Gestational exposure to organochlorine compounds and metals and infant birth weight: effect modification by maternal hardships.

BACKGROUND: Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes - six organochlorine compounds (OCs) and five metals - that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. RESULTS: Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (ß = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (ß = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (ß = 23 g; 95% CI: -25, 71) compared to those with higher educational status (ß = -9 g; 95% CI: -24, 6). CONCLUSIONS: Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

Gestational exposure to environmental chemicals and epigenetic alterations in the placenta and cord blood mononuclear cells.

Background: Exposure to environmental chemicals such as phthalates, phenols, and polycyclic aromatic hydrocarbons (PAHs) during pregnancy can increase the risk of adverse newborn outcomes. We explored the associations between maternal exposure to select environmental chemicals and DNA methylation in cord blood mononuclear cells (CBMC) and placental tissue (maternal and fetal sides) to identify potential mechanisms underlying these associations. Method: This study included 75 pregnant individuals who planned to give birth at the University of Cincinnati Hospital between 2014 and 2017. Maternal urine samples during the delivery visit were collected and analyzed for 37 biomarkers of phenols (12), phthalates (13), phthalate replacements (4), and PAHs (8). Cord blood and placenta tissue (maternal and fetal sides) were also collected to measure the DNA methylation intensities using the Infinium HumanMethylation450K BeadChip. We used linear regression, adjusting for potential confounders, to assess CpG-specific methylation changes in CBMC (n = 54) and placenta [fetal (n = 67) and maternal (n = 68) sides] associated with gestational chemical exposures (29 of 37 biomarkers measured in this study). To account for multiple testing, we used a false discovery rate q-values < 0.05 and presented results by limiting results with a genomic inflation factor of 1±0.5. Additionally, gene set enrichment analysis was conducted using the Kyoto Encyclopedia of Genes and Genomics pathways. Results: Among the 29 chemical biomarkers assessed for differential methylation, maternal concentrations of PAH metabolites (1-hydroxynaphthalene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 1-hydroxypyrene), monocarboxyisononyl phthalate, mono-3-carboxypropyl phthalate, and bisphenol A were associated with altered methylation in placenta (maternal or fetal side). Among exposure biomarkers associated with epigenetic changes, 1-hydroxynaphthalene, and mono-3-carboxypropyl phthalate were consistently associated with differential CpG methylation in the placenta. Gene enrichment analysis indicated that maternal 1-hydroxynaphthalene was associated with lipid metabolism and cellular processes of the placenta. Additionally, mono-3-carboxypropyl phthalate was associated with organismal systems and genetic information processing of the placenta. Conclusion: Among the 29 chemical biomarkers assessed during delivery, 1-hydroxynaphthalene and mono-3-carboxypropyl phthalate were associated with DNA methylation in the placenta. Supplementary Information: The online version contains supplementary material available at 10.1186/s43682-024-00027-7.

Associations of Urban Blue and Green Spaces With Coronary Artery Calcification in Black Individuals and Disadvantaged Neighborhoods.

