Associations Between Early-Life Adversity, Ambient Air Pollution, and Telomere Length in Children.

OBJECTIVE: Examine the independent associations and interaction between early-life adversity and residential ambient air pollution exposure on relative buccal telomere length (rBTL). METHODS: Experiences of abuse, neglect, household challenges, and related life events were identified in a cross-sectional sample of children ages 1-11 years (n = 197) using the 17-item Pediatric ACEs and Related Life Event Screener (PEARLS) tool. The PEARLS tool was analyzed both as a total score and across established domains (Maltreatment, Household Challenges, and Social Context). Ground-level fine particulate matter (PM 2.5 ) concentrations were matched to residential locations for the one and twelve months prior to biospecimen collection. We used multivariable linear regression models to examine for independent associations between continuous PM 2.5 exposure and PEARLS score/domains with rBTL. Additionally, effect modification by PEARLS scores and domains on associations between PM 2.5 exposure and rBTL was examined. RESULTS: Study participants were 47% girls, with mean age = 5.9 years [standard deviation: 3.4] median reported PEARLS score of 2 [interquartile range (IQR): 4], median 12-month prior PM 2.5 concentrations of 11.8 µg/m 3 [IQR: 2.7], median 1-month prior PM 2.5 concentrations of 10.9 µg/m 3 [IQR: 5.8], and rBTL of 0.1 [IQR: 0.03]. Mean 12-month prior PM 2.5 exposure was inversely associated with rBTL (ß = -0.02, 95% CI: -0.04, -0.01). While reported PEARLS scores and domains were not independently associated with rBTL, we observed a greater decrement in rBTL with increment of average annual PM 2.5 as reported Social Context domain items increased (p-interaction<0.05). CONCLUSION: Our results suggest that adverse Social Context factors may accelerate the association between chronic PM 2.5 exposure on telomere shortening during childhood.

A scoping review of wildfire smoke risk communications: issues, gaps, and recommendations.

BACKGROUND: Wildfire smoke exposure has become a growing public health concern, as megafires and fires at the wildland urban interface increase in incidence and severity. Smoke contains many pollutants that negatively impact health and is linked to a number of health complications and chronic diseases. Communicating effectively with the public, especially at-risk populations, to reduce their exposure to this environmental pollutant has become a public health priority. Although wildfire smoke risk communication research has also increased in the past decade, best practice guidance is limited, and most health communications do not adhere to health literacy principles: readability, accessibility, and actionability. This scoping review identifies peer-reviewed studies about wildfire smoke risk communications to identify gaps in research and evaluation of communications and programs that seek to educate the public. METHODS: Four hundred fifty-one articles were identified from Web of Science and PubMed databases. After screening, 21 articles were included in the final sample for the abstraction process and qualitative thematic analysis. Ten articles were based in the US, with the other half in Australia, Canada, Italy, and other countries. Fifteen articles examined communication materials and messaging recommendations. Eight papers described communication delivery strategies. Eleven articles discussed behavior change. Six articles touched on risk communications for vulnerable populations; findings were limited and called for increasing awareness and prioritizing risk communications for at-risk populations. RESULTS: This scoping review found limited studies describing behavior change to reduce wildfire smoke exposure, characteristics of effective communication materials and messaging, and communication delivery strategies. Literature on risk communications, dissemination, and behavior change for vulnerable populations was even more limited. CONCLUSIONS: Recommendations include providing risk communications that are easy-to-understand and adapted to specific needs of at-risk groups. Communications should provide a limited number of messages that include specific actions for avoiding smoke exposure. Effective communications should use mixed media formats and a wide variety of dissemination strategies. There is a pressing need for more intervention research and effectiveness evaluation of risk communications about wildfire smoke exposure, and more development and dissemination of risk communications for both the general public and vulnerable populations.

LEAP2 is associated with cardiometabolic markers but is unchanged by antidiabetic treatment in people with prediabetes.

