Does socioeconomic and environmental burden affect vulnerability to extreme air pollution and heat? A case-crossover study of mortality in California.

BACKGROUND: Extreme heat and air pollution is associated with increased mortality. Recent evidence suggests the combined effects of both is greater than the effects of each individual exposure. Low neighborhood socioeconomic status ("socioeconomic burden") has also been associated with increased exposure and vulnerability to both heat and air pollution. We investigated if neighborhood socioeconomic burden or the combination of socioeconomic and environmental exposures ("socioenvironmental burden") modified the effect of combined exposure to extreme heat and particulate air pollution on mortality in California. METHODS: We used a time-stratified case-crossover design to assess the impact of daily exposure to extreme particulate matter <2.5 µm (PM2.5) and heat on cardiovascular, respiratory, and all-cause mortality in California 2014-2019. Daily average PM2.5 and maximum temperatures based on decedent's residential census tract were dichotomized as extreme or not. Census tract-level socioenvironmental and socioeconomic burden was assessed with the CalEnviroScreen (CES) score and a social deprivation index (SDI), and individual educational attainment was derived from death certificates. Conditional logistic regression was used to estimate associations of heat and PM2.5 with mortality with a product term used to evaluate effect measure modification. RESULTS: During the study period 1,514,292 all-cause deaths could be assigned residential exposures. Extreme heat and air pollution alone and combined were associated with increased mortality, matching prior reports. Decedents in census tracts with higher socioenvironmental and socioeconomic burden experienced more days with extreme PM2.5 exposure. However, we found no consistent effect measure modification by CES or SDI on combined or separate extreme heat and PM2.5 exposure on odds of total, cardiovascular or respiratory mortality. No effect measure modification was observed for individual education attainment. CONCLUSION: We did not find evidence that neighborhood socioenvironmental- or socioeconomic burden significantly influenced the individual or combined impact of extreme exposures to heat and PM2.5 on mortality in California. IMPACT: We investigated the effect measure modification by socioeconomic and socioenvironmental of the co-occurrence of heat and PM2.5, which adds support to the limited previous literature on effect measure modification by socioeconomic and socioenvironmental burden of heat alone and PM2.5 alone. We found no consistent effect measure modification by neighborhood socioenvironmental and socioeconomic burden or individual level SES of the mortality association with extreme heat and PM2.5 co-exposure. However, we did find increased number of days with extreme PM2.5 exposure in neighborhoods with high socioenvironmental and socioeconomic burden. We evaluated multiple area-level and an individual-level SES and socioenvironmental burden metrics, each estimating socioenvironmental factors differently, making our conclusion more robust.

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.

Preeclampsia Onset, Days to Delivery, and Autism Spectrum Disorders in Offspring: Clinical Birth Cohort Study.