BACKGROUND: Proximity to urban blue and green spaces has been associated with improved cardiovascular health; however, few studies have examined the role of race and socioeconomic status in these associations. METHODS: Data were from the CARDIA study (Coronary Artery Risk Development in Young Adults). We included longitudinal measurements (1985-1986 to 2010-2011) of blue and green spaces, including percentage of blue space cover, distance to the nearest river, green space cover, and distance to the nearest major park. Presence of coronary artery calcification (CAC) was measured with noncontrast cardiac computed tomography in 2010 to 2011. The associations of blue and green spaces with CAC were assessed with generalized estimating equation regression with adjustment for demographics, individual and neighborhood socioeconomic status, health-related behaviors, and other health conditions. We conducted stratified analyses by race and neighborhood deprivation score to investigate whether the association varied according to social determinants of health. RESULTS: The analytic sample included 1365 Black and 1555 White participants with a mean±SD age of 50.1±3.6 years. Among Black participants, shorter distance to a river and greater green space cover were associated with lower odds of CAC (per interquartile range decrease [1.45 km] to the river: odds ratio [OR], 0.90 [95% CI, 0.84-0.96]; per 10 percentage-point increase of green space cover: OR, 0.85 [95% CI, 0.75-0.95]). Among participants in deprived neighborhoods, greater green space cover was associated with lower odds of CAC (per a 10 percentage-point increase: OR, 0.89 [95% CI, 0.80-0.99]), whereas shorter distance to the park was associated with higher odds of CAC (per an interquartile range decrease [5.3 km]: OR, 1.07 [95% CI, 1.00-1.15]). Black participants in deprived neighborhoods had lower odds of CAC with shorter distance to a river (per an interquartile range decrease: OR, 0.90 [95% CI, 0.82-0.98]) and greater green space cover (per a 10 percentage-point increase: OR, 0.85 [95% CI, 0.75-0.97]). There was no statistical interaction between the blue and green spaces and race or neighborhood characteristics in association with CAC. CONCLUSIONS: Longitudinally, shorter distance to a river and greater green space cover were associated with less CAC among Black participants and those in deprived neighborhoods. Shorter distance to a park was associated with increased odds of CAC among participants in deprived neighborhoods. Black participants residing in more deprived neighborhoods showed lower odds of CAC in association with greater exposure to river and green space cover.

Associations between neonicotinoids and liver function measures in US adults: National Health and Nutrition Examination Survey 2015-2016.

Background: Toxicological studies indicate that neonicotinoids may be associated with disruptions in liver function due to an increase in oxidative stress. There are scant epidemiological studies investigating the chronic hepatotoxic effects of neonicotinoids. Objective: To examine the association between detectable concentrations of parent neonicotinoids and neonicotinoid metabolites with liver function markers among US adults, and whether sex modifies this association. Methods: National Health and Nutrition Examination Survey 2015-2016 data were used to estimate associations between detectable neonicotinoids and serum alkaline phosphatase (ALP), alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transaminase (GGT), albumin, total bilirubin, total protein, and Hepatic Steatosis Index (HSI) using multiple linear regression. Results: Detectable levels of N-desmethyl-acetamiprid were associated with a decrease in GGT (ß = -3.54 unit/l; 95% confidence interval [CI] = -6.48, -0.61) and detectable levels of 5-hydroxy-imidacloprid were associated with a decrease in HSI (ß = -1.11; 95% CI = -2.14, -0.07). Sex modified the association between any parent neonicotinoid and ALP (Pint = 0.064) and the association between clothianidin and ALP (Pint = 0.019), with a pattern of positive associations in males and inverse associations in females, though stratified associations did not reach statistical significance. Sex also modified the association between 5-hydroxy-imidacloprid and total protein (Pint = 0.062), with a significant positive association in females (ß = 0.14 g/dl; 95% CI = 0.03, 0.25) and a null association in males. Conclusion: Detectable concentrations of neonicotinoid metabolites were inversely associated with GGT and HSI in US adults. Evidence suggests neonicotinoids may influence liver function differently depending on sex. Future research is recommended to replicate the findings as the study was limited in its cross-sectional nature and inability to examine continuous neonicotinoid concentrations with liver function.

Per- and polyfluoroalkyl substances and bone mineral content in early adolescence: Modification by diet and physical activity.

