Manganese and Sleep Outcomes in United States Adults: Results from the 2017-2020 National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: Manganese (Mn) is an essential micronutrient, but inadequate or excess Mn intake can have a detrimental impact on human health. Despite the essentiality, little is known about the relationship between Mn and sleep. OBJECTIVE: This study aimed to examine the relationship between blood Mn concentrations and sleep outcomes in US adults. METHODS: This cross-sectional study used data on blood Mn and sleep from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) (n = 8356, age ≥18 y). Multivariable logistic regression was used to examine associations between quintiles of blood Mn concentrations and subjective sleep outcomes (short sleep duration, late sleep midpoint, trouble sleeping, and obstructive sleep apnea [OSA] symptoms), adjusting for age, gender, body mass index, race/ethnicity, income, smoking, inflammation-adjusted serum ferritin concentration (iron status), caffeine, and alcohol intake. Gender-stratified models were used due to interactions with gender. RESULTS: The mean (SE) blood Mn concentration was 9.7 (0.1) µg/L in US adults. In males, a nonlinear association was noted in the relationship between blood Mn levels and short sleep duration on weekdays and weekends. The third Mn quintile (Q3) group had lower odds of short sleep duration (<7 h) on weekdays (odds ratio [OR]=0.6, 95% confidence interval [CI]: 0.4, 0.9) than the lowest Mn quintile (Q1, reference) after adjusting for covariates in males. The second Mn quintile (Q2) group had lower odds of late sleep midpoint on weekdays than Q1 (OR=0.6, 95% CI: 0.4, 0.8). In females, Q2 group had lower odds of OSA symptoms than Q1 (OR: 0.6, 95% CI: 0.4, 0.9). No relationship was noted between Mn and trouble sleeping. CONCLUSIONS: Gender differences exist in the association between Mn and sleep in adults. Q1 group had the poorest sleep outcomes, including higher odds of short sleep duration (in males), late sleep midpoint (in males), and OSA symptoms (in females).

Environmental chemical-wide associations with immune biomarkers in US adults: A cross-sectional analysis.

Environmental chemical exposures influence immune system functions, and humans are exposed to a wide range of chemicals, termed the chemical "exposome". A comprehensive, discovery analysis of the associations of multiple chemical families with immune biomarkers is needed. In this study, we tested the associations between environmental chemical concentrations and immune biomarkers. We analyzed the United States cross-sectional National Health and Nutrition Examination Survey (NHANES, 1999-2018). Chemical biomarker concentrations were measured in blood or urine (196 chemicals, 17 chemical families). Immune biomarkers included counts of lymphocytes, neutrophils, monocytes, basophils, eosinophils, red blood cells, white blood cells, and mean corpuscular volume. We conducted separate survey-weighted, multivariable linear regressions of each log2-transformed chemical and immune measure, adjusted for relevant covariates. We accounted for multiple comparisons using a false discovery rate (FDR). Among 45,528 adult participants, the mean age was 45.7 years, 51.4% were female, and 69.3% were Non-Hispanic White. 71 (36.2%) chemicals were associated with at least one of the eight immune biomarkers. The most chemical associations (FDR<0.05) were observed with mean corpuscular volume (36 chemicals) and red blood cell counts (35 chemicals). For example, a doubling in the concentration of cotinine was associated with 0.16 fL (95% CI: 0.15, 0.17; FDR<0.001) increased mean corpuscular volume, and a doubling in the concentration of blood lead was associated with 61,736 increased red blood cells per µL (95% CI: 54,335, 69,138; FDR<0.001). A wide variety of chemicals, such as metals and smoking-related compounds, were highly associated with immune system biomarkers. This environmental chemical-wide association study identified chemicals from multiple families for further toxicological, immunologic, and epidemiological investigation.

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.

Blood-based biomarkers for Alzheimer's disease and cognitive function from mid- to late life.

