Zhenjiang Li

BACKGROUND: Emerging omics approaches, including metabolomics and proteomics, can be integrated into obesity treatment for better blood pressure management. We tested whether preoperative metabolomic and proteomic profiles predict long-term elevated blood pressure (EBP) changes better than known risk factors in adolescents undergoing bariatric surgery. METHODS: We included 108 participants from the Teen-LABS (Teen-Longitudinal Assessment of Bariatric Surgery). Plasma untargeted metabolomics (via liquid chromatography with high-resolution mass spectrometry) and Olink proteomics were assessed pre surgery. An elastic net model with stability selection was used to identify features predictive of EBP reductions 5 years post surgery. Models including identified metabolites, proteins, and known risk factors (age, sex, race, clinical sites, parents’ education level, body mass index, systolic blood pressure, and diastolic blood pressure at baseline) were compared with known-risk-factors-only models. For biological relevance, the consistency of association directions was examined in a multiethnic non-interventional adolescent cohort (n=79). RESULTS: Metabolite-based models and protein-based models with known risk factors each outperformed known-risk- factors-only models in predicting EBP reductions ( P <0.01). Higher levels of 4 metabolites (uric acid, taurocholic acid, nonadecanoic acid, and cystine) were consistently associated with reduced likelihood of EBP improvement or blood pressure improvement across cohorts. SERPINA11 (serine protease inhibitor, clade A, member 11), ICAM5 (intercellular adhesion molecule 5), and TINAGL1 (tubulointerstitial nephritis antigen-like 1) demonstrated consistent associations in both cohorts. CONCLUSIONS: This is the first study identifying potential preoperative biomarkers for EBP reductions in adolescents following bariatric surgery. Integrating metabolomics and proteomics with known risk factors substantially improved predictive models compared with known-risk-factors-only models. Larger and more diverse cohorts are needed to confirm these findings and whether identified features are associated with other blood pressure treatments.

Background: The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), particularly among pediatric populations, requires identification of modifiable risk factors to control disease progression. Per- and polyfluoroalkyl substances (PFAS) have emerged as potential contributors to liver damage; however, their role in MASLD remains underexplored. This study aimed to develop a translational framework integrating human and in vitro data to elucidate the effect of PFAS on MASLD development. Methods: We measured PFAS plasma levels in the Teen-LABS cohort (n = 136), comprising adolescents with obesity (mean age = 16.8 years) undergoing bariatric surgery. Plasma samples were also analyzed using proteomic and metabolomic assays. MASLD was diagnosed by liver biopsy examination. Human liver spheroids were exposed to perfluoroheptanoic acid (PFHpA) in vitro and analyzed by single-cell transcriptomics. The latent unknown clustering with integrated data (LUCID) model was employed to assess associations between PFHpA exposure, multiomic signatures, and MASLD risk. Results: Here we show that, among all PFAS measured, doubling of PFHpA levels is associated with an 80% higher MASLD risk (OR, 1.8; 95% CI: 1.3–2.5). Integrated human and in vitro analyses suggest dysregulation of pathways involved in inflammation and lipid metabolism. A distinct proteome profile is associated with significantly higher odds of MASLD (OR = 7.1). Conclusions: This study offers evidence implicating PFHpA, a short-chain unregulated PFAS congener, in MASLD development in adolescents, and highlights the critical role of protein dysregulation in disease pathogenesis. The molecular mechanisms identified here can inform the development of targeted prevention and treatment strategies.

Objective: Weight regain following bariatric surgery remains a clinical challenge, with limited understanding of contributing environmental factors. Per‐ and polyfluoroalkyl substances (PFAS), persistent chemicals linked to metabolic dysfunction, may influence long‐term weight trajectories. This study aimed to evaluate associations between PFAS exposure and changes in BMI, percent weight loss, and waist circumference among adolescents after bariatric surgery.Methods: We included 186 adolescents (mean age: 17.1 years; 76.3% female; 72.0% White) from the Teen‐Longitudinal Assessment of Bariatric Surgery (Teen‐LABS) cohort who underwent surgery between 2007 and 2012. Anthropometric measurements were collected at baseline and 6, 12, 36, and 60 months post surgery. Presurgical plasma concentrations of seven PFAS were measured using liquid chromatography–tandem mass spectrometry. Associations were estimated using linear mixed‐effects models and quantile g‐computation.Results: Higher concentrations of PFOS, PFHxS, and PFHpS were associated with greater BMI regain, reduced percent weight loss, and increased waist circumference from 1 to 5 years post surgery. At PFOS concentrations of 1.45 to 2.94 log₂ ng/mL, annual BMI regain increased from 1.34 to 1.84 kg/m² (p = 0.0497). Mixture analyses confirmed cumulative PFAS effects, with sulfonic acids showing the strongest associations.Conclusions: PFAS exposure was associated with weight regain after bariatric surgery in adolescents, potentially undermining long‐term metabolic benefits.Trial Registration: ClinicalTrials.gov identifier NCT00474318 image