BACKGROUND: Per- and polyfluoroalkyl substance (PFAS) exposures may negatively impact bone mineral accrual, but little is known about potential mitigators of this relation. We assessed whether associations of PFAS and their mixture with bone mineral content (BMC) in adolescence were modified by diet and physical activity. METHODS: We included 197 adolescents enrolled in a prospective pregnancy and birth cohort in Cincinnati, Ohio (2003-2006). At age 12 years, we collected serum for PFAS measurements and used dual-energy x-ray absorptiometry to measure BMC. We calculated dietary calcium intake and Health Eating Index (HEI) scores from repeated 24-h dietary recalls, physical activity scores using the Physical Activity Questionnaire for Older Children (PAQ-C), and average moderate to vigorous physical activity (MVPA) based on accelerometry. We estimated covariate-adjusted differences in BMC z-scores per interquartile range (IQR) increase of individual PFAS concentrations using linear regression and per simultaneous IQR increase in all four PFAS using g-computation. We evaluated effect measure modification (EMM) using interaction terms between each modifier and PFAS. RESULTS: Higher serum perfluorooctanoic acid, perfluorooctanesulfonic acid, and perfluorononanoic acid concentrations and the PFAS mixture were associated with lower BMC z-scores. An IQR increase in all PFAS was associated with a 0.27 (-0.54, 0.01) lower distal radius BMC z-score. Associations with lower BMC were generally stronger among adolescents classified as < median for calcium intake, HEI scores, or MVPA compared to those ≥ median. The difference in distal radius BMC z-score per IQR increase in all PFAS was -0.38 (-0.72, -0.04) for those with

Gestational PBDE concentrations, persistent externalizing, and emerging internalizing behaviors in adolescents: The HOME study.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental chemicals used as flame retardants in commercial and consumer products. Gestational PBDE concentrations are associated with adverse behaviors in children; however, the persistence of these associations into adolescence remains understudied. OBJECTIVE: We estimated the association of gestational PBDE serum concentrations with early adolescent self- and caregiver-reported behaviors at age 12 years and determined the consistency with previously observed associations in childhood with caregiver-reported behaviors in a prospective pregnancy and birth cohort. METHODS: We measured maternal serum concentrations of five individual PBDE congeners and created a summary exposure variable (∑5BDE: 28, -47, -99, -100 and -153) during pregnancy. At age 12 years, we assessed behaviors for 237 adolescents using self- and caregiver-reports with the Behavioral Assessment System for Children-3 (BASC3). We used multivariable linear regression models to estimate covariate-adjusted associations of lipid standardized, log10-transformed gestational PBDE concentrations with BASC3 scores. We obtained estimates and 95% confidence intervals through a bootstrapping approach. We evaluated potential effect measure modification (EMM) of adolescent sex by examining sex-stratified regression models and estimating the EMM p-values. RESULTS: Gestational PBDE concentrations were positively associated with adolescent-reported BASC3 composite indices for inattention & hyperactivity (BDE-28, -47, -99, -100, ∑5BDE), internalizing problems (BDE-28, -47, -99), functional impairment (BDE-28, ∑5BDE), and emotional symptoms (BDE-28). Gestational PBDE concentrations were positively associated with caregiver-reported BASC3 composite indices for externalizing problems (BDE-28, -47, -99, -100, -153, ∑5BDE) and behavioral symptoms (BDE-99). For caregiver reported behaviors, we observed stronger associations with gestational BDE concentrations among males, especially for executive functioning (BDE-28, -47, -99, -100, ∑5BDE). DISCUSSION: Gestational PBDE serum concentrations were associated with self-reported internalizing and externalizing behavior problems in early adolescence. Caregiver-reported externalizing behaviors recognized during childhood remain associated with gestational PBDE concentrations and persist into early adolescence. Internalizing behaviors were less recognized by caregivers.

Early life exposure to secondhand tobacco smoke and eating behaviors at age 12 years.