INTRODUCTION: We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid- to late life among women. METHODS: The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid ß (Aß)42, the Aß42/40 ratio, phosphorylated tau181 (p-tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models. RESULTS: After adjusting for confounders, lower Aß42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p-tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test. DISCUSSION: Our findings suggest that mid-life serum AD biomarkers could be associated with accelerated cognitive decline from mid- to late life in women. Future studies with larger samples are needed to validate and extend our findings. HIGHLIGHTS: This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women. Mid-life serum AD biomarkers are associated with accelerated cognitive decline. A decrease in the Aß42/40 ratio was associated with a faster decline in the DSB score. A higher p-tau181 concentration was associated with a faster decline in the SDMT score.

Isomer-Specific Serum Concentrations of Perfluorooctane Sulfonic Acid among U.S. Adults: Results from the National Health and Nutrition Examination Survey (NHANES) and the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS).

Electrochemical fluorination manufacture of perfluorooctane sulfonic acid (PFOS), one of the most studied per- and polyfluoroalkyl substances, produces mixtures of linear and branched isomers, but little is known about human exposure to linear or branched PFOS isomers. We examined determinants affecting isomer-specific patterns of PFOS in serum in two adult populations in the United States, the National Health and Nutrition Examination Survey (NHANES) and the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS). After adjusting for demographic variables, fish consumption (in both populations), a glomerular filtration rate above 90 mL/min/1.73 m2 (observed in NHANES; not tested in SWAN-MPS), premenopausal status (only observed in SWAN-MPS), and less consumption of processed food (observed in SWAN-MPS; not tested in NHANES) were associated with a higher proportion of linear PFOS. Non-Hispanic Black and Asian participants were likely to have a higher proportion of linear PFOS than non-Hispanic White participants in both populations. Our findings suggest that isomer-specific patterns of PFOS serum concentrations in humans vary depending on population characteristics that affect PFOS exposure and excretion. Consideration of specific PFOS isomers in future human biomonitoring and epidemiologic studies can provide useful insight to better understand PFOS exposure.

Volatile Organic Compounds in Disposable Diapers and Baby Wipes in the US: A Survey of Products and Health Risks.

Many thousands of diapers are worn by young children and the elderly, who have thin and sensitive skin that is highly vulnerable to chemicals, including volatile organic compounds (VOCs) that may be ingredients of these products or present as inadvertent or residual components. The levels and potential health risks of VOCs in diapers have not been reported previously. In this study, we collected 31 disposable hygiene products in the US market based on market share and analyzed 98 target VOCs using purge and trap sampling and thermal desorption/gas chromatography/mass spectrometer analysis. Exposures and risks were modeled using reasonable upper level exposure scenarios. Adult diapers contained the highest total target VOC concentration (median level of 23.5 µg/g), and the predominant VOCs were alkanes. In some diapers, the estimated noncancer risk from these VOCs was sometimes very large (hazard quotient of 1609) due to n-heptane. Baby diapers contained several known or suspected carcinogens, including benzene and 1,4-dioxane, and the lifetime cancer risk from some diapers approached 1 per million under a worst-case scenario. Store-brand products had higher levels of VOCs than generic brands, and products labeled "organic" or "for sensitive skin" did not necessarily have lower levels. Our results show that toxic VOCs were found in all tested disposable diapers and wipes at trace levels, and risks from using some diapers in high use exposure scenarios are high enough to warrant additional attention and possibly corrective measures. We recommend eliminating and monitoring toxic ingredients and disclosing all chemicals that may be in these products.

Associations between mercury exposure with blood pressure and lipid levels: A cross-sectional study of dental professionals.

