Search

BACKGROUND: Evidence suggested that abiotic airborne exposures may be associated with changes in body composition. However, more evidence is needed to identify key pollutants linked to adverse health effects and their underlying biomolecular mechanisms, particularly in sensitive older adults. OBJECTIVES: Our research aimed to systematically assess the relationship between abiotic airborne exposures and changes in body composition among healthy older adults, as well as the potential mediating mechanisms through the serum lipidome. METHODS: From September 2018 to January 2019, we conducted a monthly survey among 76 healthy adults (60-69 years old) in the China Biomarkers of Air Pollutant Exposure (BAPE) study, measuring their personal exposures to 632 abiotic airborne pollutions using MicroPEM and the Fresh Air wristband, 18 body composition indicators from the InBody 770 device, and lipidomics from venous blood samples. We used an exposome-wide association study (ExWAS) and deletion/substitution/addition (DSA) model to unravel complex associations between exposure to contaminant mixtures and body composition, a Bayesian kernel machine regression (BKMR) model to assess the overall effect of key exposures on body composition, and mediation analysis to identify lipid intermediators. RESULTS: The ExWAS and DSA model identified that 2,4,5-T methyl ester (2,4,5-TME), 9,10-Anthracenedione (ATQ), 4b,8-dimethyl-2-isopropyl-phenanthrene, and 4b,5,6,7,8,8a,9,10-octahydro-(DMIP) were associated with increased body fat mass (BFM), fat mass indicators (FMI), percent body fat (PBF), and visceral fat area (VFA) in healthy older adults [Bonferroni-Hochberg false discovery rate ([FDR.sub.BH]) < 0.05]. The BKMR model demonstrated a positive correlation between contaminants (anthracene, ATQ, copaene, di-epi-a-cedrene, and DMIP) with VFA. Mediation analysis revealed that phosphatidylcholine [PC, PC(16:1e/18:1), PC(16:2e/18:0)] and sphingolipid [SM, SM(d18:2/24.1)] mediated a significant portion, ranging from 12.27% to 26.03% (p-value DISCUSSION: Based on the evidence from multiple model results, ATQ and DMIP were statistically significantly associated with the increased VFA levels of healthy older adults, potentially regulated through lipid intermediators. These findings may have important implications for identifying potentially harmful environmental chemicals and developing targeted strategies for the control and prevention of chronic diseases in the future, particularly as the global population is rapidly aging. https://doi.org/10.1289/EHP13865, Introduction The global population is currently undergoing a notable aging trend, primarily driven by declining fertility rates and increased life expectancy. (1) This demographic shift is evident as the number [...]

BACKGROUND: Environmental contaminants (ECs) are increasingly recognized as crucial drivers of dyslipidemia and cardiovascular disease (CVD), but the comprehensive impact spectrum and interlinking mechanisms remain uncertain. OBJECTIVES: We aimed to systematically evaluate the association between exposure to 80 ECs across seven divergent categories and markers of dyslipidemia and investigate their underpinning biomolecular mechanisms via an unbiased integrative approach of internal chemical exposome and multi-omics. METHODS: A longitudinal study involving 76 healthy older adults was conducted in Jinan, China, and participants were followed five times from 10 September 2018 to 19 January 2019 in 1-month intervals. A broad spectrum of seven chemical categories covering the prototypes and metabolites of 102 ECs in serum or urine as well as six serum dyslipidemia markers [total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein (Apo)A1, ApoB, and ApoE4] were measured. Multi-omics, including the blood transcriptome, serum/urine metabolome, and serum lipidome, were profiled concurrently. Exposome-wide association study and the deletion/substitution/addition algorithms were applied to explore the associations between 80 EC exposures detection frequency >50% and dyslipidemia markers. Weighted quantile sum regression was used to assess the mixture effects and relative contributions. Multi-omics profiling, causal inference model, and pathway analysis were conducted to interpret the mediating biomolecules and underlying mechanisms. Examination of cytokines and electrocardiograms was further conducted to validate the observed associations and biomolecular pathways. RESULTS: Eight main ECs [1-naphthalene, 1-pyrene, 2-fluorene, dibutyl phosphate, tri-phenyl phosphate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, chromium, and vanadium] were significantly associated with most dyslipidemia markers. Multi-omics indicated that the associations were mediated by endogenous biomolecules and pathways, primarily pertinent to CVD, inflammation, and metabolism. Clinical measures of cytokines and electrocardiograms further cross-validated the association of these exogenous ECs with systemic inflammation and cardiac function, demonstrating their potential mechanisms in driving dyslipidemia pathogenesis. DISCUSSION: It is imperative to prioritize mitigating exposure to these ECs in the primary prevention and control of the dyslipidemia epidemic. https://doi.org/10.1289/EHP13864, Introduction Cardiovascular disease (CVD) is the world's leading cause of disability and death, responsible for 18.6 million deaths globally in 2019. (1) Over the past four decades, the socioeconomic burdens [...]