BACKGROUND: Prenatal or early childhood secondhand tobacco smoke (SHS) exposure increases obesity risk. However, the potential mechanisms underlying this association are unclear, but obesogenic eating behaviors are one pathway that components of SHS could perturb. Our aim was to assess associations of prenatal and early childhood SHS exposure with adolescent eating behaviors. METHODS: Data came from a prospective pregnancy and birth cohort (N = 207, Cincinnati, OH). With multiple informant models, we estimated associations of prenatal (mean of 16 and 26 weeks of gestation maternal serum cotinine concentrations) and early childhood cotinine (average concentration across ages 12, 24, 36, and 48 months) with eating behaviors at age 12 years (Child Eating Behaviors Questionnaire). We tested whether associations differed by exposure periods and adolescent's sex. Models adjusted for maternal and child covariates. RESULTS: We found no statistically significant associations between cotinine measures and adolescent's eating behaviors. Yet, in females, prenatal cotinine was associated with greater food responsiveness (ß: 0.23; 95% CI: 0.08, 0.38) and lower satiety responsiveness (ß: -0.14; 95% CI: -0.26, -0.02); in males, prenatal and postnatal cotinine was related to lower food responsiveness (prenatal: ß: -0.25; 95% CI: -0.04, -0.06; postnatal: ß: -0.36; 95% CI: -0.06, -0.11). No significant effect modification by sex or exposure window was found for other eating behaviors. CONCLUSION: Prenatal and early childhood SHS exposures were not related to adolescent's eating behavior in this cohort; however, biological sex may modify these associations.

Time-varying associations of gestational and childhood triclosan with pubertal and adrenarchal outcomes in early adolescence.

Background: Triclosan is an endocrine-disrupting chemical, but associations with pubertal outcomes remain unclear. We examined associations of gestational and childhood triclosan with adolescent hormone concentrations and pubertal stage. Methods: We quantified urinary triclosan concentrations twice during pregnancy and seven times between birth and 12 years in participants recruited from Cincinnati, OH (2003-2006). We averaged concentrations across pregnancy and childhood and separately considered individual exposure periods in multiple informant models. At 12 years, we measured serum hormone concentrations (males [n = 72] and females [n = 84]-dehydroepiandrosterone-sulfate, luteinizing hormone, follicle-stimulating hormone; males-testosterone; females-estradiol). Also at age 12 years, participants self-reported physical development and menarchal timing. We estimated associations (95% confidence interval) of triclosan with hormone concentrations, more advanced physical development, and age at menarche. Results: For females, each doubling of childhood triclosan was associated with 16% lower estradiol concentrations (-29%, 0%), with stronger associations for measures closer to adolescence. We found suggestive evidence that higher triclosan at any age was associated with ~10% (for gestational triclosan: -18%, -2%) lower follicle-stimulating hormone concentrations among males and early postnatal (1-3 years) triclosan was associated with 63% (5%, 96%) lower odds of advanced pubic hair development in females. In multiple informant models, each doubling of gestational triclosan concentrations was associated with 5% (0%, 9%) earlier age at menarche, equivalent to 5.5 months. Conclusion: Gestational and childhood triclosan concentrations were related to some pubertal outcomes including hormone concentrations and age at menarche. Our findings highlight the relevance of elucidating potential sex-specific and time-dependent actions of triclosan.

Urinary Volatile Organic Compound Metabolites Are Associated with Reduced Lung Function in U.S. Children and Adolescents.

(1) Background: Volatile organic compounds (VOCs) are indoor pollutants absorbed by inhalation. The association of several VOCs with lung function in children and adolescents is unknown. (2) Methods: We analyzed 505 participants, 6-17-year-olds from the 2011-2012 National Health and Nutrition Examination Survey. Multiple linear regression models were fitted to estimate the associations of VOC metabolites with spirometry outcomes adjusting for covariates. (3) Results: Urinary metabolites of xylene, acrylamide, acrolein, 1,3-butadiene, cyanide, toluene, 1-bromopropane, acrylonitrile, propylene oxide, styrene, ethylbenzene, and crotonaldehyde were all detected in ≥64.5% of participants. Forced expiratory volume in 1 s (FEV1) % predicted was lower in participants with higher levels of metabolites of acrylamide (ß: -7.95, 95% CI: -13.69, -2.21) and styrene (ß: -6.33, 95% CI: -11.60, -1.07), whereas the FEV1 to forced vital capacity (FVC) ratio % was lower in children with higher propylene oxide metabolite levels (ß: -2.05, 95% CI: -3.49, -0.61). FEV1 % predicted was lower with higher crotonaldehyde metabolite levels only in overweight/obese participants (ß: -15.42, 95% CI: -26.76, -4.08) (Pinteraction < 0.001) and with higher 1-bromopropane metabolite levels only in those with serum cotinine > 1 ng/mL (ß: -6.26, 95% CI: -9.69, -2.82) (Pinteraction < 0.001). (4) Conclusions: We found novel associations of metabolites for acrylamide, propylene oxide, styrene, 1-bromopropane and crotonaldehyde with lower lung function in children and adolescents.