Mercury (Hg) exposure is a public health problem worldwide that is now being addressed through the Minamata Convention on Mercury. Fish containing methylmercury and dental amalgam containing elemental Hg are the major sources of exposure for most populations. There is some evidence that methylmercury impacts cardiovascular and metabolic health, primarily in populations with high exposure levels. Studies of elemental Hg and these outcomes are relatively rare. We aimed to examine associations between Hg exposure (both elemental and methylmercury) and blood pressure, as well as cholesterol and triglyceride levels. In 2012, we recruited dental professionals attending the Health Screening Program at the American Dental Association (ADA) Annual Session in California. Total Hg levels in hair and blood samples were analyzed as indicators of methylmercury exposure and in urine as an indicator of primarily elemental Hg exposure (n = 386; mean ± sd age 55 ± 11 years). We measured blood pressure (systolic and diastolic) and lipid profiles (total cholesterol, high-density lipoprotein cholesterol [HDL], low-density lipoprotein cholesterol [LDL] and triglycerides). The geometric means (geometric standard deviations) for blood, hair, and urine Hg were 3.64 (2.39) µg/L, 0.60 (2.91) µg/g, and 1.30 (2.44) µg/L, respectively. For every one µg/L increase in specific gravity-adjusted urine Hg, LDL increased by 2.31 mg/dL (95% CI = 0.09, 4.54), in linear regression adjusting for BMI, race, sex, polyunsaturated fatty acid intake from fish consumption, smoking status, and use of cholesterol-lowering medication. No significant associations between Hg biomarkers and blood pressure or hair or blood Hg with lipid levels were observed. Results suggest that elemental Hg exposure may influence LDL concentrations in adults with low-level exposure, and this relationship merits further study in other populations.

Phthalate exposure is associated with more rapid body fat gain in midlife women: The Study of Women's Health Across the Nation (SWAN) Multi-Pollutant Study.

Obesity is a major threat to health, but the etiology of obesity is incompletely understood. Phthalates, synthetic chemicals ubiquitous in the environment, are suspected to have obesogenic effects, but the relationship of phthalates and obesity in humans remains uncertain. We examined whether phthalate exposure was associated with body fat gain in midlife women. We analyzed data from 1369 women in the Study of Women's Health Across the Nation Multi-Pollutant Study. Eleven phthalate metabolites measured in spot urine samples at baseline (1999/2000) were standardized with covariate-adjusted creatinine. Body weight (BW), fat mass (FM) from dual-energy X-ray absorptiometry (DXA), and body fat percentage (BF%) from DXA were measured near-annually until 2016/2017. For each metabolite, linear mixed effects models with time and log2(metabolite) interactions were examined, adjusting for demographic, lifestyle, and menopause-related factors. Analyses were conducted overall and stratified by baseline obesity status. As sensitivity analyses, all analyses were repeated using a second set of metabolites measured in 2002/2003. Higher levels of all metabolites except mono-carboxy-isononyl phthalate were associated with faster increases in BF%. Per doubling of metabolite concentrations, differences in five-year BF% change ranged from 0.03 percentage point (ppt) (95% confidence interval (CI): -0.03, 0.09) for mono-isobutyl phthalate to 0.09 ppt (95% CI: 0.02, 0.16) for mono(3-carboxypropyl) phthalate. Results were similar for FM change, but associations with BW change were mostly null. In stratified analyses by baseline obesity status, positive associations were strongest in women who were normal/underweight at baseline. When metabolites from 2002/2003 were used as exposures, most associations were attenuated and not statistically significant, but they remained positive for normal/underweight women. In conclusion, phthalate metabolites were associated with more rapid body fat gain in midlife women, but our results need confirmation given attenuation of estimates in the sensitivity analyses.

The role of exposure to per- and polyfluoroalkyl substances in racial/ethnic disparities in hypertension: Results from the study of Women's health across the nation.