To examine whether fasting plasma liver-expressed antimicrobial peptide 2 (FP-LEAP2) is associated with markers of cardiometabolic disease susceptibility in a cohort with prediabetes and overweight/obesity and whether antidiabetic interventions affect FP-LEAP2 levels. The analysis included 115 individuals with prediabetes [hemoglobin A1c (HbA1c) 39-47 mmol/mol, 5.7%-6.4%] and overweight/obesity [body mass index (BMI) ≥ 25 kg/m2] from a randomized controlled trial. Changes in FP-LEAP2 levels were assessed in relation to treatment with dapagliflozin (10 mg once daily), metformin (1,700 mg daily), or interval-based exercise (5 days/wk, 30 min/session) compared with control (habitual lifestyle) after 6 and 13 wk of treatment. FP-LEAP2 levels were positively associated with [standardized beta coefficient (95% CI)]: BMI 0.22 (0.03:0.41), P = 0.027; body weight 0.27 (0.06:0.48), P = 0.013; fat mass 0.2 (0.00:0.4), P = 0.048; lean mass 0.47 (0.13:0.8), P = 0.008; HbA1c 0.35 (0.17:0.53), P < 0.001; fasting plasma glucose (FPG) 0.32 (0.12:0.51), P = 0.001; fasting serum insulin 0.28 (0.09:0.47), P = 0.005; total cholesterol 0.19 (0.01:0.38), P = 0.043; triglycerides 0.31 (0.13:0.5), P < 0.001; and transaminases and fatty liver index (standardized beta coefficients 0.23-0.32), all P < 0.020. FP-LEAP2 levels were inversely associated with insulin sensitivity [-0.22 (-0.41: -0.03), P = 0.022] and kidney function [estimated glomerular filtration rate (eGFR) -0.34 (-0.56: -0.12), P = 0.003]. FP-LEAP2 levels were not associated with fat distribution or body fat percentage, fasting glucagon, postload glucose, ß-cell function, or low-density lipoprotein. The interventions were not associated with changes in FP-LEAP2. FP-LEAP2 is associated with body mass, impaired insulin sensitivity, liver-specific enzymes, and kidney function. The findings highlight the importance of studying LEAP2 in obesity, type 2 diabetes, and nonalcoholic fatty liver disease. FP-LEAP2 was not affected by metformin, dapaglifloxin, or exercise in this population.NEW & NOTEWORTHY LEAP2, primarily secreted by the liver, increases with greater body mass, insulin resistance, and liver-specific enzymes in individuals with prediabetes and overweight or obesity. Fasting glucose, body mass, and alanine aminotransferase independently predict LEAP2 levels. LEAP2 is inversely linked to impaired kidney function. Elevated LEAP2 levels might indicate an increased metabolic risk, warranting further investigation into its potential involvement in glucose and body weight control.

Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice.

OBJECTIVE: Medium chain fatty acids (MCFAs), which are fatty acids with chain lengths of 8-12 carbon atoms, have been shown to reduce food intake in rodents and humans, but the underlying mechanisms are unknown. Unlike most other fatty acids, MCFAs are absorbed from the intestine into the portal vein and enter first the liver. We thus hypothesized that MCFAs trigger the release of hepatic factors that reduce appetite. METHODS: The liver transcriptome in mice that were orally administered MCFAs as C8:0 triacylglycerol (TG) was analyzed. Circulating growth/differentiation factor 15 (GDF15), tissue Gdf15 mRNA and food intake were investigated after acute oral gavage of MCFAs as C8:0 or C10:0 TG in mice. Effects of acute and subchronic administration of MCFAs as C8:0 TG on food intake and body weight were determined in mice lacking either the receptor for GDF15, GDNF Family Receptor Alpha Like (GFRAL), or GDF15. RESULTS: Hepatic and small intestinal expression of Gdf15 and circulating GDF15 increased after ingestion of MCFAs, while intake of typical dietary long-chain fatty acids (LCFAs) had no effect. Plasma GDF15 levels also increased in the portal vein with MCFA intake, indicating that in addition to the liver, the small intestine contributes to the rise in circulating GDF15. Acute oral provision of MCFAs decreased food intake over 24 h compared with a LCFA-containing bolus, and this anorectic effect required the GDF15 receptor, GFRAL. Moreover, subchronic oral administration of MCFAs reduced body weight over 7 days, an effect that was blunted in mice lacking either GDF15 or GFRAL. CONCLUSIONS: We have identified ingestion of MCFAs as a novel nutritional approach that increases circulating GDF15 in mice and have revealed that the GDF15-GFRAL axis is required for the full anorectic effect of MCFAs.

