Environmental pollutant risk factors for worse COVID-19 related clinical outcomes in predominately hispanic and latino populations.

BACKGROUND: Per- and poly-fluorinated compounds (PFAS) and heavy metals constitute two classes of environmental exposures with known immunotoxicant effects. In this pilot study, we aimed to evaluate the impact of exposure to heavy metals and PFAS on COVID-19 severity. We hypothesized that elevated plasma-PFAS concentrations and urinary heavy metal concentrations would be associated with increased odds of ICU admission in COVID-19 hospitalized individuals. METHODS: Using the University of Southern California Clinical Translational Sciences Institute (SC-CTSI) biorepository of hospitalized COVID-19 patients, urinary concentrations of 15 heavy metals and urinary creatinine were measured in n = 101 patients and plasma concentrations of 13 PFAS were measured in n = 126 patients. COVID-19 severity was determined based on whether a patient was admitted to the ICU during hospitalization. Associations of metals and PFAS with ICU admission were assessed using logistic regression models, controlling for age, sex, ethnicity, smoking status, and for metals, urinary dilution. RESULTS: The average age of patients was 55 ± 14.2 years. Among SC-CTSI participants with urinary measurement of heavy metals and blood measures of PFAS, 54.5% (n = 61) and 54.8% (n = 80) were admitted to the ICU, respectively. For heavy metals, we observed higher levels of Cd, Cr, and Cu in ICU patients. The strongest associations were with Cadmium (Cd). After accounting for covariates, each 1 SD increase in Cd resulted in a 2.00 (95% CI: 1.10-3.60; p = 0.03) times higher odds of admission to the ICU. When including only Hispanic or Latino participants, the effect estimates between cadmium and ICU admission remained similar. Results for PFAS were less consistent, with perfluorodecanesulfonic acid (PFDS) exhibiting a positive but non-significant association with ICU admission (Odds ratio, 95% CI: 1.50, 0.97-2.20) and perfluorodecanoic acid (PFDA) exhibiting a negative association with ICU admission (0.53, 0.31-0.88). CONCLUSIONS: This study supports the hypothesis that environmental exposures may impact COVID-19 severity.

Exposure to perfluoroalkyl substances and longitudinal changes in bone mineral density in adolescents and young adults: A multi-cohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) may impair bone development in adolescence, which impacts life-long bone health. No previous studies have examined prospective associations of individual PFAS and their mixture with bone mineral density (BMD) changes in Hispanic young persons, a population at high risk of osteoporosis in adulthood. OBJECTIVES: To examine associations of individual PFAS and PFAS mixtures with longitudinal changes in BMD in an adolescent Hispanic cohort and examine generalizability of findings in a mixed-ethnicity young adult cohort (58.4% Hispanic). METHODS: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n = 304; mean follow-up = 1.4 years) and young adults from the Southern California Children's Health Study (CHS; n = 137; mean follow-up = 4.1 years) were included in this study. Plasma PFAS were measured at baseline and dual x-ray absorptiometry scans were performed at baseline and follow-up to measure BMD. We estimated longitudinal associations between BMD and five PFAS via separate covariate-adjusted linear mixed effects models, and between BMD and the PFAS mixture via quantile g-computation. RESULTS: In SOLAR adolescents, baseline plasma perfluorooctanesulfonic acid (PFOS) was associated with longitudinal changes in BMD. Each doubling of PFOS was associated with an average -0.003 g/cm2 difference in change in trunk BMD per year over follow-up (95% CI: -0.005, -0.0002). Associations with PFOS persisted in CHS young adults, where each doubling of plasma PFOS was associated with an average -0.032 g/cm2 difference in total BMD at baseline (95% CI -0.062, -0.003), though longitudinal associations were non-significant. We did not find associations of other PFAS with BMD; associations of the PFAS mixture with BMD outcomes were primarily negative though non-significant. DISCUSSION: PFOS exposure was associated with lower BMD in adolescence and young adulthood, important periods for bone development, which may have implications on future bone health and risk of osteoporosis in adulthood.

Per- and polyfluoroalkyl substances, polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers and dysregulation of MicroRNA expression in humans and animals-A systematic review.