BACKGROUND: Racial/ethnic disparities in hypertension are a pressing public health problem. The contribution of environmental pollutants including PFAS have not been explored, even though certain PFAS are higher in Black population and have been associated with hypertension. OBJECTIVES: We examined the extent to which racial/ethnic disparities in incident hypertension are explained by racial/ethnic differences in serum PFAS concentrations. METHODS: We included 1058 hypertension-free midlife women with serum PFAS concentrations in 1999-2000 from the multi-racial/ethnic Study of Women's Health Across the Nation with approximately annual follow-up visits through 2017. Causal mediation analysis was conducted using accelerated failure time models. Quantile-based g-computation was used to evaluate the joint effects of PFAS mixtures. RESULTS: During 11,722 person-years of follow-up, 470 participants developed incident hypertension (40.1 cases per 1000 person-years). Black participants had higher risks of developing hypertension (relative survival: 0.58, 95% CI: 0.45-0.76) compared with White participants, which suggests racial/ethnic disparities in the timing of hypertension onset. The percent of this difference in timing that was mediated by PFAS was 8.2% (95% CI: 0.7-15.3) for PFOS, 6.9% (95% CI: 0.2-13.8) for EtFOSAA, 12.7% (95% CI: 1.4-22.6) for MeFOSAA, and 19.1% (95% CI: 4.2, 29.0) for PFAS mixtures. The percentage of the disparities in hypertension between Black versus White women that could have been eliminated if everyone's PFAS concentrations were dropped to the 10th percentiles observed in this population was 10.2% (95% CI: 0.9-18.6) for PFOS, 7.5% (95% CI: 0.2-14.9) for EtFOSAA, and 17.5% (95% CI: 2.1-29.8) for MeFOSAA. CONCLUSIONS: These findings suggest differences in PFAS exposure may be an unrecognized modifiable risk factor that partially accounts for racial/ethnic disparities in timing of hypertension onset among midlife women. The study calls for public policies aimed at reducing PFAS exposures that could contribute to reductions in racial/ethnic disparities in hypertension.

Per- and polyfluoroalkyl substances and incident diabetes in midlife women: the Study of Women's Health Across the Nation (SWAN).

AIMS/HYPOTHESIS: Diabetogenic effects of per- and polyfluoroalkyl substances (PFAS) have been suggested. However, evidence based on prospective cohort studies is limited. We examined the association between serum PFAS concentrations and incident diabetes in the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS). METHODS: We included 1237 diabetes-free women aged 45-56 years at baseline (1999-2000) who were followed up to 2017. At each follow-up visit, women with incident diabetes were identified by the presence of one or more of the following conditions: (1) use of a glucose-lowering medication at any visit; (2) fasting glucose ≥7 mmol/l on two consecutive visits while not on steroids; and (3) any two visits with self-reported diabetes and at least one visit with fasting blood glucose ≥7 mmol/l. Serum concentrations of 11 PFAS were quantified by online solid-phase extraction-HPLC-isotope dilution-tandem MS. Seven PFAS with high detection rates (>96%) (n-perfluorooctanoic acid [n-PFOA], perfluorononanoic acid [PFNA], perfluorohexane sulfonic acid [PFHxS], n-perfluorooctane sulfonic acid [n-PFOS], sum of perfluoromethylheptane sulfonic acid isomers [Sm-PFOS], 2-[N-methyl-perfluorooctane sulfonamido] acetic acid [MeFOSAA] and 2-[N-ethyl-perfluorooctane sulfonamido] acetic acid) were included in data analysis. Cox proportional hazards models were used to compute HRs and 95% CIs. Quantile-based g-computation was used to evaluate the joint effects of PFAS mixtures. RESULTS: After adjustment for race/ethnicity, site, education, smoking status, alcohol consumption, total energy intake, physical activity, menopausal status and BMI, the HR (95% CI) comparing the lowest with the highest tertile was 1.67 (1.21, 2.31) for n-PFOA (ptrend = 0.001), 1.58 (1.13, 2.21) for PFHxS (ptrend = 0.003), 1.36 (0.97, 1.90) for Sm-PFOS (ptrend = 0.05), 1.85 (1.28, 2.67) for MeFOSAA (ptrend = 0.0004) and 1.64 (1.17, 2.31) for the sum of four common PFAS (n-PFOA, PFNA, PFHxS and total PFOS) (ptrend = 0.002). Exposure to seven PFAS as mixtures was associated with an HR of 2.62 (95% CI 1.12, 6.20), comparing the top with the bottom tertiles for all seven PFAS. CONCLUSIONS/INTERPRETATION: This study suggests that PFAS may increase diabetes risk in midlife women. Reduced exposure to these 'forever and everywhere chemicals' may be an important preventative approach to lowering population-wide diabetes risk.

