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.

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 16.6 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 476 miRNAs in the Teen-LABs study and 13 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.

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.

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.

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.

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.

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.

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.

Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children and adolescents. NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), wherein hepatocellular inflammation and/or fibrosis coexist with steatosis. Circulating microRNA (miRNA) levels have been suggested to be altered in NAFLD, but the extent to which miRNA are related to NAFLD features remains unknown. This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents. AIM: To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD. METHODS: This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study. Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD. Plasma samples were collected during surgery for miRNA profiling. A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform. We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age, sex, race, and other key covariates. Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD. RESULTS: We identified 16 upregulated plasma miRNAs, including miR-193a-5p and miR-193b-5p, and 22 downregulated plasma miRNAs, including miR-1282 and miR-6734-5p, in adolescents with NAFLD. Moreover, 52, 16, 15, and 9 plasma miRNAs were associated with NASH, fibrosis, ballooning degeneration, and lobular inflammation, respectively. Collectively, 16 miRNAs were associated with two or more histological features of NAFLD. Among those miRNAs, miR-411-5p was downregulated in NASH, ballooning, and fibrosis, while miR-122-5p, miR-1343-5p, miR-193a-5p, miR-193b-5p, and miR-7845-5p were consistently and positively associated with all histological features of NAFLD. Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression, while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B. CONCLUSION: Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity. Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.

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.

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 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.

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.

Metabolic Signatures of Youth Exposure to Mixtures of Per- and Polyfluoroalkyl Substances: A Multi-Cohort Study.

BACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous and has been associated with an increased risk of several cardiometabolic diseases. However, the metabolic pathways linking PFAS exposure and human disease are unclear. OBJECTIVE: We examined associations of PFAS mixtures with alterations in metabolic pathways in independent cohorts of adolescents and young adults. METHODS: Three hundred twelve overweight/obese adolescents from the Study of Latino Adolescents at Risk (SOLAR) and 137 young adults from the Southern California Children's Health Study (CHS) were included in the analysis. Plasma PFAS and the metabolome were determined using liquid-chromatography/high-resolution mass spectrometry. A metabolome-wide association study was performed on log-transformed metabolites using Bayesian regression with a g-prior specification and g-computation for modeling exposure mixtures to estimate the impact of exposure to a mixture of six ubiquitous PFAS (PFOS, PFHxS, PFHpS, PFOA, PFNA, and PFDA). Pathway enrichment analysis was performed using Mummichog and Gene Set Enrichment Analysis. Significance across cohorts was determined using weighted Z-tests. RESULTS: In the SOLAR and CHS cohorts, PFAS exposure was associated with alterations in tyrosine metabolism (meta-analysis p=0.00002) and de novo fatty acid biosynthesis (p=0.03), among others. For example, when increasing all PFAS in the mixture from low (∼30th percentile) to high (∼70th percentile), thyroxine (T4), a thyroid hormone related to tyrosine metabolism, increased by 0.72 standard deviations (SDs; equivalent to a standardized mean difference) in the SOLAR cohort (95% Bayesian credible interval (BCI): 0.00, 1.20) and 1.60 SD in the CHS cohort (95% BCI: 0.39, 2.80). Similarly, when going from low to high PFAS exposure, arachidonic acid increased by 0.81 SD in the SOLAR cohort (95% BCI: 0.37, 1.30) and 0.67 SD in the CHS cohort (95% BCI: 0.00, 1.50). In general, no individual PFAS appeared to drive the observed associations. DISCUSSION: Exposure to PFAS is associated with alterations in amino acid metabolism and lipid metabolism in adolescents and young adults. https://doi.org/10.1289/EHP11372.

Iron Status and Homeostasis Across 2 Competitive Seasons in NCAA Division I Collegiate Cross-Country Runners Residing at Low Altitude.