BACKGROUND: Persistent organic pollutants (POPs) are chemicals characterized by their environmental persistence. Evidence suggests that exposure to POPs, which is ubiquitous, is associated with microRNA (miRNA) dysregulation. miRNA are key regulators in many physiological processes. It is thus of public health concern to understand the relationships between POPs and miRNA as related to health outcomes. OBJECTIVES: This systematic review evaluated the relationship between widely recognized, intentionally manufactured, POPs, including per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (dichlorodiphenyltrichloroethane [DDT], dichlorodiphenyldichloroethylene [DDE], hexachlorobenzene [HCB]), with miRNA expression in both human and animal studies. METHODS: We used PubMed and Embase to systematically search the literature up to September 29th, 2023. Search results for human and animal studies were included if they incorporated at least one POP of interest in relation to at least one miRNA. Data were synthesized to determine the direction and significance of associations between POPs and miRNA. We utilized ingenuity pathway analysis to review disease pathways for miRNA that were associated with POPs. RESULTS: Our search identified 38 eligible studies: 9 in humans and 29 in model organisms. PFAS were associated with decreased expression of miR-19, miR-193b, and miR-92b, as well as increased expression of miR-128, miR-199a-3p, and miR-26b across species. PCBs were associated with increased expression of miR-15a, miR-1537, miR-21, miR-22-3p, miR-223, miR-30b, and miR-34a, as well as decreased expression of miR-130a and let-7b in both humans and animals. Pathway analysis for POP-associated miRNA identified pathways related to carcinogenesis. DISCUSSION: This is the first systematic review of the association of POPs with miRNA in humans and model organisms. Large-scale prospective human studies are warranted to examine the role of miRNA as mediators between POPs and health outcomes.

Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans. OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children. METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 17.1 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs. RESULTS: Plasma PFAS concentrations were associated with alterations in 475 miRNAs in the Teen-LABs study and 5 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis. CONCLUSION: Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.

Associations of per- and polyfluoroalkyl substances, polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers with oxidative stress markers: A systematic review and meta-analysis.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs) are intentionally produced persistent organic pollutants (POPs) that are resistant to environmental degradation. Previous in-vitro and in-vivo studies have shown that POPs can induce oxidative stress, which is linked to neurodegenerative diseases, cardiovascular diseases, and cancer. However, findings in epidemiological studies are inconsistent and an evidence synthesis study is lacking to summarize the existing literature and explore research gaps. OBJECTIVE: We evaluated the effects of PFAS, PCBs, OCPs, and PBDEs, on oxidative stress biomarkers in epidemiological studies. METHODS: A literature search was conducted in PubMed, Embase, and Cochrane CENTRAL to identify all published studies related to POPs and oxidative stress up to December 7th, 2022. We included human observational studies reporting at least one exposure to POPs and an oxidative stress biomarker of interest. Random-effects meta-analyses on standardized regression coefficients and effect direction plots with one-tailed sign tests were used for quantitative synthesis. RESULTS: We identified 33 studies on OCPs, 35 on PCBs, 49 on PFAS, and 12 on PBDEs. Meta-analyses revealed significant positive associations of α-HCH with protein carbonyls (0.035 [0.017, 0.054]) and of 4'4-DDE with malondialdehyde (0.121 [0.056, 0.187]), as well as a significant negative association between 2'4-DDE and total antioxidant capacity (TAC) (-0.042 [-0.079, -0.004]), all ß [95%CI]. Sign tests showed a significant positive association between PCBs and malondialdehyde (pone-tailed = 0.03). Additionally, we found significant negative associations of OCPs with acetylcholine esterase (pone-tailed = 0.02) and paraoxonase-1 (pone-tailed = 0.03). However, there were inconsistent associations of OCPs with superoxide dismutase, glutathione peroxidase, and catalase. CONCLUSIONS: Higher levels of OCPs were associated with increased levels of oxidative stress through increased pro-oxidant biomarkers involving protein oxidation, DNA damage, and lipid peroxidation, as well as decreased TAC. These findings have the potential to reveal the underlying mechanisms of POPs toxicity.

Plasma concentrations of lipophilic persistent organic pollutants and glucose homeostasis in youth populations.