BACKGROUND: Maternal preeclampsia is associated with a risk of autism spectrum disorders (ASD) in offspring. However, it is unknown whether the increased ASD risk associated with preeclampsia is due to preeclampsia onset or clinical management of preeclampsia after onset, as clinical expectant management of preeclampsia allows pregnant women with this complication to remain pregnant for potentially weeks depending on the onset and severity. Identifying the risk associated with preeclampsia onset and exposure provides evidence to support the care of high-risk pregnancies and reduce adverse effects on offspring. OBJECTIVE: This study aimed to fill the knowledge gap by assessing the ASD risk in children associated with the gestational age of preeclampsia onset and the number of days from preeclampsia onset to delivery. METHODS: This retrospective population-based clinical cohort study included 364,588 mother-child pairs of singleton births between 2001 and 2014 in a large integrated health care system in Southern California. Maternal social demographic and pregnancy health data, as well as ASD diagnosis in children by the age of 5 years, were extracted from electronic medical records. Cox regression models were used to assess hazard ratios (HRs) of ASD risk in children associated with gestational age of the first occurrence of preeclampsia and the number of days from first occurrence to delivery. RESULTS: Preeclampsia occurred in 16,205 (4.4%) out of 364,588 pregnancies; among the 16,205 pregnancies, 2727 (16.8%) first occurred at <34 weeks gestation, 4466 (27.6%) first occurred between 34 and 37 weeks, and 9012 (55.6%) first occurred at ≥37 weeks. Median days from preeclampsia onset to delivery were 4 (IQR 2,16) days, 1 (IQR 1,3) day, and 1 (IQR 0,1) day for those first occurring at <34, 34-37, and ≥37 weeks, respectively. Early preeclampsia onset was associated with greater ASD risk (P=.003); HRs were 1.62 (95% CI 1.33-1.98), 1.43 (95% CI 1.20-1.69), and 1.23 (95% CI 1.08-1.41), respectively, for onset at <34, 34-37, and ≥37 weeks, relative to the unexposed group. Within the preeclampsia group, the number of days from preeclampsia onset to delivery was not associated with ASD risk in children; the HR was 0.995 (95% CI 0.986-1.004) after adjusting for gestational age of preeclampsia onset. CONCLUSIONS: Preeclampsia during pregnancy was associated with ASD risk in children, and the risk was greater with earlier onset. However, the number of days from first preeclampsia onset to delivery was not associated with ASD risk in children. Our study suggests that ASD risk in children associated with preeclampsia is not increased by expectant management of preeclampsia in standard clinical practice. Our results emphasize the need to identify effective approaches to preventing the onset of preeclampsia, especially during early pregnancy. Further research is needed to confirm if this finding applies across different populations and clinical settings.

Exposure to 4,4'-DDE in visceral adipose tissue and weight loss in adolescents from the Teen-LABS cohort.

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

Disposable E-Cigarette Use and Subsequent Use Patterns in Adolescents and Young Adults.

BACKGROUND AND OBJECTIVES: Disposable electronic cigarettes (e-cigarettes) are widely used by adolescents and young adults (AYAs). Whether using disposable devices is associated with future e-cigarette use patterns is unknown but important for informing e-cigarette regulation. METHODS: Prospective longitudinal study combining data from adolescent (14-17 years) and young adult (21-24 years) cohorts from Southern California surveyed at baseline and approximately 8-month follow-up during 2021 to 2022. The analyses included AYAs who used e-cigarettes in the past 30 days at baseline and had exposure and outcome data (N = 403; adolescent n = 124, young adult n = 279). RESULTS: In the pooled sample of AYAs who used e-cigarettes at baseline (57.2% cis-gender female, 56.2% Hispanic), 278 (69.0%) reported past 30-day disposable e-cigarette use, and 125 (31.0%) used only nondisposable e-cigarettes. Baseline use of disposable (versus only nondisposable) devices was associated with higher odds of continued e-cigarette use (adjusted odds ratio = 1.92; 95% confidence interval = 1.09-3.42) and a greater number of times used e-cigarettes per day at follow-up (adjusted incidence rate ratio = 1.29; 95% confidence interval = 1.02-1.63). In supplemental analyses, disposable e-cigarette use was associated with greater odds of no changes (versus reductions) in e-cigarette use frequency and puffs per episode from baseline to follow-up but was not associated with increases in use frequency and intensity. No differences in e-cigarette use outcomes were found between those with poly-device (disposable and nondisposable) versus only disposable device use. CONCLUSIONS: Use of disposable e-cigarette devices among AYAs may be associated with higher risks for persistent e-cigarette use patterns, which should be considered in tobacco product regulation designed to protect AYAs.

Predicting the Climate Impact of Healthcare Facilities Using Gradient Boosting Machines.