Bariatric surgery is an intervention for severe obesity, leading to significant weight loss and metabolic improvements. However, the release of lipophilic chemicals accumulated in adipose tissue during weight loss presents a unique clinical challenge and research opportunity. Dichlorodiphenyldichloroethylene (DDE) is a persistent organic pollutant increasingly recognized as obesogen, while the biological mechanisms through which DDE influences body mass index (BMI) and waist circumference remain underexplored. We aimed to identify metabolic signatures mediating the association between DDE exposure and weight loss by plasma and adipose tissue metabolomics. We conducted a longitudinal study involving 60 adolescents with severe obesity undergoing bariatric surgery. We quantified p,p'-DDE concentrations in visceral adipose tissue collected during surgery and analyzed metabolic profiles from both adipose tissues collected at surgery and plasma samples collected at surgery, 6 months, 1 year, and 3 years postoperatively, using gas/liquid chromatography and high-resolution mass spectrometry. We used meet-in-the-middle approach coupled with a series of metabolome-wide association analyses to identify overlapping metabolite associated with both DDE exposure and weight loss outcomes. Our findings revealed that DDE concentrations in visceral adipose tissue are associated with significant alterations in metabolites locally in adipose tissue pre-surgery and systemically in plasma post-surgery. Eight plasma metabolites were significantly associated with DDE exposure over time, while 27 were associated with BMI. Notably, methylbutyroylcarnitine was identified as a potential mediator, showing a positive association with both exposure and outcome. Eight adipose tissue metabolites were associated with both DDE and longitudinal changes in plasma metabolites, suggesting an indirect pathway linking DDE and weight changes. These findings enhance our understanding of DDE's obesogenic effect. The involved metabolic changes could attenuate the efficacy of bariatric surgery in achieving sustained weight loss, underscoring the importance of integrating environmental health considerations into clinical practice. https://doi.org/10.1289/EHP16341.

The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), particularly among pediatric populations, requires identification of modifiable risk factors to control disease progression. Per- and polyfluoroalkyl substances (PFAS) have emerged as potential contributors to liver damage; however, their role in the etiology of MASLD remains underexplored. This study aimed to bridge the gap between human epidemiological data and in vitro experimental findings to elucidate the effect of perfluoroheptanoic acid (PFHpA), a short chain, unregulated PFAS congener on MASLD development. Our analysis of the Teen-LABS cohort, a national multi-site study on obese adolescents undergoing bariatric surgery, revealed that doubling of PFHpA plasma levels was associated with an 80% increase in MASLD risk (OR, 1.8; 95% CI: 1.3–2.5) based on liver biospies. To further investigate the underlying mechanisms, we used 3D human liver spheroids and single-cell transcriptomics to assess the effect of PFHpA on hepatic metabolism. Integrative analysis identified dysregulation of common pathways in both human and spheroid models, particularly those involved in innate immunity, inflammation, and lipid metabolism. We applied the latent unknown clustering with integrated data (LUCID) model to assess associations between PFHpA exposure, multiomic signatures, and MASLD risk. Our results identified a proteome profile with significantly higher odds of MASLD (OR = 7.1), whereas a distinct metabolome profile was associated with lower odds (OR = 0.51), highlighting the critical role of protein dysregulation in disease pathogenesis. A translational framework was applied to uncover the molecular mechanisms of PFAS-induced MASLD in a cohort of obese adolescents. Identifying key molecular mechanisms for PFAS-induced MASLD can guide the development of targeted prevention and treatment.

Persistent organic pollutants (POPs) are lipophilic environmental contaminants accumulated in the adipose tissue. Weight loss interventions, such as bariatric surgery, can mobilize POPs from adipose tissue into the bloodstream. We hypothesized that this mobilization could contribute to increases in blood pressure among 57 adolescents with severe obesity undergoing bariatric surgery. POPs and metabolic features were measured from visceral adipose tissue collected during surgery using gas and liquid chromatography, coupled with high-resolution mass spectrometry. Blood pressure was assessed at baseline, 6 months, and 5 years post-surgery. We used quantile g-computation to estimate associations of POP mixtures with blood pressure changes. With one quartile increase in POP mixtures, systolic blood pressure (SBP) increased by 6.4% five years after bariatric surgery compared to baseline SBP [95% confidence interval (CI): 0.4%, 12.4%]. The meet-in-the-middle approach identified overlapping metabolic features and pathways linking POP mixtures to SBP changes, highlighting the role of prostaglandin formation via arachidonic acid metabolism. POP mixtures were negatively associated with indole-3-acetate (-0.729, 95% CI: -1.234, -0.223), which was negatively associated with SBP changes at five years (-3.49%, 95% CI: -6.51%, -0.48%). Our findings suggested that lipophilic POP mixtures attenuated the beneficial effect of bariatric surgery on improved blood pressure among adolescents via alterations in lipid metabolism.