BACKGROUND: Exposure to lipophilic persistent organic pollutants (POPs) is ubiquitous. POPs are metabolic disrupting chemicals and are potentially diabetogenic. METHODS: Using a multi-cohort study including overweight adolescents from the Study of Latino Adolescents at Risk (SOLAR, N = 301, 2001-2012) and young adults from the Southern California Children's Health Study (CHS, N = 135, 2014-2018), we examined associations of POPs and risk factors for type 2 diabetes. SOLAR participants underwent annual visits for a median of 2.2 years and CHS participants performed a single visit, during which a 2-h oral glucose tolerance test was performed. Linear mixed models were used to examine associations between plasma concentrations of POPs [4,4'-dichlorodiphenyldichloroethylene (4,4'-DDE), hexachlorobenzene (HCB), PCBs-153, 138, 118, 180 and PBDEs-154, 153, 100, 85, 47] and changes in glucose homeostasis across age and pubertal stage. RESULTS: In SOLAR, exposure to HCB, PCB-118, and PBDE-153 was associated with dysregulated glucose metabolism. For example, each two-fold increase in HCB was associated with approximately 2 mg/dL higher glucose concentrations at 30 min (p = 0.001), 45 min (p = 0.0006), and 60 min (p = 0.03) post glucose challenge. Compared to individuals with low levels of PCB-118, individuals with high levels exhibited a 4.7 mg/dL (p = 0.02) higher glucose concentration at 15 min and a 3.6 mg/dL (p = 0.01) higher glucose concentration at 30 min. The effects observed with exposure to organochlorine compounds were independent of pubertal stages. PBDE-153 was associated with the development of dysregulated glucose metabolism beginning in late puberty. At Tanner stage 4, exposure to PBDE-153 was associated with a 12.7 mg/dL higher 60-min glucose concentration (p = 0.009) and a 16.1 mg*dl-1*hr-1 higher glucose AUC (p = 0.01). These associations persisted at Tanner 5. In CHS, PBDE-153 and total PBDE were associated with similar increases in glucose concentrations. CONCLUSION: Our results suggest that childhood exposure to lipophilic POPs is associated with dysregulated glucose metabolism.

Combined Lateral Osseolabral Coverage Is Normal in Hips With Acetabular Dysplasia.

PURPOSE: To compare the lateral osseolabral coverage between groups of patients with different degrees of acetabular bony coverage using a magnetic resonance imaging parameter known as the combined lateral center-edge angle (cLCEA). METHODS: The cLCEA was measured among a consecutive series of patients presenting to a dedicated hip preservation surgeon with a magnetic resonance imaging scan. The cLCEA was measured using a coronal T1 or proton density image and was defined as the angle subtended by (1) a line through the center of the femoral head and orthogonal to the transverse line passing through the teardrops of both hips and (2) an oblique line drawn from the center of the femoral head to the free edge of the lateral acetabular labrum. The average difference between the lateral center-edge angle (LCEA) and the cLCEA was calculated and compared between groups based on acetabular bony coverage: dysplasia (LCEA <20°), borderline dysplasia (LCEA 20°-24.9°), normal coverage (LCEA 25°-39.9°), and overcoverage (LCEA ≥40°). RESULTS: In total, 341 patients (386 hips) were included. There were no significant differences in cLCEA between hips with normal acetabular coverage and dysplasia (P = .10) or borderline dysplasia (P = .46). Despite the large difference in mean LCEA between dysplasia (14.8° ± 3.9°) and acetabular overcoverage (43.1° ± 2.8°), the mean cLCEA values exhibited only a modest difference (44.7° ± 4.9° vs 52.7° ± 4.5°, respectively). Concordantly, hips with dysplasia exhibited the largest difference between mean LCEA and cLCEA (delta = 29.9° ± 4.7°) and hips with acetabular overcoverage had the smallest difference between measures (9.6° ± 5.2°). CONCLUSIONS: With decreasing acetabular bony coverage, there is increasing labral size such that the total osseolabral coverage, measured by the combined LCEA, remains equivalent between hips with normal acetabular coverage versus dysplasia. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Increased Prevalence of Femoroacetabular Impingement in Patients With Proximal Hamstring Tendon Injuries.

PURPOSE: To determine the prevalence of clinically diagnosed femoroacetabular impingement (FAI) in a consecutive series of patients presenting with proximal hamstring tendon injury and to correlate this with pelvic anatomic factors. METHODS: The prevalence of clinically symptomatic cam-, pincer-, and mixed-type and overall FAI was calculated among a consecutive series of patients presenting to a hip preservation clinic with a confirmed clinical and radiographic diagnosis of proximal hamstring tendon injury between 2012 and 2017. The presence of a cam lesion was determined by an alpha angle > 50° on radiographs and computed tomography radial sequences of the head-neck junction and a femoral head-neck offset ratio < 0.18. Clinical diagnoses of osseous impingement were determined according to accepted pathomorphologic signs and measurements. A diagnosis of FAI was confirmed by imaging findings of acetabular overcoverage for pincer-type FAI and the presence of an anterior or lateral cam lesion for cam-type FAI. RESULTS: Overall, 120 hips in 97 patients (mean age, 45 years) were included in this study. A clinical diagnosis of FAI was noted in 70.8% of hips (pincer-type 9.2%, cam-type 40.8%, mixed-type 20.8%), an approximate 2- to 7-fold increased prevalence in comparison with the general population from prior studies. CONCLUSIONS: The prevalence of FAI is high in patients with symptomatic proximal hamstring tendon pathology. Because FAI results in restriction of hip range of motion and altered pelvic tilt, future studies are warranted to investigate whether the presence of FAI acts as a predisposing factor for injury to the hamstring muscle complex. LEVEL OF EVIDENCE: Level IV, case series.