Background: Organophosphate esters (OPEs) are common endocrine-disrupting chemicals, and OPE exposure may be associated with type 2 diabetes (T2D). However, greater knowledge regarding the biomolecular intermediators underlying the impact of OPEs on T2D in humans are needed to understand biological etiology. Objectives: We explored the associations between OPE exposure and glycometabolic markers among older Chinese adults 60- 69 years of age to elucidate the underlying mechanisms using a multi-omics approach. Methods: This was a longitudinal panel study comprising 76 healthy participants 60-69 years of age who lived in Jinan city of northern China. The study was conducted once every month for 5 months, from September 2018 to January 2019. We measured a total of 17 OPEs in the blood, 11 OPE metabolites in urine, and 4 glycometabolic markers (fasting plasma glucose, glycated serum protein, fasting insulin, and homeostatic model assessment for insulin resistance). The blood transcriptome and serum/urine metabolome were also evaluated. The associations between individual OPEs and glycometabolic markers were explored. An adverse outcome pathway (AOP) was established to determine the biomolecules mediating the associations. Results: Exposure to five OPEs and OPE metabolites (trimethylolpropane phosphate, triphenyl phosphate, tri-iso- butyl phosphate, dibutyl phosphate, and diphenyl phosphate) was associated with increased levels of glycometabolic markers. The mixture effect analysis further indicated the adverse effect of OPE mixtures. Multi-omics analyses revealed that the endogenous changes in the transcriptional and metabolic levels were associated with OPE exposure. The putative AOPs model suggested that triggers of molecular initiation events (e.g., insulin receptor and glucose transporter type 4) with subsequent key events, including disruptions in signal transduction pathways (e.g., phosphatidylinositol 3- kinase/protein kinase B and insulin secretion signaling) and biological functions (glucose uptake and insulin secretion), may constitute the diabetogenic effects of OPEs. Discussion: OPEs are associated with the elevated risk of T2D among older Chinese adults 60-69 years of age. Implementing OPE exposure reduction strategies may help reduce the T2D burden among these individuals, if the relationship is causal. https://doi.org/10.1289/EHP11896, Introduction Diabetes mellitus, mainly type 2 diabetes (T2D), is one of the four most prevalent noncommunicable diseases. (1,2) In 2021, 536.6 (10.5%) million adults 20-79 years of age worldwide were [...]

Background: Phthalates may disturb metabolic homeostasis in the liver by interfering with the peroxisome proliferator-activated receptors (PPARs). However, the role of hepatic macrophages in the lipid metabolic dysregulation induced by diethylhexyl phthalate (DEHP) remains unclear. Objectives: We aimed to evaluate the respective role of hepatocyte- and macrophage-specific PPAR[gamma] in the hepatotoxicity induced by DEHP. Methods: Wild-type (WT), hepatocyte-specific PPAR[gamma] knockout (Hep-KO), and macrophage-specific PPAR knockout (Mac-KO) mice were administered DEHP (625 mg/kg body weight) by daily gavage for 28 d, followed by hepatotoxicity examination and macrophage analysis. RNA sequencing and lipid metabolomic analysis were used to characterize the molecular changes in mouse liver. Mouse bone marrowderived macrophages (BMDMs) and human monocytic THP-1 cell-derived macrophages were used to investigate the mechanistic regulation of macrophages' polarization by DEHP and mono(2-ethylhexyl) phthalate (MEHP). Results: The levels of hepatic steatosis and triglyceride were significantly higher in the mice treated with DEHP compared with the control mice in the WT and Hep-KO model. Lipid accumulation induced by DEHP was notably attenuated in the Mac-KO mice, but M2-polarization of hepatic macrophages in the Mac-KO mice was significantly higher compared with the WT mice under DEHP treatment. The M2-polarization of BMDMs and human macrophages was suppressed by DEHP and MEHP. Transcriptomic and lipidomic data suggested lower levels of lipid biosynthesis, fatty acid oxidation, and oxidative phosphorylation in the Mac-KO mice compared with the WT and Hep-KO mice under DEHP treatment. Conclusions: Our data suggested that the orchestrated activation of PPAR[alpha] and PPAR[gamma] by MEHP may reprogram hepatic macrophages' polarization, thereby affecting lipid homeostasis in the mouse liver. Although this conclusion was based on studies conducted in mice and in vitro, these findings may aid in elucidating the health effect of environmental phthalate exposure. https://doi.org/10.1289/EHP9373, Introduction Phthalates are widely used as industrial plasticizers in the manufacture of plastics, resins, rubbers, paints, emulsifiers, medical devices, personal care products, and so on. Diethylhexyl phthalate (DEHP) is the [...]