The dietary regulation of LEAP2 depends on meal composition in mice.

Ghrelin represents a key hormone regulating energy balance. Upon activation of the growth hormone secretagogue receptor (GHSR), ghrelin increases blood glucose levels, food intake, and promotes weight gain. The liver-expressed antimicrobial peptide 2 (LEAP2) acts as an endogenous antagonist of the GHSR. While the regulation of LEAP2 and its effect on the GHSR likely occur in an opposite pattern to that of ghrelin, the dietary regulation of LEAP2 remains to be described. We, therefore, examined the regulation of LEAP2 by different acute meal challenges (glucose, mixed meal, olive, lard, and fish oil) and diets (chow vs. high-fat) in C57BL/6 male mice. In addition, the effect of specific fatty acids (oleic, docosahexaenoic, and linoleic acid) on LEAP2 was assessed in murine intestinal organoids. While only mixed meal increased liver Leap2 expression, all meal challenges except fish oil increased jejunal Leap2 expression compared to water. Leap2 expression correlated with levels of hepatic glycogen and jejunal lipids. Lipid versus water dosing increased LEAP2 levels in the systemic circulation and portal vein where fish oil was associated with the smallest increase. In line with this, oleic acid, but not docosahexaenoic acid increased Leap2 expression in intestinal organoids. Feeding mice with high-fat versus chow diet not only increased plasma LEAP2 levels, but also the increment in plasma LEAP2 upon dosing with olive oil versus water. Taken together, these results show that LEAP2 is regulated by meal ingestion in both the small intestine and the liver according to the meal/diet of interest and local energy stores.

Cognitive Development and Prenatal Air Pollution Exposure in the CHAMACOS Cohort.

BACKGROUND: Because fine particulate matter [PM, with aerodynamic diameter ≤2.5µm (PM2.5)] is a ubiquitous environmental exposure, small changes in cognition associated with PM2.5 exposure could have great societal costs. Prior studies have demonstrated a relationship between in utero PM2.5 exposure and cognitive development in urban populations, but it is not known whether these effects are similar in rural populations and whether they persist into late childhood. OBJECTIVES: In this study, we tested for associations between prenatal PM2.5 exposure and both full-scale and subscale measures of IQ among a longitudinal cohort at age 10.5 y. METHODS: This analysis used data from 568 children enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a birth cohort study in California's agricultural Salinas Valley. Exposures were estimated at residential addresses during pregnancy using state of the art, modeled PM2.5 surfaces. IQ testing was performed by bilingual psychometricians in the dominant language of the child. RESULTS: A 3-µg/m3 higher average PM2.5 over pregnancy was associated with -1.79 full-scale IQ points [95% confidence interval (CI): -2.98, -0.58], with decrements specifically in Working Memory IQ (WMIQ) and Processing Speed IQ (PSIQ) subscales [WMIQ -1.72 (95% CI: -2.98, -0.45) and PSIQ -1.19 (95% CI: -2.54, 0.16)]. Flexible modeling over the course of pregnancy illustrated mid-to-late pregnancy (months 5-7) as particularly susceptible times, with sex differences in the timing of susceptible windows and in which subscales were most affected [Verbal Comprehension IQ (VCIQ) and WMIQ in males; and PSIQ in females]. DISCUSSION: We found that small increases in outdoor PM2.5 exposure in utero were associated with slightly lower IQ in late childhood, robust to many sensitivity analyses. In this cohort there was a larger effect of PM2.5 on childhood IQ than has previously been observed, perhaps due to differences in PM composition or because developmental disruption could alter the cognitive trajectory and thus appear more pronounced as children get older. https://doi.org/10.1289/EHP10812.

Associations between prenatal and early-life air pollution exposure and lung function in young children: Exploring influential windows of exposure on lung development.