Objective: Dichlorodiphenyldichloroethylene (DDE), an obesogen accumulating in adipose tissue, is released into circulation with weight loss, although its impact is underexplored among adolescents. We tested the association using an integrative translational approach of epidemiological analysis among adolescents with obesity and in vitro measures exploring the impact of DDE on adipogenesis via preadipocytes.Methods: We included 63 participants from the Teen‐Longitudinal Assessment of Bariatric Surgery (Teen‐LABS) cohort. We assessed 4,4′‐DDE in visceral adipose tissue at surgery and BMI and waist circumference at surgery and 0.5, 1, 3, and 5 years after. We conducted longitudinal analysis to estimate the interaction on weight loss between DDE and time since surgery. In vitro analysis quantified adipogenic differentiation in commercial human preadipocytes exposed to 4,4′‐DDE via fluorescent staining and imaging.Results: A dose–response relationship was observed, with the low‐exposure group having a greater reduction in BMI during the first year compared to higher‐exposure groups and showing smaller regains compared to higher‐exposure groups after the first year. In vitro analysis of preadipocytes treated with 4,4′‐DDE during adipogenic differentiation for 12 days showed a concentration‐dependent increase in lipid accumulation.Conclusions: DDE could contribute to weight trajectory among adolescents undergoing bariatric surgery, potentially mediated via promoted adipogenesis in preadipocytes.

Fine particulate matter (PM_2.5) exposure has been found to be associated with Alzheimer disease (AD) and is hypothesized to cause inflammation and oxidative stress in the brain, contributing to neuropathology. The APOE gene, a major genetic risk factor of AD, has been hypothesized to modify the association between PM_2.5 and AD. However, little prior research exists to support these hypotheses. This study investigates the association between traffic-related PM_2.5 and AD hallmark pathology, including effect modification by APOE genotype, in an autopsy cohort. A cross-sectional study was conducted using brain tissue donors enrolled in the Emory Goizueta AD Research Center who died before 2020 (n = 224). Donors were assessed for AD pathology including the Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC) score. Traffic-related PM_2.5 concentrations were modeled for the metro-Atlanta area during 2002-2019 with a spatial resolution of 200-250 m. One-year, 3-year, and 5-year average PM_2.5 concentrations before death were matched to participants' home address. We assessed the association between traffic-related PM_2.5 and AD hallmark pathology and effect modification by APOE genotype, using adjusted ordinal logistic regression models. Among the 224 participants, the mean age of death was 76 years, and 57% had at least 1 APOE ε4 copy. Traffic-related PM_2.5 was significantly associated with the CERAD score for the 1-year exposure window (odds ratio [OR] 1.92; 95% CI 1.12-3.30) and the 3-year exposure window (OR 1.87; 95% CI 1.01-3.17). PM_2.5 was also associated with higher Braak stage and ABC score albeit nonsignificantly. The strongest associations between PM_2.5 and neuropathology markers were among those without APOE ε4 alleles (e.g., for the CERAD score and 1-year exposure window, OR 2.31; 95% CI 1.36-3.94), though interaction between PM_2.5 and APOE genotype was not statistically significant. Our study found traffic-related PM_2.5 exposure was associated with the CERAD score in an autopsy cohort, contributing to epidemiologic evidence that PM_2.5 affects β-amyloid deposition in the brain. This association was particularly strong among donors without APOE ε4 alleles. Future studies should further investigate the biological mechanisms behind this association.

INTRODUCTION: Growing evidence indicates that fine particulate matter (PM_2.5) is a risk factor for Alzheimer's disease (AD), but the underlying mechanisms have been insufficiently investigated. We hypothesized differential DNA methylation (DNAm) in brain tissue as a potential mediator of this association.METHODS: We assessed genome‐wide DNAm (Illumina EPIC BeadChips) in prefrontal cortex tissue and three AD‐related neuropathological markers (Braak stage, CERAD, ABC score) for 159 donors, and estimated donors’ residential traffic‐related PM_2.5 exposure 1, 3, and 5 years prior to death. We used a combination of the Meet‐in‐the‐Middle approach, high‐dimensional mediation analysis, and causal mediation analysis to identify potential mediating CpGs.RESULTS: PM_2.5 was significantly associated with differential DNAm at cg25433380 and cg10495669. Twenty‐four CpG sites were identified as mediators of the association between PM_2.5 exposure and neuropathology markers, several located in genes related to neuroinflammation.DISCUSSION: Our findings suggest differential DNAm related to neuroinflammation mediates the association between traffic‐related PM_2.5 and AD.Highlights: First study to evaluate the potential mediation effect of DNA methylation for the association between PM2.5 exposure and neuropathological changes of Alzheimer's disease. Study was based on brain tissues rarely investigated in previous air pollution research. Cg10495669, assigned to RBCK1 gene playing a role in inflammation, was associated consistently with 1‐year, 3‐year, and 5‐year traffic‐related PM2.5 exposures prior to death. Meet‐in‐the‐middle approach and high‐dimensional mediation analysis were used simultaneously to increase the potential of identifying the differentially methylated CpGs. Differential DNAm related to neuroinflammation was found to mediate the association between traffic‐related PM2.5 and Alzheimer's disease.