinary fluoride concentrations were measured in the pregnant women at gestational week 8 and in their children at 5 and 10 years, using an ion-selective electrode and adjusting for specific gravity. Cognitive abilities were assessed using the Wechsler Preschool and Primary Scale for Intelligence-Third Edition and the Wechsler Intelligence Scale-Fourth Edition at age 5 and 10 years, respectively. Associations of urinary fluoride concentrations (log2-transformed) with cognitive abilities (raw scores) were assessed with multivariable-adjusted linear or spline regression models. Water fluoride concentrations were measured at the 10-year-old visit.

Results: Maternal urinary fluoride concentrations (median: 0.63 mg/L, 5th-95th percentiles: 0.26-1.41 mg/L) were inversely associated with full-scale raw scores at 5 and 10 years (B [95% confidence interval]: -2.8 [-5.1, -0.6] and -4.9 [-8.0, -1.8], respectively, by exposure doubling). In cross-sectional analysis at 10 years, child urinary fluoride (overall median: 0.66 mg/L, 5th-95th percentiles: 0.34-1.26 mg/L) above -0.47 on the log2-scale (corresponding to 0.72 mg/L) was inversely associated with full-scale raw scores (B [95% CI]: -12.1 [-21.2, -3.0]). The association at 5 years was also negative but non-significant. For both prenatal and childhood exposure, associations were most noticeable with perceptual reasoning, but also verbal scores. The estimate for the association between urinary fluoride at 10 years and perceptual reasoning became 18% lower after adjustment for prenatal exposure. Non consistent sex-specific differences were observed.

Conclusion: Urinary fluoride concentrations measured prenatally and during childhood (child urinary fluoride concentrations above -0.47 on the log2 scale (corresponding to 0.72 mg/L) were associated with lower cognitive abilities, especially perceptual reasoning and verbal abilities, in Bangladeshi children. https://doi.org/10.1289/EHP14534.

Background: Given the difficulty of collecting air pollution measurements for individuals, researchers use mobile monitoring to develop accurate models that predict long-term average exposure to air pollution allowing the investigation of its association with human health. While recent mobile monitoring studies focused on predictive models' abilities to select optimal designs, cost is also an important feature.

Objectives: This study aims to compare costs to predictive model performance for different mobile monitoring designs.

Methods: We used data on ultrafine particle stationary roadside mobile monitoring and associated costs collected by the Adult Changes in Thought Air Pollution (ACT-AP) study. By assuming a single-instrument, local monitoring, and constant costs of equipment and investigator oversight, we focused on the incremental cost of staff work days composed mostly of sampling drives and quality control procedures. The ACT-AP complete design included data collection from 309 sites, ~29 visits per site, during 4 seasons, every day of the week. We considered alternative designs by selecting subsets of fewer sites, visits, seasons, days of week, and hours of day. Then, we developed exposure prediction models from each alternative design and calculated cross-validation (CV) statistics using all observations from the complete design. Finally, we compared CV R²s and the numbers of staff work days from alternative designs to those from the complete design and demonstrate this exercise in a web application.

Results: For designs with less visits per site, the costs for number of work days were lower and model performance (CV R²) also worsened, but with mild decline above 12 visits per site. The costs were also less for designs with fewer sites when considering at least 100 sites, while the reduction in performance was minimal. For temporally-restricted designs that were constrained to have the same number of work days and thus the same cost, restrictions on the number of seasons, days of week, and/or hours of the day adversely impacted model performance.

Discussion: Our study provides practical guidance to future mobile monitoring campaigns that have the ultimate goal of assessing the health effect of long-term air pollution. Temporally-balanced designs with 12 visits per site are a cost-effective option that provide relatively good prediction accuracy with reduced costs. https://doi.org/10.1289/EHP15100.

Background: Emerging evidence has suggested negative associations between maternal urinary fluoride adjusted for specific gravity (MUFsg) and offspring IQ. Two prior studies report the MUFsg of pregnant women in the US, both in California, and more information is needed on population levels of MUFsg.