Perfluoroalkyl Substances and Incident Natural Menopause in Midlife Women: The Mediating Role of Sex Hormones.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been associated with earlier natural menopause; however, the underlying mechanisms are not well understood, particularly the extent to which this relationship is mediated by sex hormones. We analyzed data (1999-2017) on 1,120 premenopausal women from the Study of Women's Health Across the Nation (SWAN). Causal mediation analysis was applied to quantify the degree to which follicle-stimulating hormone (FSH) and estradiol levels could mediate the associations between PFAS and incident natural menopause. Participants with higher PFAS concentrations had shorter times to natural menopause, with a relative survival of 0.82 (95% confidence interval (CI): 0.69, 0.96) for linear perfluorooctane sulfonate (n-PFOS), 0.84 (95% CI: 0.69, 1.00) for sum of branched-chain perfluorooctane sulfonate (Sm-PFOS), 0.79 (95% CI: 0.66, 0.93) for linear-chain perfluorooctanoate (n-PFOA), and 0.84 (95% CI: 0.71, 0.97) for perfluorononanoate (PFNA), comparing the highest tertile of PFAS concentrations with the lowest. The proportion of the effect mediated through FSH was 8.5% (95% CI: -11.7, 24.0) for n-PFOS, 13.2% (95% CI: 0.0, 24.5) for Sm-PFOS, 26.9% (95% CI: 15.6, 38.4) for n-PFOA, and 21.7% (6.8, 37.0) for PFNA. No significant mediation by estradiol was observed. The effect of PFAS on natural menopause may be partially explained by variations in FSH concentrations.

Metals and risk of incident metabolic syndrome in a prospective cohort of midlife women in the United States.

Exposure to metals may contribute to the development of metabolic syndrome (MetS); however, evidence from midlife women who are at greater risk of cardiometabolic disease is limited. We assessed the associations of 15 urinary metal concentrations with incident MetS in a prospective cohort of midlife women in the United States. The study population included 947 White, Black, Chinese and Japanese women, aged 45-56 years, free of MetS at baseline (1999-2000), who participated in the Study of Women's Health Across the Nation Multi-Pollutant Study. Fifteen metals were detected in almost all participants urine samples using inductively coupled plasma mass spectrometry at the baseline. Incident MetS was identified annually through 2017 as having at least three of the following five components: high blood pressure, impaired fasting glucose, abdominal obesity, high triglycerides, and poor high-density lipoprotein cholesterol. We used the Cox proportional hazards models to investigate the associations between individual metals and MetS incidence. The adjusted hazard ratios (HR) (95% CI) for MetS in associations with each doubling of urinary metal concentration were 1.14 (1.08, 1.23) for arsenic, 1.14 (1.01, 1.29) for cobalt, and 1.20 (1.06, 1.37) for zinc. We further evaluated the associations between metal mixtures and MetS using the elastic net penalized Cox model and summarized the results into the environmental risk score (ERS). Arsenic, barium, cobalt, copper, nickel, antimony, thallium, and zinc had positive weights, and cadmium, cesium, mercury, molybdenum, lead, and tin had negative weights in the construction of the ERS. The adjusted HR of MetS comparing 75th vs. 25th percentiles of the ERS was 1.45 (1.13, 1.87). These findings support the view that arsenic, cobalt, zinc, as well as metal mixtures, might influence the risks of incident MetS in midlife women.

Long-term exposure to ambient air pollutants and age-related macular degeneration in middle-aged and older adults.

Absract In developed countries, age-related macular degeneration (AMD) is a leading cause of irreversible blindness in adults. The key pathways of AMD are suggested to be excessive oxidative stress and inflammation in the central retina. Because air pollution has been found capable of inducing oxidative stress and inflammation, it may play a role in development of AMD. This study investigated the association between ambient air pollution and AMD in 15,115 middle-aged and older adults (≥40 years) from Korean National Health and Nutrition Examination Survey 2008-2012. After controlling for important confounders, ambient NO2 and CO in current-to-5 prior years and PM10 in 2-to-5 prior years were significantly associated with higher prevalence of early AMD, while O3 in current-to-5 prior years was significantly associated with lower prevalence of early AMD. When modeled air pollution within administrative division units, its ORs with an IQR increase in NO2, CO, and O3 at current year were 1.24 (95% CI: 1.05-1.46), 1.22 (95% CI: 1.09-1.38), and 0.80 (95% CI: 0.70-0.92), respectively. Overall, results from air pollution at local/town units were consistent with those at administrative division units. Long-term exposures to ambient air pollution may play a role in the risk of AMD in middle-aged and older adults.