Health care accounts for 9-10% of greenhouse gas (GHG) emissions in the United States. Strategies for monitoring these emissions at the hospital level are needed to decarbonize the sector. However, data collection to estimate emissions is challenging, especially for smaller hospitals. We explored the potential of gradient boosting machines (GBM) to impute missing data on resource consumption in the 2020 survey of a consortium of 283 hospitals participating in Practice Greenhealth. GBM imputed missing values for selected variables in order to predict electricity use and beef consumption (R2=0.82) and anesthetic gas desflurane use (R2=0.51), using administrative data readily available for most hospitals. After imputing missing consumption data, estimated GHG emissions associated with these three examples totaled over 3 million metric tons of CO2 equivalent emissions (MTCO2e). Specifically, electricity consumption had the largest total carbon footprint (2.4 MTCO2e), followed by beef (0.6 million MTCO2e) and desflurane consumption (0.03 million MTCO2e) across the 283 hospitals. The approach should be applicable to other sources of hospital GHGs in order to estimate total emissions of individual hospitals and to refine survey questions to help develop better intervention strategies.

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.

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.

Perceived Stress From Childhood to Adulthood and Cardiometabolic End Points in Young Adulthood: An 18-Year Prospective Study.

BACKGROUND: We investigated how childhood-to-adulthood perceived stress patterns predict adult cardiometabolic risk. METHODS AND RESULTS: This study included 276 participants from the Southern California Children's Health Study (2003-2014), and a follow-up assessment (2018-2021). Perceived stress (Perceived Stress Scale) was initially reported by participants' parents for themselves during early childhood (mean age, 6.3 years), and later self-reported during adolescence (13.3 years) and young adulthood (23.6 years). Participants were grouped into 4 stress patterns: consistently high, decreasing, increasing, and consistently low. Cardiometabolic risk was assessed in young adulthood by carotid artery intima-media thickness, systolic and diastolic blood pressure, obesity, percent body fat, android/gynoid ratio, and glycated hemoglobin. A cardiometabolic risk score was generated by summing the clinically abnormal markers. Multivariable linear and logistic regression models were used to (1) examine the associations between Perceived Stress Scale at 3 time points and adult cardiometabolic risk, and (2) assess the impact of stress pattern on adult cardiometabolic risk. Findings suggested that in adulthood, higher Perceived Stress Scale score was associated with increased overall cardiometabolic risk (ß=0.12 [95% CI, 0.01-0.22]), carotid artery intima-media thickness (ß=0.01 [95% CI, 0.0003-0.02]), systolic blood pressure (ß=1.27 [95% CI, 0.09-2.45]), and diastolic blood pressure (ß=0.94 [95% CI, 0.13-1.75]). Individuals with a consistently high adolescence-to-adulthood stress pattern had greater overall cardiometabolic risk (ß=0.31 [95% CI, 0.02-0.60]), android/gynoid ratio (ß=0.07 [95% CI, 0.02-0.13]), percent body fat (ß=2.59 [95% CI, 0.01-5.17]), and greater odds of obesity (odds ratio, 5.57 [95% CI, 1.62-19.10]) in adulthood, compared with those with a consistently low Perceived Stress Scale score. CONCLUSIONS: Consistently high perceived stress from adolescence to adulthood may contribute to greater cardiometabolic risk in young adulthood.

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.

Neighborhood Disadvantage and Autism Spectrum Disorder in a Population With Health Insurance.