BACKGROUND: Evidence in the literature suggests that air pollution exposures experienced prenatally and early in life can be detrimental to normal lung development, however the specific timing of critical windows during development is not fully understood. OBJECTIVES: We evaluated air pollution exposures during the prenatal and early-life period in association with lung function at ages 6-9, in an effort to identify potentially influential windows of exposure for lung development. METHODS: Our study population consisted of 222 children aged 6-9 from the Fresno-Clovis metro area in California with spirometry data collected between May 2015 and May 2017. We used distributed-lag non-linear models to flexibly model the exposure-lag-response for monthly average exposure to fine particulate matter (PM2.5) and ozone (O3) during the prenatal months and first three years of life in association with forced vital capacity (FVC), and forced expiratory volume in the first second (FEV1), adjusted for covariates. RESULTS: PM2.5 exposure during the prenatal period and the first 3-years of life was associated with lower FVC and FEV1 assessed at ages 6-9. Specifically, an increase from the 5th percentile of the observed monthly average exposure (7.55 µg/m3) to the median observed exposure (12.69 µg/m3) for the duration of the window was associated with 0.42 L lower FVC (95% confidence interval (CI): -0.82, -0.03) and 0.38 L lower FEV1 (95% CI: -0.75, -0.02). The shape of the lag-response indicated that the second half of pregnancy may be a particularly influential window of exposure. Associations for ozone were not as strong and typically CIs included the null. CONCLUSIONS: Our findings indicate that prenatal and early-life exposures to PM2.5 are associated with decreased lung function later in childhood. Exposures during the latter months of pregnancy may be especially influential.

Insulin Sensitization Following a Single Exercise Bout Is Uncoupled to Glycogen in Human Skeletal Muscle: A Meta-analysis of 13 Single-Center Human Studies.

Exercise profoundly influences glycemic control by enhancing muscle insulin sensitivity, thus promoting glucometabolic health. While prior glycogen breakdown so far has been deemed integral for muscle insulin sensitivity to be potentiated by exercise, the mechanisms underlying this phenomenon remain enigmatic. We have combined original data from 13 of our studies that investigated insulin action in skeletal muscle either under rested conditions or following a bout of one-legged knee extensor exercise in healthy young male individuals (n = 106). Insulin-stimulated glucose uptake was potentiated and occurred substantially faster in the prior contracted muscles. In this otherwise homogenous group of individuals, a remarkable biological diversity in the glucometabolic responses to insulin is apparent both in skeletal muscle and at the whole-body level. In contrast to the prevailing concept, our analyses reveal that insulin-stimulated muscle glucose uptake and the potentiation thereof by exercise are not associated with muscle glycogen synthase activity, muscle glycogen content, or degree of glycogen utilization during the preceding exercise bout. Our data further suggest that the phenomenon of improved insulin sensitivity in prior contracted muscle is not regulated in a homeostatic feedback manner from glycogen. Instead, we put forward the idea that this phenomenon is regulated by cellular allostatic mechanisms that elevate the muscle glycogen storage set point and enhance insulin sensitivity to promote the uptake of glucose toward faster glycogen resynthesis without development of glucose overload/toxicity or feedback inhibition.

The Association between Ambient PM2.5 and Low Birth Weight in California.

Previous studies have shown associations between air pollutants and low birth weight. However, few studies assess whether poverty and race/ethnicity are effect modifiers for this relationship. We used publicly available data on 7785 California census tracts from the California Communities Environmental Health Screening Tool (CalEnviroScreen). Multivariable linear regression was used to examine the association between outdoor PM2.5 and low birth weight (LBW), including stratification by poverty and race/ethnicity (as a proxy for experienced racism). A 1 µg m-3 increase in PM2.5 was associated with a 0.03% (95% CI: 0.01, 0.04) increase in the percentage of LBW infants in a census tract. The association between PM2.5 and LBW was stronger in census tracts with the majority living in poverty (0.06% increase; 95% CI: 0.03, 0.08) compared to those with fewer people living in poverty (0.02% increase; 95% CI: 0.00, 0.03). Our results show that exposure to outdoor PM2.5 is associated with a small increase in the percentage of LBW infants in a census tract, with a further increase in tracts with high poverty. The results for effect modification by race/ethnicity were less conclusive.