Background: Thousands of per- and polyfluoroalkyl substances (PFAS) with diverse structures have been detected in the ambient environment. Apart from a few well-studied PFAS, the structure-related toxicokinetics of a broader set of PFAS remain unclear. Objectives: To understand the toxicokinetics of PFAS, we attempted to characterize the metabolism pathways of 74 structurally diverse PFAS samples from the U.S. Environmental Protection Agency's PFAS screening library. Methods: Using the early life stages of zebrafish (Danio rerio) as a model, we determined the bioconcentration factors and phenotypic toxicities of 74 PFAS. Then, we applied high-resolution mass spectrometry-based nontargeted analysis to identify metabolites of PFAS in zebrafish larvae after 5 d of exposure by incorporating retention time and mass spectra. In vitro enzymatic activity experiments with human recombinant liver carboxylesterase (hCES1) were employed to validate the structure-related hydrolysis of 11 selected PFAS. Results: Our findings identified five structural categories of PFAS prone to metabolism. The metabolism pathways of PFAS were highly related to their structures as exemplified by fluorotelomer alcohols that the predominance of [beta]-oxidation or taurine conjugation pathways were primarily determined by the number of hydrocarbons. Hydrolysis was identified as a major metabolism pathway for diverse PFAS, and perfluoroalkyl carboxamides showed the highest in vivo hydrolysis rates, followed by carboxyesters and sulfonamides. The hydrolysis of PFAS was verified with recombinant hCES1, with strong substrate preferences toward perfluoroalkyl carboxamides. Conclusions: We suggest that the roadmap of the structure-related metabolism pathways of PFAS established in this study would provide a starting point to inform the potential health risks of other PFAS. https://doi.org/10.1289/EHP7169, Introduction Per- and polyfluoroalkyl substances (PFAS) have been widely used in textiles, firefighting foams, and surface coatings in the past decades (Giesy and Kannan 2002; Houde et al. 2011; Lau [...]

BACKGROUND: Research on the relationship between long-term exposure to particulate matter with aerodynamic diameter [less than or equal to] 2.5 [micro]m (P[M.sub.2.5]) and poor cognitive function is lacking in developing countries, especially in highly polluted areas. OBJECTIVES: We evaluated associations of long-term exposure to P[M.sub.2.5] with poor cognitive function in a diverse, national sample of older adults in China. METHODS: This analysis included data on 13,324 older adults (5,879 who were 65-79 years of age, 3,052 who were 80-89 years of age, 2,634 who were 90-99 years of age, and 1,759 who were [greater than or equal to] 100 years of age) with normal cognitive function at baseline from March 2002 to September 2014, with 64,648 person-years of follow-up. We used a geographic information system analysis to estimate the annual average satellite-derived P[M.sub.2.5] concentration for the geocoded location of the participants' baseline residences. Poor cognitive function was defined as a score of less than 18 on the Chinese version of the Mini-Mental State Examination (MMSE). Competing risk models were performed to explore the association of P[M.sub.2.5] with poor cognitive function. RESULTS: Each 10-[micro]g/[m.sup.3] increase in P[M.sub.2.5] was associated with a 5.1% increased risk of poor cognitive function [adjusted hazard ratio (HR): 1.051; 95% confidence interval (CI): 1.023, 1.079]. Compared to the lowest quartile of P[M.sub.2.5] ( CONCLUSION: P[M.sub.2.5] was identified as a risk factor for poor cognitive function in Chinese older adults. Improving air quality may reduce the future population burden of poor cognitive function, especially in areas with high air pollution. https://doi.org/10.1289/EHP5304, Introduction The aging population is projected to continuously increase in developed and developing parts of the world (Gerland et al. 2014). With the decline in fertility and mortality rates, China [...]