Could nerve transplantation be the future of this field: a bibliometric analysis about lumbosacral plexus injury.

BACKGROUND: Lumbosacral plexus injury is a highly distressing clinical issue with profound implications for patients' quality of life. Since the publication of the first relevant study in 1953, there has been very limited progress in basic research and clinical treatment in this field, and the developmental trajectory and research priorities in this field have not been systematically summarized using scientific methods, leaving the future direction of this research to be explored. METHODS: Utilizing publications from the Web of Science (WoS) database, our research employed bibliometric methodology to analyze the fundamental components of publications, synthesize research trends, and forecast future directions. RESULTS: A total of 150 publications were included in our study, and the impressive advancement of research heat in this field can be attributed to the continuous increase in the number of papers, ranging from 14 papers in 2000 to 34 papers in 2023 over 5 years. Regarding the country, a central position in both quantity (H-index=125) and quality of publications (65 publications) is occupied by the United States, and close collaborations with other countries are observed. In terms of publication institutions, the highest number of publications (nine publications) is held by the Second Military Medical University. The journal with the most publications (five publications) is the Journal of Trauma-Injury Infection and Critical Care. A pivotal role has been played by basic medical research in the development of this field. Concerning hotspots, the focus of the research core can be divided into three clusters (etiology, diagnosis and treatment; molecular, cells and mechanisms; physiology, and pathology). CONCLUSION: This marks the inaugural bibliometric analysis of lumbosacral plexus injuries, offering a comprehensive overview of current publications. Our findings illuminate future research directions, international collaborations, and interdisciplinary relationships. Future research will emphasize clinical treatment and mechanism research, with a focus on sacral nerve stimulation and nerve transplantation.

Integration of single-cell and RNA-seq data to explore the role of focal adhesion-related genes in osteoporosis.

Integrin-based focal adhesion is one of the major mechanosensory in osteocytes. The aim of this study was to mine the hub genes associated with focal adhesion and investigate their roles in osteoporosis based on the data of single-cell RNA sequencing and RNA-sequencing. Two hub genes (FAM129A and RNF24) with the same expression trend and AUC values greater than 0.7 in both GSE56815 and GSE56116 cohorts were uncovered. The nomogram was created to predict the risk of OP based on two hub genes. Subsequently, the competing endogenous RNA network was established based on two hub genes, 14 microRNAs and five long noncoding RNAs. Meanwhile, transcription factors-hub gene network was established based on two hub genes and 14 TFs. Finally, 73 drugs were predicted, of which there were 13 drugs targeting FAM129A and 66 drugs targeting RNF24. In both mouse and human blood samples, FAM129A expression was decreased in granulocytes and RNF24 expression was increased in monocytes. In the mouse experiment, FAM129A and anti-RNF24 were found to partially alleviate the progression of osteoporosis. In conclusion, two hub genes related to focal adhesion were identified by combined scRNA-seq and RNA-seq analyses, which might supply a new insight for the treatment and evaluation of OP.

Gestational thyroid hormones and autism-related traits in the EARLI and HOME studies.