LEAP2 reduces postprandial glucose excursions and ad libitum food intake in healthy men.

The gastric hormone ghrelin stimulates food intake and increases plasma glucose through activation of the growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) has been proposed to inhibit actions of ghrelin through inverse effects on GHSR activity. Here, we investigate the effects of exogenous LEAP2 on postprandial glucose metabolism and ad libitum food intake in a randomized, double-blind, placebo-controlled, crossover trial of 20 healthy men. We report that LEAP2 infusion lowers postprandial plasma glucose and growth hormone concentrations and decreases food intake during an ad libitum meal test. In wild-type mice, plasma glucose and food intake are reduced by LEAP2 dosing, but not in GHSR-null mice, pointing to GHSR as a potential mediator of LEAP2's glucoregulatory and appetite-suppressing effects in mice.

Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2.

INTRODUCTION: Liver-expressed antimicrobial peptide-2 (LEAP2) is an endogenous ghrelin receptor antagonist, which is upregulated in the fed state and downregulated during fasting. We hypothesized that the ketone body beta-hydroxybutyrate (BHB) is involved in the downregulation of LEAP2 during conditions with high circulating levels of BHB. METHODS: Hepatic and intestinal Leap2 expression were determined in 3 groups of mice with increasing circulating levels of BHB: prolonged fasting, prolonged ketogenic diet, and oral BHB treatment. LEAP2 levels were measured in lean and obese individuals, in human individuals following endurance exercise, and in mice after BHB treatment. Lastly, we investigated Leap2 expression in isolated murine hepatocytes challenged with BHB. RESULTS: We confirmed increased circulating LEAP2 levels in individuals with obesity compared to lean individuals. The recovery period after endurance exercise was associated with increased plasma levels of BHB levels and decreased LEAP2 levels in humans. Leap2 expression was selectively decreased in the liver after fasting and after exposure to a ketogenic diet for 3 weeks. Importantly, we found that oral administration of BHB increased circulating levels of BHB in mice and decreased Leap2 expression levels and circulating LEAP2 plasma levels, as did Leap2 expression after direct exposure to BHB in isolated murine hepatocytes. CONCLUSION: From our data, we suggest that LEAP2 is downregulated during different states of energy deprivation in both humans and rodents. Furthermore, we here provide evidence that the ketone body, BHB, which is highly upregulated during fasting metabolism, directly downregulates LEAP2 levels. This may be relevant in ghrelin receptor-induced hunger signaling during energy deprivation.

Traffic-related air pollution, biomarkers of metabolic dysfunction, oxidative stress, and CC16 in children.

BACKGROUND: Previous research has revealed links between air pollution exposure and metabolic syndrome in adults; however, these associations are less explored in children. OBJECTIVE: This study aims to investigate the association between traffic-related air pollutants (TRAP) and biomarkers of metabolic dysregulation, oxidative stress, and lung epithelial damage in children. METHODS: We conducted cross-sectional analyses in a sample of predominantly Latinx, low-income children (n = 218) to examine associations between air pollutants (nitrogen dioxide (NO2), nitrogen oxides (NOx), elemental carbon, polycyclic aromatic hydrocarbons, carbon monoxide (CO), fine particulates (PM2.5)) and biomarkers of metabolic function (high-density lipoprotein (HDL), hemoglobin A1c (HbA1c), oxidative stress (8-isoprostane), and lung epithelial damage (club cell protein 16 (CC16)). RESULTS: HDL cholesterol showed an inverse association with NO2 and NOx, with the strongest relationship between HDL and 3-month exposure to NO2 (-15.4 mg/dL per IQR increase in 3-month NO2, 95% CI = -27.4, -3.4). 8-isoprostane showed a consistent pattern of increasing values with 1-day and 1-week exposure across all pollutants. Non-significant increases in % HbA1c were found during 1-month time frames and decreasing CC16 in 3-month exposure time frames. CONCLUSION: Our results suggest that TRAP is significantly associated with decreased HDL cholesterol in longer-term time frames and elevated 8-isoprostane in shorter-term time frames. TRAP could have the potential to influence lifelong metabolic patterns, through metabolic effects in childhood.