Quadriceps Tendon Autograft for Primary Anterior Cruciate Ligament Reconstruction: A Systematic Review of Comparative Studies With Minimum 2-Year Follow-Up.

PURPOSE: To systematically review the literature in an effort to compare outcomes of patients undergoing primary anterior cruciate ligament reconstruction (ACLR) with a quadriceps tendon (QT) autograft versus a bone-patellar tendon-bone (BPTB) or hamstring tendon (HT) autograft. METHODS: A systematic review was performed by searching PubMed, the Cochrane Library, and Embase to locate studies (Level of Evidence I-III) comparing the clinical outcomes of the QT autograft versus the BPTB or HT autograft in patients undergoing primary ACLR. Patients were evaluated based on graft failure rate, examination of knee laxity, and patient-reported outcome scores. RESULTS: Eight studies (1 Level II, 7 Level III) were identified that met inclusion criteria, including a total of 368 patients undergoing primary ACLR with a QT autograft, 225 with a BPTB autograft, and 150 with an HT autograft. The average follow-up duration for all patients was 2.9 years. Overall, 2.8% of patients (17/603) experienced graft failure. Within the studies that compared the QT versus BPTB autograft, no study found a significant difference in graft failure rate between groups, and the odds ratio for graft failure between QT and BPTB was found to be 1.58 (95% confidence interval: 0.49-5.07; P = .44). Within the studies that compared graft failure rate between the QT and HT autograft, none found significant differences between groups, although a meta-analysis was not performed because of a low number of trials. Two studies found significantly greater postoperative knee laxity in HT patients compared with QT patients (P < .05), although there were no significant differences found in laxity measurements between QT and BPTB patients. CONCLUSIONS: Patients undergoing primary ACLR with either a QT, BPTB, or HT autograft can all be expected to experience improvement in clinical outcomes. QT patients experienced less knee laxity postoperatively compared with HT patients, although no significant differences were found in graft failure rate between groups. LEVEL OF EVIDENCE: Level III, systematic review of Level II and III studies.

Standardizing the Prearthritic Hip Joint Space Width: An Analysis of 994 Hips.

PURPOSE: The purposes of this study were (1) to define a normal prearthritic hip joint space width (JSW) in symptomatic and asymptomatic patients with various degrees of acetabular coverage based on the lateral center edge angle (LCEA) and (2) to determine predictors of JSW using patient-specific variables. METHODS: In a consecutive series of patients presenting to a hip preservation clinic between July 2012 and April 2016, a standard weight-bearing anteroposterior pelvic view was obtained. JSW was defined as the distance between the bony contour of the acetabular rim and femoral head in 2 locations (lateral and medial weight-bearing zone). Hips with severe anatomic deformity, a Tönnis grade >0, or a lateral or medial JSW <2.5 mm were excluded. A linear mixed model analysis was performed in order to determine which variables (age, sex, side, height, weight, symptomatic/asymptomatic, LCEA, and clinical diagnosis) were significantly related to JSW. RESULTS: A total of 994 hips were included. LCEA was found to be a significant predictor of both the lateral and medial JSW, with a decreased JSW associated with increasing degrees of acetabular bony coverage (P < .02). A mean 0.9 mm (20%) difference in medial JSW was found between patients with frank dysplasia (LCEA <20°) compared with those with pincer-type FAI (LCEA ≥40°). There was no difference between symptomatic and asymptomatic hips, either for lateral (asymptomatic: 4.51 ± 0.83 mm; symptomatic: 4.52 ± 0.85 mm; P = .58) or medial JSW (asymptomatic: 4.02 ± 0.96 mm; symptomatic: 3.97 ± 0.84 mm; P = .49). CONCLUSIONS: The LCEA is a significant predictor of hip JSW, with the mean JSW decreasing with increasing degrees of acetabular bony coverage. Joint space is not a major factor in symptomatology in adults with prearthritic hip pain. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Beneficial Effects of Cooling during Constant Power Non-steady State Cycling.