Thyroid hormones are essential for neurodevelopment. Few studies have considered associations with quantitatively measured autism spectrum disorder (ASD)-related traits, which may help elucidate associations for a broader population. Participants were drawn from two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI), enrolling pregnant women who already had a child with ASD, and the Health Outcomes and Measures of the Environment (HOME) Study, following pregnant women from the greater Cincinnati, OH area. Gestational thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were measured in mid-pregnancy 16 (±3) weeks gestation serum samples. ASD-related traits were measured using the Social Responsiveness Scale (SRS) at ages 3-8 years. The association was examined using quantile regression, adjusting for maternal and sociodemographic factors. 278 participants (132 from EARLI, 146 from HOME) were included. TSH distributions were similar across cohorts, while FT4 levels were higher in EARLI compared to HOME. In pooled analyses, particularly for those in the highest SRS quantile (95th percentile), higher FT4 levels were associated with increasing SRS scores (ß = 5.21, 95% CI = 0.93, 9.48), and higher TSH levels were associated with decreasing SRS scores (ß = -6.94, 95% CI = -11.04, -2.83). The association between TSH and SRS remained significant in HOME for the 95% percentile of SRS scores (ß = -6.48, 95% CI = -12.16, -0.80), but not EARLI. Results for FT4 were attenuated when examined in the individual cohorts. Our results add to evidence that gestational thyroid hormones may be associated with ASD-related outcomes by suggesting that relationships may differ across the distribution of ASD-related traits and by familial likelihood of ASD.

Exact results for gene-expression models with general waiting-time distributions.

Complex molecular details of transcriptional regulation can be coarse-grained by assuming that reaction waiting times for promoter-state transitions, the mRNA synthesis, and the mRNA degradation follow general distributions. However, how such a generalized two-state model is analytically solved is a long-standing issue. Here we first present analytical formulas of burst-size distributions for this model. Then, we derive an iterative equation for the mRNA moment-generating function, by which mRNA raw and binomial moments of any order can be conveniently calculated. The analytical results obtained in the special cases of phase-type waiting-time distributions not only provide insights into the mechanisms of complex transcriptional regulations but also bring conveniences for experimental data-based statistical inferences.

Photoionization of the Propargyl Radical Using the R-Matrix Method.

The absolute photoionization cross section of the propargyl radical measured by Savee et al. [J. Chem. Phys. 2012, 136, 134307] is about 2-3 times larger than the experimental result from Robinson et al. [J. Chem. Phys. 2003, 119, 5311]. Meanwhile, there is a significant discrepancy in the shapes of the propargyl photoionization spectra between these two measurements and the result measured by Zhang et al. [J. Chem. Phys. 2006, 124, 074302]. To estimate the accuracy of the various results, we carried out comprehensive calculations with the multichannel R-matrix method, which uses multiconfigurational wave functions to generate accurate initial and final states. Three scattering models including static-exchange, correlated 1 state, and 80 state close-coupling (CC) approximations are employed to reveal the dynamic interaction. The autoionization peaks near the ionization threshold are predicted for the first time. Two resonances are detected with the photon energy around 41.4 and 49.6 eV in the 80 state CC model. We checked the sensitivity of the results to change descriptions of the active spaces, the different partial waves, and the R-matrix radii in the theoretical model. Our best results are compared with the experimental measurements, and discussions are provided. The cross sections and asymmetry parameters for the valence orbitals are reported for photon energies from ionization thresholds of 70 eV.

Balanced implicit Patankar-Euler methods for positive solutions of stochastic differential equations of biological regulatory systems.

Stochastic differential equations (SDEs) are a powerful tool to model fluctuations and uncertainty in complex systems. Although numerical methods have been designed to simulate SDEs effectively, it is still problematic when numerical solutions may be negative, but application problems require positive simulations. To address this issue, we propose balanced implicit Patankar-Euler methods to ensure positive simulations of SDEs. Instead of considering the addition of balanced terms to explicit methods in existing balanced methods, we attempt the deletion of possible negative terms from the explicit methods to maintain positivity of numerical simulations. The designed balanced terms include negative-valued drift terms and potential negative diffusion terms. The proposed method successfully addresses the issue of divisions with very small denominators in our recently designed stochastic Patankar method. Stability analysis shows that the balanced implicit Patankar-Euler method has much better stability properties than our recently designed composite Patankar-Euler method. Four SDE systems are used to examine the effectiveness, accuracy, and convergence properties of balanced implicit Patankar-Euler methods. Numerical results suggest that the proposed balanced implicit Patankar-Euler method is an effective and efficient approach to ensure positive simulations when any appropriate stepsize is used in simulating SDEs of biological regulatory systems.