Serum antioxidant status and mortality from influenza and pneumonia in US adults.

OBJECTIVE: We examined the association between serum antioxidant status and mortality from influenza and pneumonia in US adults. DESIGN: Serum concentrations of antioxidants included vitamin C, vitamin A, vitamin E, sum of α- and ß-carotene, ß-cryptoxanthin, lutein + zeaxanthin and lycopene. We computed total antioxidant capacity (TAC) as a measure of composite antioxidant status in serum. Survey-weighted Cox proportional hazard models were used to compute hazard ratios (HR) and 95 % CI comparing quartiles of each antioxidant and TAC. SETTING: Data from the US National Health and Nutrition Examination Survey (NHANES)-III. PARTICIPANTS: A total of 7428 NHANES-III participants ≥45 years of age. RESULTS: With a weighted-median follow-up of 16·8 years, 154 participants died from influenza/pneumonia. After adjustment for covariates, serum vitamin C, the sum of α- and ß-carotene and TAC were nonlinearly associated with influenza/pneumonia mortality, with the statistically significant smallest HR at the third quartile v. the first quartile (HR = 0·38 (95 % CI: 0·19, 0·77), 0·29 (0·16, 0·51) and 0·30 (0·15, 0·59), respectively). HR comparing the fourth v. the first quartiles were weaker and nonsignificant: 0·57 (95 % CI: 0·27, 1·17), 0·70 (0·41, 1·19) and 0·65 (0·31, 1·35), respectively. Serum lycopene had a monotonic association with influenza/pneumonia mortality (HR = 0·43 (95 % CI: 0·23, 0·83) comparing the fourth v. the first quartile, Pfor trend = 0·01). CONCLUSIONS: The current study suggests that antioxidant intake as reflected by serum concentrations may reduce mortality risk from influenza or pneumonia in the US general population. These findings warrant further confirmation in other populations with different settings (e.g. a shorter-term association with influenza infection).

Pronounced cohabitation of active immunoglobulin genes from three different chromosomes in transcription factories during maximal antibody synthesis.

To understand the relationships between nuclear organization and gene expression in a model system, we employed three-dimensional imaging and chromatin immunoprecipitation (ChIP)-chromosome conformation capture (3C) techniques to investigate the topographies of the immunoglobulin (Ig) genes and transcripts during B-cell development. Remarkably, in plasma cells, when antibody synthesis peaks, active Ig genes residing on three different chromosomes exhibit pronounced colocalizations in transcription factories, often near the nuclear periphery, and display trans-chromosomal enhancer interactions, and their transcripts frequently share interchromatin trafficking channels. Conceptually, these features of nuclear organization maximize coordinated transcriptional and transcript trafficking control for potentiating the optimal cytoplasmic assembly of the resulting translation products into protein multimers.

Perfluoroalkyl and polyfluoroalkyl substances and body size and composition trajectories in midlife women: the study of women's health across the nation 1999-2018.