Objectives: The primary objective was to measure MUFsg in a large pregnancy cohort of women recruited from health departments and academic hospitals in Ohio and Kansas. A secondary objective was to compare associations between water fluoridation level and estimated fluoride intake from tap water, and MUFsg.

Methods: Pregnant women (n=965) from the ADORE (Assessment of DHA on Reducing Early Preterm Birth) cohort provided a urine sample and dietary assessment, at enrollment, between 14-20 weeks gestation. MUFsg was measured by fluoride-sensitive electrode and corrected for specific gravity. Water fluoridation levels were obtained for public water systems (PWS), matched to participant residence, and multiplied by their tap water intake from dietary assessment. The association between MUFsg and water fluoridation level was estimated using a generalized linear model with gamma distribution and log link.

Results: MUFsg (median: 1.0 mg/L, Q1, Q3: 0.6, 1.5) was correlated with PWS fluoridation (r_s=0.30, p<0.01) and self-reported tap water consumption (r_s=0.29, p<0.01). For 87% of the cohort, MUFsg was above the 0.45 mg/L safety benchmark for pregnancy proposed in a previous study. Similarly, 76.7% lived in areas with PWS fluoridation ≥0.7 mg/L. The median MUFsg (1.0 mg/L; Q1, Q3: 0.7, 1.5) of those living in areas with PWS fluoridation level ≥0.7 mg/L was higher than the median MUFsg (0.8 mg/L; Q1, Q3: 0.5, 1.2) of women living in areas with PWS fluoridation <0.7 mg/L (p<0.01).

Discussion: MUFsg in this population of midwestern US women exceeds the safety benchmark for pregnancy. While we cannot account for all sources of fluoride, MUFsg was correlated to PWS fluoridation. Because so many exceeded the safety benchmark for MUFsg, there is a need for MUFsg evaluation in other US regions, especially where the PWS fluoridation exceeds US Department of Health and Human Services recommendations (≥0.7 mg/L). https://doi.org/10.1289/EHP14711.

Background: Environmental contamination by endocrine disrupting chemicals (EDCs) has created serious public health, ecological, and regulatory concerns. Prenatal exposures can affect a wide range of developing organ systems and are associated with adverse changes to behavior, metabolism, fertility, and disease risk in the adult. The most serious and puzzling observation for some EDC exposures is the transmission of effects to subsequent unexposed generations (transgenerational effects) in animal models. This requires the induction of epigenetic aberrations to the germline that are not subject to the normal processes of erasure and resetting in subsequent generations. Understanding when and how the germline is vulnerable to environmental contaminants is an essential first step in devising strategies to prevent and reverse their effects.

Methods: Fetal mouse oocytes were collected after exposure of the dam to various concentrations of bisphenol A (BPA) or placebo. Meiotic effects were assessed by immunostaining to visualize the synaptonemal complex and recombination sites, as well as whole chromosome fluorescence in situ hybridization probes. Enriched oocyte pools were analyzed by mass spectrometry and RNA sequencing to determine differences in histone post-translational modifications and gene expression, respectively.

Results: We found germline effects across a wide range of exposure levels, the severity of which was positively associated with BPA concentration. We identified the onset of meiotic prophase as the vulnerable window of exposure and found surprising exposure-related differences in chromatin. Oocyte analysis by mass spectrometry and immunofluorescence suggested H4K20me2, a histone posttranslational modification involved in DNA damage repair, was particularly affected. Subsequent RNA-seq analysis revealed a relatively small number of differentially expressed genes, but in addition to genes involved in chromatin dynamics, several with important roles in DNA repair/recombination and centromere stability were affected.

Discussion: Together, our data from a mouse model suggest BPA exposure induced complex molecular differences in the germline that dysregulated chromatin and affected several critical and interrelated meiotic pathways. https://doi.org/10.1289/EHP15046.