This study compared the effects of cooling on the energetic and associated physiological and perceptual responses to constant power, non-steady state cycling. Twelve males cycled at their lactate threshold power for 60 min or until exhaustion under 3 conditions: wearing a cooling vest and sleeves (COOL), a synthetic shirt embedded with an active particle technology claimed to facilitate evaporative heat loss (EVAP), and a standard synthetic shirt (CON). When adjusted for time, the increase in gastrointestinal temperature from baseline was reduced during COOL and EVAP compared to CON (1.44±0.45 and 1.52±0.43 vs. 1.66±0.45°C, p<0.05). Sweat rate was reduced during COOL compared to EVAP and CON (1 312±331 vs. 1 525±393 and 1 550±548 mL·h-1, p<0.01). Gross efficiency decreased over time across conditions (p<0.01), but COOL attenuated this decrease by 22% compared to CON (p<0.05). The rating of perceived exertion was reduced during COOL and EVAP compared to CON (p<0.01). In conclusion, cooling using a vest and sleeves or wearing an active particle technology shirt reduced the rise in gastrointestinal temperature and rating of perceived exertion compared to a standard synthetic shirt. Cooling using a vest and sleeves also reduced the decrease in gross efficiency and sweat rate compared to wearing the standard synthetic shirt.

Haemoglobin mass alterations in healthy humans following four-day head-down tilt bed rest.

NEW FINDINGS: What is the central question of this study? Is haemoglobin mass (Hbmass) decreased following 4 days of head-down tilt bed rest (HDTBR), and does increased red blood cell (RBC) destruction mediate this adaptation? What is the main finding and its importance? Haemoglobin mass was increased immediately following HDTBR, before decreasing below baseline 5 days after return to normal living conditions. The transient increase in Hbmass might be the result of decreased RBC destruction, but it is also possible that spleen contraction after HDTBR contributed to this adaptation. Our data suggest that the decreased Hbmass 5 days following HDTBR resulted from decreased RBC production, not increased RBC destruction. Rapid decreases in haemoglobin mass (Hbmass) have been reported in healthy humans following spaceflight and descent from high altitude. It has been proposed that a selective increase in the destruction of young red blood cells (RBCs) mediates these decreases, but conclusive evidence demonstrating neocytolysis in humans is lacking. Based on the proposed triggers and time course of adaptation during spaceflight, we hypothesized that Hbmass would be reduced after 4 days of -6 deg head-down tilt bed rest (HDTBR) and that this would be associated with evidence for increased RBC destruction. We assessed Hbmass in seven healthy, recreationally active men before (PRE), 5 h after (POST) and 5 days after (POST5) 4 days of HDTBR. The concentration of erythropoietin decreased from 7.1 ± 1.8 mIU ml(-1) at PRE to 5.2 ± 2.8 mIU ml(-1) at POST (mean ± SD; P = 0.028). Contrary to our hypothesis, Hbmass was increased from 817 ± 135 g at PRE to 849 ± 141 g at POST (P = 0.014) before decreasing below PRE to 789 ± 139 g at POST5 (P = 0.027). From PRE to POST, the concentration of haptoglobin increased from 0.54 ± 0.32 to 0.68 ± 0.28 g l(-1) (P = 0.013) and the concentration of bilirubin decreased from 0.50 ± 0.24 to 0.32 ± 0.11 mg dl(-1) (P = 0.054), suggesting that decreased RBC destruction might have contributed to the increased Hbmass. However, it is possible that spleen contraction following HDTBR also played a role in the increase in Hbmass at POST, but as the transient increase in Hbmass was unexpected, we did not collect data that would provide direct evidence for or against spleen contraction. From PRE to POST5, the concentration of soluble transferrin receptor decreased from 20.7 ± 3.9 to 17.1 ± 3.3 nmol l(-1) (P = 0.018) but the concentrations of ferritin, haptoglobin and bilirubin were not significantly altered, suggesting that the decrease in Hbmass was mediated by decreased RBC production rather than increased RBC destruction. Peak oxygen uptake decreased by 0.31 ± 0.16 l min(-1) from PRE to POST (P = 2 × 10(-4) ) but was not significantly altered at POST5 compared with PRE. Overall, these findings indicate that 4 days of HDTBR does not increase RBC destruction and that re-examination of the time course and mechanisms of Hbmass alterations following short-term spaceflight and simulated microgravity is warranted.

Metabolic Perturbations Associated with both PFAS Exposure and Perinatal/Antenatal Depression in Pregnant Individuals: A Meet-in-the-Middle Scoping Review.