BACKGROUND/OBJECTIVES: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been suggested as obesogens but epidemiologic evidence is limited. We examined associations of serum PFAS concentrations with longitudinal trajectories of weight, waist circumference (WC), fat mass, and proportion fat in midlife women. SUBJECTS/METHODS: This study included 1,381 midlife women, with a total of 15,000 repeated measures from the multi-racial/ethnic Study of Women's Health Across the Nation between 1999 and 2018. The average follow-up was 14.9 (range: 0-18.6) years. Body size (objectively measured weight and WC) and body composition from dual-energy X-ray absorptiometry were assessed at near-annual visits. Linear mixed models with piecewise linear splines were utilized to model non-linear trajectories of body size and composition. RESULTS: After multivariable adjustment, PFAS concentrations were positively associated with weight, WC, fat mass, and proportion fat at baseline and during follow-up. Comparing the highest to the lowest tertiles of PFAS concentrations, adjusted geometric mean weight was 73.9 kg vs. 69.6 kg for PFOS (P < 0.0001), and 74.0 vs. 69.4 kg for linear PFOA (P < 0.0001) at baseline. Women with the highest tertile of PFOS had an annual increase rate of 0.33% (95% CI: 0.27%, 0.40%) in weight, compared to the lowest tertile with 0.10% (95% CI: 0.04%, 0.17%) (P < 0.0001). PFOS was also significantly related to higher increase rates in WC (difference = 0.12% per year, P = 0.002) and fat mass (difference = 0.25% per year, P = 0.0002). EtFOSAA and MeFOSAA showed similar effects to PFOS. Although PFHxS was not related to body size or fat at baseline, PFHxS was significantly associated with accelerated increases in weight (P < 0.0001), WC (P = 0.003), fat mass (P < 0.0001), and proportion fat (P = 0.0009). No significant results were found for PFNA. CONCLUSIONS: Certain PFAS were positively associated with greater body size and body fat, and higher rates of change over time. PFAS may be an underappreciated contributing factor to obesity risk.

Crlz-1 Controls Germinal Center Reaction by Relaying a Wnt Signal to the Bcl-6 Expression in Centroblasts during Humoral Immune Responses.

Crlz-1 was expressed along with Wnt3a in the rapidly proliferating centroblasts within the dark zone of germinal center (GC) during humoral immune responses. Significantly, Crlz-1 relayed a Wnt/ß-catenin signal to the expression of Bcl-6, the master regulator of centroblasts, by mobilizing the cytoplasmic CBFß into the nucleus to allow Runx/CBFß heterodimerization and its subsequent binding to the Bcl-6 promoter. The knockdown of Crlz-1 or ß-catenin, as well as inhibition of Wnt signaling in the centroblasts, led to the decreased expression of Bcl-6 and, thereby, the altered expression of its various target genes, resulting in their diminished proliferation. Consistently, the administration of Wnt inhibitors into the immunized mice impaired or abolished GC reaction, with concomitant decreases of Crlz-1 and Bcl-6 expression and, thus, centroblastic proliferation. Our observation that Wnt/ß-catenin signaling via Crlz-1 regulates GC reaction would suggest developmental strategies for vaccine adjuvants and cancer therapeutics because both immune efficacy and accidental lymphoma depend on GC reaction. Our studies of Crlz-1 were performed using human cell lines, mice, and their primary cells.

Perfluoroalkyl substances and cognitive function in older adults: Should we consider non-monotonic dose-responses and chronic kidney disease?

BACKGROUND: Although potential neurotoxicity of perfluoroalkyl and polyfluoroalkyl substances (PFAS) is suggested, previous epidemiologic studies have reported a 'protective' association between serum PFAS concentration and cognition function. Poor outcome assessment, residual confounding, non-monotonic dose-responses (NMDRs), and the role of reduced kidney function in PFAS excretion may be alternative explanations of these findings. OBJECTIVES: We examined the association of perfluoroalkyls with cognitive functions assessed using the Consortium to Establish a Registry for Alzheimer's Disease word learning and recall; the Animal Fluency; and the Digit Symbol Substitution tests. METHODS: We included 903 adults aged ≥60 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. We computed a composite z-score as an average of four individual cognitive z-scores and used it as the outcome. Linear and generalized additive models were used to evaluate linear and non-linear associations. RESULTS: With the linearity assumption, perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) were significantly positively associated with composite z-score after adjustment for age, sex, race/ethnicity, education, smoking, poverty-income ratio, health insurance, food security, alcohol, and physical activity. Smoothing plots suggested NMDRs, especially for perfluorooctane sulfonate (PFOS) with a U-shape dose-response. When restricting to participants without chronic kidney disease (CKD) (n = 613), the positive associations for PFOA and PFNA observed in the whole population diminished, whereas PFOS was inversely and significantly associated with composite z-score. Also, negative confounding effects of fish/seafood consumption seem to be substantial. Effect estimates of composite z-score were -0.055 (95% CI: -0.097, -0.012, P = 0.01) for a doubling increase in PFOS. DISCUSSION: These findings suggest that the previous epidemiologic findings of a 'protective' association between PFAS and cognition may be explained by CKD, NMDRs and confounding by fish consumption. PFOS at the current population exposure level in the U.S. may be a risk factor for cognitive decline in older adults with normal kidney function.