Estimating effects of longitudinal and cumulative exposure to PFAS mixtures on early adolescent body composition.

Few methods have been used to characterize repeatedly measured biomarkers of chemical mixtures. We applied latent profile analysis (LPA) to serum concentrations of 4 perfluoroalkyl and polyfluoroalkyl substances (PFAS) measured at 4 time points from gestation to age 12 years. We evaluated the relationships between profiles and z scores of height, body mass index, fat mass index, and lean body mass index at age 12 years (n = 218). We compared LPA findings with an alternative approach for cumulative PFAS mixtures using g-computation to estimate the effect of simultaneously increasing the area under the receiver operating characteristic curve (AUC) for all PFAS. We identified 2 profiles: a higher PFAS profile (35% of sample) and a lower PFAS profile (relative to each other), based on their average PFAS concentrations at all time points. The higher PFAS profile had generally lower z scores for all outcomes, with somewhat larger effects for males, though all 95% CIs crossed the null. For example, the higher PFAS profile was associated with a 0.50-unit lower (ß = -0.50; 95% CI, -1.07 to 0.08) BMI z score among males but not among females (ß = 0.04; 95% CI, -0.45 to 0.54). We observed similar patterns with AUCs. We found that a higher childhood PFAS profile and higher cumulative PFAS mixtures may be associated with altered growth in early adolescence. This article is part of a Special Collection on Environmental Epidemiology.

Evaluating the association between longitudinal exposure to a PFAS mixture and adolescent cardiometabolic risk in the HOME Study.

Background: Exposure to per- and polyfluoroalkyl substances (PFAS) throughout gestation and childhood may impact cardiometabolic risk. Methods: In 179 HOME Study participants (Cincinnati, OH; recruited 2003-2006), we used latent profile analysis to identify two distinct patterns of PFAS exposure from serum concentrations of four PFAS measured at birth and ages 3, 8, and 12 years. We assessed the homeostatic model of insulin resistance, triglycerides-to-high-density lipoprotein cholesterol ratio, leptin-to-adiponectin ratio, systolic blood pressure, visceral fat, and hemoglobin A1c levels at age 12 years. We used multivariable linear regression to assess the association of membership in the longitudinal PFAS mixture exposure group with a summary measure of overall cardiometabolic risk and individual components. Results: One PFAS exposure profile (n = 66, 39%) had higher geometric means of all PFAS across all visits than the other. Although adjusted associations were null in the full sample, child sex modified the association of longitudinal PFAS mixture exposure group with overall cardiometabolic risk, leptin-to-adiponectin ratio, systolic blood pressure, and visceral fat (interaction term P values: 0.02-0.08). Females in the higher exposure group had higher cardiometabolic risk scores (ß = 0.43; 95% CI = -0.08, 0.94), systolic blood pressures (ß = 0.6; 95% CI = 0.1, 1.1), and visceral fat (ß = 0.44; 95% CI = -0.13, 1.01); males had lower cardiometabolic risk scores (ß = -0.52; 95% CI = -1.06, -0.06), leptin-to-adiponectin ratios (ß = -0.7; 95% CI = -1.29, -0.1), systolic blood pressures (ß = -0.14; 95% CI = -0.7, 0.41), and visceral fat (ß = -0.52; 95% CI = -0.84, -0.19). Conclusions: Exposure to this PFAS mixture throughout childhood may have sex-specific effects on adolescent cardiometabolic risk.

The U.S. PFAS exposure burden calculator for 2017-2018: Application to the HOME Study, with comparison of epidemiological findings from NHANES.