Importance: Family socioeconomic status has been associated with autism spectrum disorder (ASD) diagnoses. Less is known regarding the role of neighborhood disadvantage in the United States, particularly when children have similar access to health insurance. Objective: To evaluate the association between neighborhood disadvantage and the diagnosis of ASD and potential effect modification by maternal and child demographic characteristics. Design, Setting, and Participants: This cohort study examined a retrospective birth cohort from Kaiser Permanente Southern California (KPSC), an integrated health care system. Children born in 2001 to 2014 at KPSC were followed up through KPSC membership records. Electronic medical records were used to obtain an ASD diagnosis up to December 31, 2019, or the last follow-up. Data were analyzed from February 2022 to September 2023. Exposure: Socioeconomic disadvantage at the neighborhood level, an index derived from 7 US census tract characteristics using principal component analysis. Main Outcomes and Measures: Clinical ASD diagnosis based on electronic medical records. Associations between neighborhood disadvantage and ASD diagnosis were determined by hazard ratios (HRs) from Cox regression models adjusted for birth year, child sex, maternal age at delivery, parity, severe prepregnancy health conditions, maternal race and ethnicity, and maternal education. Effect modification by maternal race and ethnicity, maternal education, and child sex was assessed. Results: Among 318 372 mothers with singleton deliveries during the study period, 6357 children had ASD diagnoses during follow-up; their median age at diagnosis was 3.53 years (IQR, 2.57-5.34 years). Neighborhood disadvantage was associated with a higher likelihood of ASD diagnosis (HR, 1.07; 95% CI, 1.02-1.11, per IQR = 2.70 increase). Children of mothers from minoritized racial and ethnic groups (African American or Black, Asian or Pacific Islander, Hispanic or Latinx groups) had increased likelihood of ASD diagnosis compared with children of White mothers. There was an interaction between maternal race and ethnicity and neighborhood disadvantage (difference in log-likelihood = 21.88; P < .001 for interaction under χ24); neighborhood disadvantage was only associated with ASD among children of White mothers (HR, 1.17; 95% CI, 1.09-1.26, per IQR = 2.00 increase). Maternal education and child sex did not significantly modify the neighborhood-ASD association. Conclusions and Relevance: In this study, children residing in more disadvantaged neighborhoods at birth had higher likelihood of ASD diagnosis among a population with health insurance. Future research is warranted to investigate the mechanisms behind the neighborhood-related disparities in ASD diagnosis, alongside efforts to provide resources for early intervention and family support in communities with a higher likelihood of ASD.

Prospective study of e-cigarette use and respiratory symptoms in adolescents and young adults.

RATIONALE: Electronic cigarette (e-cigarette) aerosol contains volatile aldehydes, including flavourings and oxidant metals with known pulmonary toxicity. OBJECTIVES: To evaluate the associations of e-cigarette use with symptoms of wheeze, bronchitic symptoms and shortness of breath (SOB) across 4 years of prospective data. METHODS: Participants completed questionnaires on respiratory symptoms and past 30-day e-cigarette, cigarette and cannabis use in 2014 (wave 1; N=2094; mean age 17.3 years, SD=0.6 years). Follow-up information was collected in 2015 (wave 2; n=1609), 2017 (wave 3; n=1502) and 2018 (wave 4; n=1637) using online surveys. Mixed-effects logistic regression models evaluated associations of e-cigarette use with respiratory symptoms. MEASUREMENTS AND MAIN RESULTS: Participants were mostly Hispanic white (51.8%) and evenly representative by sex (49.6% female; 50.4% male). Compared with never e-cigarette users, past 30-day e-cigarette users reported increased odds of wheeze (OR 1.81; 95% CI 1.28, 2.56), bronchitic symptoms (OR 2.06; 95% CI 1.58, 2.69) and SOB (OR 1.78; 95% CI 1.23, 2.57), adjusting for study wave, age, sex, race, lifetime asthma diagnosis and parental education. Effect estimates were attenuated (wheeze (OR 1.41; 95% CI 0.99, 2.01), bronchitic symptoms (OR 1.55; 95% CI 1.18, 2.05), SOB (OR 1.48; 95% CI 1.01, 2.18)), after adjusting additionally for current cigarette use, cannabis use and secondhand exposure to e-cigarettes/cigarettes/cannabis. CONCLUSIONS: E-cigarette use in young adults was associated with respiratory symptoms, independent of combustible cannabis and cigarette exposures.

Maternal obesity and diabetes during pregnancy and early autism screening score at well-child visits in standard clinical practice.