Systematic Review of Ozone Effects on Human Lung Function, 2013 Through 2020.

BACKGROUND: Ozone effects on lung function are particularly important to understand in the context of the air pollution-health outcomes epidemiologic literature, given the complex relationships between ozone and other air pollutants with known lung function effects. RESEARCH QUESTION: What has been learned about the association between ozone exposures and lung function from epidemiology studies published from 2013 through 2020? STUDY DESIGN AND METHODS: On March 18, 2018, and September 8, 2020, PubMed was searched using the terms health AND ozone, filtering to articles in English and about humans, from 2013 or later. An additional focused review searching for ozone AND (lung function OR FEV1OR FVC) was performed June 26, 2021. Articles were selected for this review if they reported a specific relationship between a lung function outcome and ozone exposure. RESULTS: Of 3,271 articles screened, 53 ultimately met criteria for inclusion. A systematic review with assessment of potential for bias was conducted, but a meta-analysis was not carried out because of differences in exposure duration and outcome quantification. Consistent evidence exists of small decreases in children's lung function, even associated with very low levels of short-term ozone exposure. The effects on adult lung function from exposure to low-level, short-term ozone are less clear, although ozone-associated decrements may occur in the elderly. Finally, long-term ozone exposure decreases both lung function and lung function growth in children, although few new studies have examined long-term ozone and lung function in adults. INTERPRETATION: Much of this literature involves concentrations below the current US Environmental Protection Agency's National Ambient Air Quality Standard of 70 parts per billion over an 8-h averaging time, suggesting that this current standard may not protect children adequately from ozone-related decrements in lung function.

No fire without smoke (particles).

Pollution from landscape fires, which are increasing with climate change, leads to babies being born with lower birthweights in low- and middle-income countries.

Traffic-related air pollution is associated with glucose dysregulation, blood pressure, and oxidative stress in children.

BACKGROUND: Metabolic syndrome increases the risk of cardiovascular disease in adults. Antecedents likely begin in childhood and whether childhood exposure to air pollution plays a contributory role is not well understood. OBJECTIVES: To assess whether children's exposure to air pollution is associated with markers of risk for metabolic syndrome and oxidative stress, a hypothesized mediator of air pollution-related health effects. METHODS: We studied 299 children (ages 6-8) living in the Fresno, CA area. At a study center visit, questionnaire and biomarker data were collected. Outcomes included hemoglobin A1c (HbA1c), urinary 8-isoprostane, systolic blood pressure (SBP), and BMI. Individual-level exposure estimates for a set of four pollutants that are constituents of traffic-related air pollution (TRAP) - the sum of 4-, 5-, and 6-ring polycyclic aromatic hydrocarbon compounds (PAH456), NO2, elemental carbon, and fine particulate matter (PM2.5) - were modeled at the primary residential location for 1-day lag, and 1-week, 1-month, 3-month, 6-month, and 1-year averages prior to each participant's visit date. Generalized additive models were used to estimate associations between each air pollutant exposure and outcome. RESULTS: The study population was 53% male, 80% Latinx, 11% Black and largely low-income (6% were White and 3% were Asian/Pacific Islander). HbA1c percentage was associated with longer-term increases in TRAP; for example a 4.42 ng/m3 increase in 6-month average PAH456 was associated with a 0.07% increase (95% CI: 0.01, 0.14) and a 3.62 µg/m3 increase in 6-month average PM2.5 was associated with a 0.06% increase (95% CI: 0.01, 0.10). The influence of air pollutants on blood pressure was strongest at 3 months; for example, a 6.2 ppb increase in 3-month average NO2 was associated with a 9.4 mmHg increase in SBP (95% CI: 2.8, 15.9). TRAP concentrations were not significantly associated with anthropometric or adipokine measures. Short-term TRAP exposure averages were significantly associated with creatinine-adjusted urinary 8-isoprostane. DISCUSSION: Our results suggest that both short- and longer-term estimated individual-level outdoor residential exposures to several traffic-related air pollutants, including ambient PAHs, are associated with biomarkers of risk for metabolic syndrome and oxidative stress in children.