PURPOSE: Inflammatory cytokines including interleukin-6 can upregulate hepcidin and decrease iron absorption. Endurance exercise is associated with transient increases in cytokines, which may alter the risk of iron deficiency (ID). This study examined whether chronic elevations in basal levels of cytokines and hepcidin were associated with ID in highly trained runners. METHODS: Fifty-four collegiate runners (26 males and 28 females) living at ∼1625 m were recruited from an NCAA Division I cross-country team for this prospective cohort study. Over 2 seasons, fasted, preexercise blood draws were performed in the morning 4 times per season and were analyzed for hemoglobin concentration, ferritin, soluble transferrin receptor (sTfR), hepcidin, and 10 cytokines. Stages of ID were defined using ferritin, sTfR, and hemoglobin concentration. During the study, a registered dietician provided all runners with iron supplements using athletic department-created guidelines. RESULTS: Fifty-seven percent of females and 35% of males exhibited stage 2 ID (ferritin <20 ng/mL or sTfR >29.5 nmol/L) at least once. Cytokines, ferritin, and sTfR exhibited changes through the 2 years, but changes in cytokines were not associated with alterations in hepcidin, ferritin, or sTfR. In males and females, lower ferritin was associated with lower hepcidin (both P < .0001). One female exhibited higher hepcidin and lower iron stores compared with other individuals, suggesting a different etiology of ID. CONCLUSION: ID is common in highly trained collegiate runners. In general, the high prevalence of ID in this population is not associated with alterations in basal hepcidin or cytokine levels.

Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort.

Background & Aims: Exposure to poly- and perfluoroalkyl substances (PFAS), a class of persistent organic pollutants, is ubiquitous. Animal studies suggest that PFAS may increase risk of fatty liver and hepatocellular carcinoma (HCC) via impacts on hepatic lipid, amino acid, and glucose metabolism, but human data is lacking. We examined associations between PFAS exposure, altered metabolic pathways, and risk of non-viral HCC. Methods: In this nested case-control study, pre-diagnostic plasma PFAS and metabolomics were measured in 50 incident HCC cases and 50 individually matched controls from the Multiethnic Cohort (MEC) study. Cases/controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolome-wide association study and pathway enrichment analysis was performed for PFAS exposure and HCC risk, and key metabolites/metabolic pathways were identified using a meet in the middle approach. Results: High perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES; >55 µg/L) were associated with 4.5-fold increased risk of HCC (odds ratio 4.5, 95% CI 1.2-16.0). Pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were also associated with HCC risk. We identified 4 metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short-chain fatty acid), α-ketoisovaleric acid (a branched-chain α-keto acid), and 7α-hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC. Conclusion: This proof-of-concept analysis shows that exposure to high PFOS levels was associated with increased risk of non-viral HCC, likely via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are needed to confirm these findings. Lay summary: Per- and polyfluoroalkyl substances (PFAS), often referred to as "forever chemicals" because they are difficult to break down and stay in the human body for years, are extremely common and can cause liver damage. In a first of its kind study, we found that exposure to high levels of perfluorooctanesulfonic acid, one of the most common PFAS chemicals, was linked to increased risk of hepatocellular carcinoma in humans. Hepatocellular carcinoma is difficult to treat and is one of the most common forms of liver cancer, and these findings may provide new avenues for helping to prevent this disease.

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.

Exposure to Perfluoroalkyl Substances and Glucose Homeostasis in Youth.

BACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes. OBJECTIVE: We examined associations between PFAS exposure and glucose metabolism in youth. METHODS: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n=310) participated in annual visits for an average of 3.3±2.9y. Generalizability of findings were tested in young adults from the Southern California Children's Health Study (CHS; n=135) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and ß-cell function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography-high-resolution mass spectrometry; high levels were defined as concentrations >66th percentile. RESULTS: In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels (≥2.0 ng/mL) were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had 25-mg/dL higher 60-min glucose (95% CI: 12, 39mg/dL; p<0.0001), 15-mg/dL higher 2-h glucose (95% CI: 1, 28mg/dL; p=0.04), and 25% lower ß-cell function (p=0.02) compared with females with low levels. Results were largely consistent in the CHS, where females with elevated PFHxS levels had 26-mg/dL higher 60-min glucose (95% CI: 6.0, 46mg/dL; p=0.01) and 19-mg/dL higher 2-h glucose, which did not meet statistical significance (95% CI: -1, 39mg/dL; p=0.08). In males, no consistent associations between PFHxS and glucose metabolism were observed. No consistent associations were observed for other PFAS and glucose metabolism. DISCUSSION: Youth exposure to PFHxS was associated with dysregulated glucose metabolism in females, which may be due to changes in ß-cell function. These associations appeared during puberty and were most pronounced postpuberty. https://doi.org/10.1289/EHP9200.