Breeding of the poorly known Snowy-cheeked Laughingthrush (Garrulax sukatschewi) was studied in a conifer-dominated forest at Lianhuashan (southern Gansu), China. Snowy-cheeked Laughingthrushes nested at sites with fewer conifers and denser shrubs compared with the available vegetation. Bowl-shaped nests were 2.4 [+ or -] 0.1 m ([bar.x] [+ or -] SE, n = 31) above ground in six plant species. Spruce (Picea spp.) was used (74%) more often than expected based on availability at nest sites. The breeding season (early May to mid Jul) was shorter than for other timaliids. Twelve of 20 (60%) nests with known outcomes were successful. The average clutch size was 3.5 [+ or -] 0.2 eggs (2-5, n = 21) with 2.7 [+ or -] 0.2 hatchlings (2-4, n = 15) and 2.2 [+ or -] 0.2 fledglings (1-3, n = 12) per nest. Incubation was by both males and females and lasted 14 days (n = 1); both parents cared for the nestlings for 16-18 days (n = 3). Received 5 April 2010. Accepted 12 August 2010., The Snowy-cheeked Laughingthrush (Garrulax sukatschewi) is largely restricted to a range of 28,500 [km.sup.2] in the Min Shan Mountains of southern Gansu and northcentral Sichuan, China at elevations of 2,000-3,500 [...]

We describe the nest sites, nests, eggs, and incubation and provisioning behavior of the endemic Giant Laughingthrush (Garrulax maximus) in a coniferous forest (2,850-2,950 m asl) at Lianhuashan, southern Gansu, central China. We found seven shallow bowl-shaped nests in Picea-Abies trees, 4.0 ± 1.5 m ([bar.x] ± SD, n = 7) above the ground during May and June 2003, 2007, and 2008. Clutch size was 2.2 ± 0.4 unspotted blue eggs (2-3, n = 6) of which 1.4 ± 0.5 nestlings hatched (1-2, n = 7), and 1.0 ± 1.0 young fledged (0-2, n = 7). Three nests failed, possibly due to predation or abandonment during prolonged rainfall. Both males and females incubated clutches; nest attentiveness during the day decreased from 92.6 ± 0.9% before hatching to 59.4 ± 1.5% during days 3-7 of the nestling period. Both parents fed the nestlings (1.0 ± 1.0 times/hr) and consumed the feces (0.3 ± 0.5 times/hr) during the 7-15 days after hatching, The endemic Giant Laughingthrush (Garrulax maximus) is distributed from southern Gansu and southeastern Qinghai to southern and southeastern Tibet and northern Yunnan in southern and central China (Zheng 2005, Thompson [...]

The role of sialic acid-binding epitope of myelin-associated glycoprotein (MAG) on neurite outgrowth was demonstrated through site-directed mutagenesis. Results show that the neurite inhibitory activity of MAG is distinct from its sialic acid site since by itself, sialic acid binding is not sufficient to effect inhibition of axonal growth. MAG's sialic acid-dependent binding is lost when it is mutated to either aspartic acid or alanine. Meanwhile MAG retains its ability to inhibit axonal regeneration when it is expressed at the surface of either Schwann or Chinese hamster ovary cells.

Neurotrophic factors such as nerve growth factor (NGF) promote a wide variety of responses in neurons including differentiation, survival plasticity, and repair. Such actions often require changes in gene expression. To identify the regulated genes and thereby to more fully understand the NGF mechanism, we carried out serial analysis of gene expression (SAGE) profiling of transcripts derived from rat PC12 cells before and after NGF-promoted neuronal differentiation. Multiple criteria supported the reliability of the profile. Approximately 157,000 SAGE tags were analyzed, representing at least 21,000 unique transcripts. Of these, nearly 800 were regulated by 6-fold or more in response to NGF. Approximately 150 of the regulated transcripts have been matched to named genes, the majority of which were not previously known to be NGF-responsive. Functional categorization of the regulated genes provides insight into the complex, integrated mechanism by which NGF promotes its multiple actions. It is anticipated that as genomic sequence information accrues the data derived here will continue to provide information about neurotrophic factor mechanisms.