LAY ABSTRACT: Early intervention and treatment can help reduce disability in children diagnosed with autism spectrum disorder. Screening for autism spectrum disorder in young children identifies those at increased likelihood of diagnosis who may need further support. Previous research has reported that exposure to maternal obesity and diabetes during pregnancy is associated with higher likelihood of autism spectrum disorder diagnosis in children. However, little is known about whether these maternal conditions are associated with how very young children score on autism spectrum disorder screening tools. This study examined associations between exposure to maternal obesity and diabetes during pregnancy and offspring scores on the Quantitative Checklist for Autism in Toddlers, an autism spectrum disorder screening questionnaire administered between 18-24 months at well-child visits. A higher score on the Quantitative Checklist for Autism in Toddlers suggests a higher likelihood of autism spectrum disorder; children with scores 3 or greater are referred to developmental pediatricians for evaluation. Our study found that children of mothers with obesity or diabetes during pregnancy had higher scores than children whose mothers did not have these conditions. Associations with maternal obesity and gestational diabetes diagnosed at or before 26 weeks of pregnancy were also present in children who did not have later autism spectrum disorder diagnoses, suggesting that exposure to these conditions during early pregnancy may be associated with a broad range of social and behavioral abilities. Identifying associations between maternal health conditions and early Quantitative Checklist for Autism in Toddlers screening scores could influence future screening and provision of support for children of mothers with these conditions.

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.

Longitudinal Transitions Between Use of Combustible, Noncombustible, and Multiple Cannabis Products From Adolescence to Young Adulthood and Intersections With Nicotine Use.

Understanding transitions across use of different types of cannabis products and multiple cannabis products and how they intersect with nicotine use in young people can inform etiology and prevention. In this study, we examined transitions across use of combustible and noncombustible forms of cannabis and multiple types of cannabis from adolescence to young adulthood and the role of nicotine use in transitions. In a Southern California longitudinal cohort study (n = 3,298; baseline mean age = 16.1 (standard deviation, 0.4) years) with 9 semiannual survey waves (2015-2021), we used Markov multistate transition modeling to estimate short-term (2-wave) and long-term (9-wave) probabilities of transition across 5 cannabis use states: never use of any product, prior use with no past-6-month (P6M) use of any product, and P6M use of exclusively noncombustible products, exclusively combustible products, and multiple (noncombustible + combustible) products. Sizable transition probabilities from prior and exclusive P6M noncombustible or combustible cannabis use to P6M poly-cannabis-product use were observed in short-term (10.7%-38.9%) and long-term (43.4%-43.8%) analyses. P6M nicotine use increased risk of transitioning from never and prior use to exclusive P6M noncombustible and combustible cannabis use. Cannabis use in any form, even temporary use, during midadolescence may often be followed by poly-cannabis-product use. Nicotine use may amplify the probability of future cannabis use onset or recurrence.

Types of diabetes during pregnancy and risk of depression and anxiety in offspring from childhood to young adulthood.

AIMS: To assess maternal pre-existing type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM) during pregnancy and risk of depression and anxiety from childhood to young adulthood in offspring. MATERIALS AND METHODS: This birth cohort included singletons born during 1995-2015, followed using electronic medical records through 2020. Cox regression was used to estimate hazard ratio (HR) of depression or anxiety diagnosis during follow-up associated with in-utero exposure to maternal diabetes. RESULTS: Among 439 590 offspring, 29 891 (6.8%) had depression and 51 918 (11.8%) had anxiety. T1D, followed by T2D and GDM requiring antidiabetes medication were associated with risk of depression and anxiety in offspring. Compared with no diabetes during pregnancy, the adjusted HRs (95% confidence interval) of depression in offspring associated with T1D, T2D or GDM requiring medications were 1.44 (1.09-1.91), 1.30 (1.15-1.47) and 1.18 (1.11-1.26) respectively; conversely, HRs were 0.97 (0.82-1.15) for T2D and 0.99 (0.94-1.04) for GDM without medications. The associations with anxiety followed similar patterns. The significant associations were observed for offspring ages 5-12 and >12-18 years and attenuated for 18-25 years. CONCLUSION: These data suggest that the severity of diabetes (T1D vs. T2D requiring medications vs. GDM requiring medications) during pregnancy may increase the vulnerability of offspring for depression or anxiety.