PURPOSE OF REVIEW: Depression during the perinatal or antenatal period affects at least 1 in 10 women worldwide, with long term health implications for the mother and child. Concurrently, there is increasing evidence associating maternal exposure to per- and poly-fluoroalkyl substances (PFAS) to adverse pregnancy outcomes. We reviewed the body of evidence examining both the associations between PFAS exposure and perturbations in the maternal metabolome, and the associations between the maternal metabolome and perinatal/antenatal depression. Through this, we sought to explore existing evidence of the perinatal metabolome as a potential mediation pathway linking PFAS exposure and perinatal/antenatal depression. RECENT FINDINGS: There are few studies examining the metabolomics of PFAS exposure-specifically in pregnant women-and the metabolomics of perinatal/antenatal depression, let alone studies examining both simultaneously. Of the studies reviewed (N = 11), the majority were cross sectional, based outside of the US, and conducted on largely homogenous populations. Our review identified 23 metabolic pathways in the perinatal metabolome common to both PFAS exposure and perinatal/antenatal depression. Future studies may consider findings from our review to conduct literature-derived hypothesis testing focusing on fatty acid metabolism, alanine metabolism, glutamate metabolism, and tyrosine metabolism when exploring the biochemical mechanisms conferring the risk of perinatal/antenatal depression due to PFAS exposure. We recommend that researchers also utilize heterogenous populations, longitudinal study designs, and mediation approaches to elucidate key pathways linking PFAS exposures to perinatal/antenatal depression.

Cardiometabolic profiles and proteomics associated with obesity phenotypes in a longitudinal cohort of young adults.

To assess cardiometabolic profiles and proteomics to identify biomarkers associated with the metabolically healthy and unhealthy obesity. Young adults (N = 156) enrolled were classified as not having obesity, metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO) based on NCEP ATP-III criteria. Plasma proteomics at study entry were measured using Olink Cardiometabolic Explore panel. Linear regression was used to assess associations between proteomics and obesity groups as well as cardiometabolic traits of glucose, insulin, and lipid profiles at baseline and follow-up visits. Enriched biological pathways were further identified based on the significant proteomic features. Among the baseline 95 (61%) and 61 (39%) participants classified as not having obesity and having obesity (8 MHO and 53 MUHO), respectively. Eighty of the participants were followed-up with an average 4.6 years. Forty-one proteins were associated with obesity (FDR < 0.05), 29 of which had strong associations with insulin-related traits and lipid profiles (FDR < 0.05). Inflammation, immunomodulation, extracellular matrix remodeling and endoplasmic reticulum lumen functions were enriched by 40 proteins. In this study population, obesity and MHO were associated with insulin resistance and dysregulated lipid profiles. The underlying mechanism included elevated inflammation and deteriorated extracellular matrix remodeling function.

Associations of dietary intake and longitudinal measures of per- and polyfluoroalkyl substances (PFAS) in predominantly Hispanic young Adults: A multicohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are pollutants linked to adverse health effects. Diet is an important source of PFAS exposure, yet it is unknown how diet impacts longitudinal PFAS levels. OBJECTIVE: To determine if dietary intake and food sources were associated with changes in blood PFAS concentrations among Hispanic young adults at risk of metabolic diseases. METHODS: Predominantly Hispanic young adults from the Children's Health Study who underwent two visits (CHS; n = 123) and young adults from NHANES 2013-2018 who underwent one visit (n = 604) were included. Dietary data at baseline was collected using two 24-hour dietary recalls to measure individual foods and where foods were prepared/consumed (home/restaurant/fast-food). PFAS were measured in blood at both visits in CHS and cross-sectionally in NHANES. In CHS, multiple linear regression assessed associations of baseline diet with longitudinal PFAS; in NHANES, linear regression was used. RESULTS: In CHS, all PFAS except PFDA decreased across visits (all p < 0.05). In CHS, A 1-serving higher tea intake was associated with 24.8 %, 16.17 %, and 12.6 % higher PFHxS, PFHpS, and PFNA at follow-up, respectively (all p < 0.05). A 1-serving higher pork intake was associated with 13.4 % higher PFOA at follow-up (p < 0.05). Associations were similar in NHANES, including unsweetened tea, hot dogs, and processed meats. For food sources, in CHS each 200-gram increase in home-prepared food was associated with 0.90 % and 1.6 % lower PFOS at baseline and follow-up, respectively, and in NHANES was associated with 0.9 % lower PFDA (all p < 0.05). CONCLUSION: Results suggest that beverage consumption habits and food preparation are associated with differences in PFAS levels in young adults. This highlights the importance of diet in determining PFAS exposure and the necessity of public monitoring of foods and beverages for PFAS contamination.

Proteomic and Metabolomic Signatures of Diet Quality in Young Adults.