Platelet-Rich Plasma Versus Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Platelet-rich plasma (PRP) and hyaluronic acid (HA) are 2 nonoperative treatment options for knee osteoarthritis (OA) that are supposed to provide symptomatic relief and help delay surgical intervention. PURPOSE: To systematically review the literature to compare the efficacy and safety of PRP and HA injections for the treatment of knee OA. STUDY DESIGN: Meta-analysis of level 1 studies. METHODS: A systematic review was performed by searching PubMed, the Cochrane Library, and Embase to identify level 1 studies that compared the clinical efficacy of PRP and HA injections for knee OA. The search phrase used was platelet-rich plasma hyaluronic acid knee osteoarthritis randomized. Patients were assessed via the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale (VAS) for pain, and Subjective International Knee Documentation Committee (IKDC) scale. A subanalysis was also performed to isolate results from patients who received leukocyte-poor and leukocyte-rich PRP. RESULTS: A total of 18 studies (all level 1) met inclusion criteria, including 811 patients undergoing intra-articular injection with PRP (mean age, 57.6 years) and 797 patients with HA (mean age, 59.3 years). The mean follow-up was 11.1 months for both groups. Mean improvement was significantly higher in the PRP group (44.7%) than the HA group (12.6%) for WOMAC total scores (P < .01). Of 11 studies based on the VAS, 6 reported PRP patients to have significantly less pain at latest follow-up when compared with HA patients (P < .05). Of 6 studies based on the Subjective IKDC outcome score, 3 reported PRP patients to have significantly better scores at latest follow-up when compared with HA patients (P < .05). Finally, leukocyte-poor PRP was associated with significantly better Subjective IKDC scores versus leukocyte-rich PRP (P < .05). CONCLUSION: Patients undergoing treatment for knee OA with PRP can be expected to experience improved clinical outcomes when compared with HA. Additionally, leukocyte-poor PRP may be a superior line of treatment for knee OA over leukocyte-rich PRP, although further studies are needed that directly compare leukocyte content in PRP injections for treatment of knee OA.

The importance of lean mass and iron deficiency when comparing hemoglobin mass in male and female athletic groups.

Hemoglobin mass (Hbmass) is important for athletes because it helps determine maximal aerobic power. This study examined how lean mass, iron deficiency (ID), and sex influence Hbmass in athletic and nonathletic groups. NCAA Division I student athletes (21 men, 75 women; altitude: 1,625 m) were recruited from six athletic teams; 14 male and 12 female full-time students (non-varsity athletes) served as control subjects. Hbmass, body composition, and iron homeostasis parameters, including ferritin, soluble transferrin receptor (sTfR), hepcidin, erythroferrone, and 10 inflammatory cytokines, were measured two to four times across a competitive/training season. ID was defined as ferritin < 25 ng/mL. Hbmass was more closely related to lean mass (r2 = 0.90) than body mass (r2 = 0.69, P < 0.01). Compared with female subjects, male subjects had 19.9% higher Hbmass relative to body mass (HbmassBM) but only 7.5% higher Hbmass relative to lean mass (HbmassLEAN) (both P < 0.001). Prevalence of ID was higher in female than male subjects (47% vs. 9%, P < 0.01) but did not vary between groups. HbmassLEAN was 5% lower in ID vs. non-ID female subjects; HbmassBM was not different. ID was associated with lower hepcidin, elevated sTfR, and elevated erythroferrone but not with differences in inflammatory cytokines. Hbmass varied significantly between athletic groups and across sex, but the majority of these differences are explained by differences in lean mass. ID was common in female subjects and was associated with lower HbmassLEAN and hepcidin but not with differences in HbmassBM or inflammatory cytokines. Hbmass relative to lean mass seems advantageous when monitoring iron deficiency.NEW & NOTEWORTHY Differences in hemoglobin mass (Hbmass) between groups and across sex are primarily due to differences in lean mass. Iron deficiency (ID) independently decreases Hbmass; this effect is best characterized with Hbmass relative to lean mass. ID is common in females and is associated with lower hepcidin and elevated erythroferrone but not with differences in inflammatory cytokines. Hbmass relative to lean mass accurately quantifies hematological alterations secondary to iron deficiency.