Air pollution and age-dependent changes in emotional behavior across early adolescence in the U.S.

Recent studies have linked air pollution to increased risk for behavioral problems during development, albeit with inconsistent findings. Additional longitudinal studies are needed that consider how emotional behaviors may be affected when exposure coincides with the transition to adolescence - a vulnerable time for developing mental health difficulties. This study investigates if annual average PM2.5 and NO2 exposure at ages 9-10 years moderates age-related changes in internalizing and externalizing behaviors over a 2-year follow-up period in a large, nationwide U.S. sample of participants from the Adolescent Brain Cognitive Development (ABCD) Study®. Air pollution exposure was estimated based on the residential address of each participant using an ensemble-based modeling approach. Caregivers answered questions from the Child Behavior Checklist (CBCL) at the baseline, 1-year follow-up, and 2-year follow-up visits, for a total of 3 waves of data; from the CBCL we obtained scores on internalizing and externalizing problems plus 5 syndrome scales (anxious/depressed, withdrawn/depressed, rule-breaking behavior, aggressive behavior, and attention problems). Zero-inflated negative binomial models were used to examine both the main effect of age as well as the interaction of age with each pollutant on behavior while adjusting for various socioeconomic and demographic characteristics. Against our hypothesis, there was no evidence that greater air pollution exposure was related to more behavioral problems with age over time.

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.

Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

The interaction of e-cigarette use and mental health symptoms on risk of cigarette smoking initiation among young adults in the United States.

BACKGROUND AND AIMS: It is unknown whether young adults who vape nicotine and have poor mental health have greater risk of smoking initiation than expected based on individual risks of vaping and mental health alone. This study aimed to estimate the joint association of vaping and mental health symptoms with smoking initiation among young adults, and test for additive interaction between vaping and mental health in smoking initiation risk. DESIGN: Using five waves of the Population Assessment of Tobacco and Health (wave 1, 2013-2014; wave 2, 2014-2015; wave 3, 2015-2016; wave 4, 2016-2018; wave 5, 2018-2019), we estimated risk differences (RD) for the association of time-varying and time-lagged vaping and internalizing (e.g., anxiety, depressive) and externalizing (e.g., inattention/hyperactivity) mental health symptoms with cigarette smoking initiation at follow-up, over four 1-year intervals. We calculated interaction contrasts (IC) to estimate the excess risk of smoking initiation attributable to the interaction of vaping and mental health symptoms. SETTING: United States. PARTICIPANTS: A total of 6908 cigarette-naïve individuals aged 18-24 years. MEASUREMENTS: Exposures included current (past-30 day) vaping and internalizing and externalizing mental health symptoms (high vs moderate/low symptoms). The outcome was smoking initiation (ever cigarette use) after 1 year. FINDINGS: The per-interval risk of smoking initiation was 7.6% (1039 cases/13 712 person-intervals). Compared with noncurrent vaping and moderate/low mental health symptoms, adjusted RDs for current vaping and high mental health symptoms were 17.2% (95% confidence interval [CI]: 7.2% to 27.3%) for internalizing and 18.7% (95%CI: 8.1% to 29.2%) for externalizing symptoms. The excess risk attributed to interaction of current vaping and high externalizing symptoms was IC = 11.3% (95%CI: 1.3% to 21.2%; P = 0.018), with inconclusive findings for internalizing symptoms (IC = 7.7% [95%CI: -2.2% to 17.7%; P = 0.097]). CONCLUSIONS: There is possible, but inconclusive, superadditivity between vaping and mental health in risk of smoking initiation among young adults in the United States.