The assessment of "omics" signatures may contribute to personalized medicine and precision nutrition. However, the existing literature is still limited in the homogeneity of participants' characteristics and in limited assessments of integrated omics layers. Our objective was to use post-prandial metabolomics and fasting proteomics to identify biological pathways and functions associated with diet quality in a population of primarily Hispanic young adults. We conducted protein and metabolite-wide association studies and functional pathway analyses to assess the relationships between a priori diet indices, Healthy Eating Index-2015 (HEI) and Dietary Approaches to Stop Hypertension (DASH) diets, and proteins (n = 346) and untargeted metabolites (n = 23,173), using data from the MetaAIR study (n = 154, 61% Hispanic). Analyses were performed for each diet quality index separately, adjusting for demographics and BMI. Five proteins (ACY1, ADH4, AGXT, GSTA1, F7) and six metabolites (undecylenic acid, betaine, hyodeoxycholic acid, stearidonic acid, iprovalicarb, pyracarbolid) were associated with both diets (p < 0.05), though none were significant after adjustment for multiple comparisons. Overlapping proteins are involved in lipid and amino acid metabolism and in hemostasis, while overlapping metabolites include amino acid derivatives, bile acids, fatty acids, and pesticides. Enriched biological pathways were involved in macronutrient metabolism, immune function, and oxidative stress. These findings in young Hispanic adults contribute to efforts to develop precision nutrition and medicine for diverse populations.

Postprandial Metabolite Profiles and Risk of Prediabetes in Young People: A Longitudinal Multicohort Study.

OBJECTIVE: Prediabetes in young people is an emerging epidemic that disproportionately impacts Hispanic populations. We aimed to develop a metabolite-based prediction model for prediabetes in young people with overweight/obesity at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: In independent, prospective cohorts of Hispanic youth (discovery; n = 143 without baseline prediabetes) and predominately Hispanic young adults (validation; n = 56 without baseline prediabetes), we assessed prediabetes via 2-h oral glucose tolerance tests. Baseline metabolite levels were measured in plasma from a 2-h postglucose challenge. In the discovery cohort, least absolute shrinkage and selection operator regression with a stability selection procedure was used to identify robust predictive metabolites for prediabetes. Predictive performance was evaluated in the discovery and validation cohorts using logistic regression. RESULTS: Two metabolites (allylphenol sulfate and caprylic acid) were found to predict prediabetes beyond known risk factors, including sex, BMI, age, ethnicity, fasting/2-h glucose, total cholesterol, and triglycerides. In the discovery cohort, the area under the receiver operator characteristic curve (AUC) of the model with metabolites and known risk factors was 0.80 (95% CI 0.72-0.87), which was higher than the risk factor-only model (AUC 0.63 [0.53-0.73]; P = 0.001). When the predictive models developed in the discovery cohort were applied to the replication cohort, the model with metabolites and risk factors predicted prediabetes more accurately (AUC 0.70 [95% CI 40.55-0.86]) than the same model without metabolites (AUC 0.62 [0.46-0.79]). CONCLUSIONS: Metabolite profiles may help improve prediabetes prediction compared with traditional risk factors. Findings suggest that medium-chain fatty acids and phytochemicals are early indicators of prediabetes in high-risk youth.

Exposure to per- and polyfluoroalkyl substances and high-throughput proteomics in Hispanic youth.

BACKGROUND: Strong epidemiological evidence shows positive associations between exposure to per- and polyfluoroalkyl substances (PFAS) and adverse cardiometabolic outcomes (e.g., diabetes, hypertension, and dyslipidemia). However, the underlying cardiometabolic-relevant biological activities of PFAS in humans remain largely unclear. AIM: We evaluated the associations of PFAS exposure with high-throughput proteomics in Hispanic youth. MATERIAL AND METHODS: We included 312 overweight/obese adolescents from the Study of Latino Adolescents at Risk (SOLAR) between 2001 and 2012, along with 137 young adults from the Metabolic and Asthma Incidence Research (Meta-AIR) between 2014 and 2018. Plasma PFAS (i.e., PFOS, PFOA, PFHxS, PFHpS, PFNA) were quantified using liquid-chromatography high-resolution mass spectrometry. Plasma proteins (n = 334) were measured utilizing the proximity extension assay using an Olink Explore Cardiometabolic Panel I. We conducted linear regression with covariate adjustment to identify PFAS-associated proteins. Ingenuity Pathway Analysis, protein-protein interaction network analysis, and protein annotation were used to investigate alterations in biological functions and protein clusters. RESULTS: Results after adjusting for multiple comparisons showed 13 significant PFAS-associated proteins in SOLAR and six in Meta-AIR, sharing similar functions in inflammation, immunity, and oxidative stress. In SOLAR, PFNA demonstrated significant positive associations with the largest number of proteins, including ACP5, CLEC1A, HMOX1, LRP11, MCAM, SPARCL1, and SSC5D. After considering the mixture effect of PFAS, only SSC5D remained significant. In Meta-AIR, PFAS mixtures showed positive associations with GDF15 and IL6. Exploratory analysis showed similar findings. Specifically, pathway analysis in SOLAR showed PFOA- and PFNA-associated activation of immune-related pathways, and PFNA-associated activation of inflammatory response. In Meta-AIR, PFHxS-associated activation of dendric cell maturation was found. Moreover, PFAS was associated with common protein clusters of immunoregulatory interactions and JAK-STAT signaling in both cohorts. CONCLUSION: PFAS was associated with broad alterations of the proteomic profiles linked to pro-inflammation and immunoregulation. The biological functions of these proteins provide insight into potential molecular mechanisms of PFAS toxicity.