Serum selenium and non-alcoholic fatty liver disease (NAFLD) in U.S. adults: National Health and Nutrition Examination Survey (NHANES) 2011-2016.

BACKGROUND: Selenium is an essential trace element that shows beneficial or adverse health effects depending on the dose. Laboratory studies suggest that high selenium may contribute to the development of non-alcoholic fatty liver disease (NAFLD). However, human evidence is limited. We evaluated the associations of serum selenium level with serum alanine aminotransferase (ALT) activity and suspected NAFLD prevalence in U.S. adults. METHODS: We conducted the cross-sectional analysis in 3827 adults aged 20 years and older without viral hepatitis, hemochromatosis, or alcoholic liver disease who participated in the National Health and Nutrition Examination Survey (NHANES) 2011-2012, 2013-2014, and 2015-2016. Serum selenium was measured using inductively coupled plasma dynamic reaction cell mass spectrometry. Suspected NAFLD cases were defined in the presence of serum ALT >30 international units (IU)/L in men and >19 I.U./L in women in the absence of other identifiable causes of liver disease. RESULTS: The median (interquartile range) of serum selenium level was 127.9 (117.9, 139.4) µg/L. Non-linear associations of serum selenium with NAFLD prevalence and serum ALT activity were observed in the generalized additive models with penalized splines. After adjustment for sociodemographic variables, lifestyle factors, body mass index, and NHANES survey cycles, positive associations were found at > ~130 µg/L serum selenium with both NAFLD and ALT, whereas the associations were flattened at < ~130 µg/L. CONCLUSIONS: Our findings provide evidence of non-linear associations of serum selenium with ALT activity and NAFLD prevalence. In particular, positive associations were found above serum selenium level of 130 µg/L, whereas no association was observed below this value. This finding requires confirmation in future prospective cohort studies.

Urinary metals and adipokines in midlife women: The Study of Women's Health Across the nation (SWAN).

BACKGROUND: Information on the associations between metal exposures and adipokines in human populations is limited and results are inconsistent. We evaluated the associations between metals and adipokines. METHODS: Urinary concentrations of 15 metals (arsenic, barium, cadmium, cobalt, cesium, copper, mercury, manganese, molybdenum, nickel, lead, antimony, tin, thallium, and zinc) were measured in 1999-2000 among 1228 women of the Study of Women's Health Across the Nation Multi-Pollutant Study. Serum adipokines including high molecular weight (HMW)-adiponectin, leptin, and soluble leptin receptor (sOB-R) were measured at the follow-up visit (2002-2003). Linear regression models with adaptive elastic-net (AENET) were fit to identify metals associated with adipokines and to compute estimated percent changes in adipokines for one standard deviation increase in log-transformed urinary metal concentrations. RESULTS: After adjustment for confounders, urinary molybdenum was associated with a 5.54% higher level (95% CI: 1.36%, 9.90%), whereas cadmium was associated with a 4.53% lower level (95% CI: -8.17%, -0.76%) of HMW-adiponectin. Urinary molybdenum was also associated with a 5.95% lower leptin level (95% CI: -10.15%, -1.56%) and a 2.98% (95% CI: 0.69%, 5.32%) higher sOB-R level. Urinary cesium and lead were associated with a 3.58% (95% CI: -6.06%, -1.03%) and a 2.53% (95% CI: -4.80%, -0.21%) lower level of sOB-R, respectively. CONCLUSIONS: Our findings suggest that molybdenum was associated with favorable profiles of HMW-adiponectin, leptin, and sOB-R. Exposures to cadmium, cesium, and lead were associated with adverse adipokine profiles.