The potential mediating role of the gut microbiome and metabolites in the association between PFAS and kidney function in young adults: A proof-of-concept study.

BACKGROUND: Chronic kidney disease (CKD) affects over 10 % of the global population and can lead to kidney failure and death. Exposure to per- and polyfluoroalkyl substances (PFAS) is associated with increased risk of CKD, yet studies examining the mechanisms linking PFAS and kidney function are lacking. In this exploratory study, we examined longitudinal associations of PFAS exposure with kidney function, and tested if associations were mediated by altered gut bacterial taxa or plasma metabolites using a multi-omics mediation analysis. METHODS: Seventy-eight young adults from the Children's Health Study were included in this longitudinal cohort study. At baseline, seven plasma PFAS and untargeted plasma metabolomics were measured using liquid chromatography/mass-spectrometry. Baseline gut bacterial abundance was characterized using 16S rRNA sequencing and examined at the genus level. At follow-up, serum creatinine and cystatin-C concentrations were quantified to estimate glomerular filtration rate (eGFR). High-dimensional multi-omics analyses were conducted to assess the association between baseline PFAS exposure with follow-up eGFR, mediated by gut microbiome and circulating metabolite levels. RESULTS: PFAS burden score, a variable developed to estimate exposure to chemical mixtures, was associated with kidney function. Each standard deviation increase in baseline PFAS burden score was associated with a 2.4 % lower eGFR at follow-up (95 % CI:[0.1 %,4.8 %]). Following high-dimensional mediation analyses with the microbiome and circulating metabolites, a joint component (characterized by reduced Lachnospiraceae and 17b-estradiol and increased succinate, retinoate and dodecanoic acid) and a metabolite component (characterized by increased hypotaurine and decreased D-pinitol and ureidopropionate) mediated 38 % and 50 % of the effect between PFAS burden score and eGFR, respectively. CONCLUSION: Our proof-of-concept analysis provides the first evidence that reduced short-chain fatty acid-producing bacteria and anti-inflammatory metabolites may link PFAS exposure with impaired kidney function. This study raises the possibility of future targeted interventions that can alter gut microbiome or circulating metabolite profiles to prevent PFAS induced kidney damage.

Changes in plasma concentrations of per- and Polyfluoroalkyl substances after bariatric surgery in adolescents from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study.

Exposure to per- and poly-fluoroalkyl substances (PFAS) is ubiquitous due to their persistence in the environment and in humans. Extreme weight loss has been shown to influence concentrations of circulating persistent organic pollutants (POPs). Using data from the multi-center perspective Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort, we investigated changes in plasma-PFAS in adolescents after bariatric surgery. Adolescents (Mean age = 17.1 years, SD = 1.5 years) undergoing bariatric surgery were enrolled in the Teen-LABS study. Plasma-PFAS were measured at the time of surgery and then 6-, 12-, and 36 months post-surgery. Linear mixed effect models were used to evaluate longitudinal changes in plasma-PFAS after the time of bariatric surgery. This study included 214 adolescents with severe obesity who had available longitudinal measures of plasma-PFAS and underwent bariatric surgery between 2007 and 2012. Underlying effects related to undergoing bariatric surgery were found to be associated with an initial increase or plateau in concentrations of circulating PFAS up to 6 months after surgery followed by a persistent decline in concentrations of 36 months (p < 0.001 for all plasma-PFAS). Bariatric surgery in adolescents was associated with a decline in circulating PFAS concentrations. Initially following bariatric surgery (0-6 months) concentrations were static followed by decline from 6 to 36 months following surgery. This may have large public health implications as PFAS are known to be associated with numerous metabolic related diseases and the significant reduction in circulating PFAS in individuals who have undergone bariatric surgery may be related to the improvement of such metabolic related diseases following bariatric surgery.