BACKGROUND: The 2017-2018 U.S. PFAS exposure burden calculator was designed to provide a summary exposure score for per- and polyfluoroalkyl substances (PFAS) mixtures using targeted PFAS analyte data. Its aim was to place PFAS burden score estimates onto a common scale based on nationally representative U.S. reference ranges from 2017 to 2018, enabling comparisons of overall PFAS burden scores across studies even if they did not measure the same set of PFAS analytes. OBJECTIVE: To use the U.S. PFAS exposure burden calculator for comparing the same mixture of PFAS compounds in similarly aged adolescents and their associations with cardiometabolic outcomes in the HOME Study and NHANES between 2015 and 2018. METHODS: We applied the PFAS burden calculator to 8 PFAS analytes measured in the serum of adolescents from the HOME Study (Cincinnati, Ohio; age range 11-14 years; years: 2016-2019; n = 207) and NHANES (US; age range 12-14 years; years 2015-2018; n = 245). We used the non-parametric Mann-Whitney U test and chi-squared test to compare the two study samples. In both studies, we examined associations of PFAS burden scores with the same cardiometabolic outcomes, adjusted for the same core set of covariates using regression analyses. We conducted sensitivity analyses to verify robustness of exposure-outcome associations, by accounting for measurement error of PFAS burden scores. RESULTS: PFAS burden scores were significantly different (p = 0.004) between the HOME Study (median: 0.00, interquartile range - 0.37, 0.34) and the NHANES samples (median: 0.04, IQR -0.11, 0.54), while no significant difference was found for PFAS summed concentrations (p = 0.661). In the HOME Study, an interquartile (IQR) increase in PFAS burden score was associated with higher total cholesterol [7.0 mg/dL, 95% CI: 0.6, 13.4]; HDL [2.8 mg/dL, 95% CI: 0.4, 5.2]; LDL [5.9 mg/dL, 95% CI: 0.5, 11.3], insulin [0.1 log(mIU/L), 95% CI: 0.01, 0.2], and HOMA-IR [0.1, 95% CI: 0.01, 0.2]. In NHANES, an IQR increase in PFAS burden score was associated with higher diastolic blood pressure [2.4 mmHg, 95% CI: 0.4, 4.4] but not with other outcomes. Sensitivity analyses in the HOME Study and NHANES were consistent with the main findings. CONCLUSIONS: Performance of the U.S. PFAS exposure burden calculator was similar in a local versus national sample of adolescents, and may be a useful tool for the assessment of PFAS mixtures across studies.

High levels of sleep disturbance across early childhood increases cardiometabolic disease risk index in early adolescence: longitudinal sleep analysis using the Health Outcomes and Measures of the Environment study.

STUDY OBJECTIVES: This study examines the impact of sleep duration, bedtime, and sleep disturbance during early childhood on the risk of cardiometabolic disorder (CMD) in early adolescence. METHODS: Within the Health Outcomes and Measures of Environment Study, we examined sleep patterns of 330 children from ages 2 to 8 years and the relationship of these sleep patterns with cardiometabolic risk measures at age 12 (N = 220). We used a group-based semi-parametric mixture model to identify distinct trajectories in sleep duration, bedtime timing, and sleep disturbance for the entire sample. We then examined the associations between sleep trajectories and CMD risk measures using general linear models using both an unadjusted model (no covariates) and an adjusted model (adjusting for child pubertal stage, child sex, duration of breastfeeding, household income, maternal education, and maternal serum cotinine). RESULTS: In the unadjusted and adjusted models, we found significant differences in CMD risk scores by trajectories of sleep disturbance. Children in the "high" disturbance trajectory had higher CMD risk scores than those in the 'low' disturbance trajectory (p's = 0.002 and 0.039, respectively). No significant differences in CMD risk were observed for bedtime timing or total sleep time trajectories in the unadjusted or adjusted models. CONCLUSIONS: In this cohort, caregiver-reported sleep disturbance in early childhood was associated with more adverse cardiometabolic profiles in early adolescence. Our findings suggest that trials to reduce CMD risk via sleep interventions-which have been conducted in adolescents and adults-may be implemented too late.

Activation of Beta-adrenergic Receptors Upregulates the Signal-to-Noise Ratio of Auditory Input in the Medial Prefrontal Cortex and Mediates Auditory Fear Conditioning.

Norepinephrine (NE) is involved in auditory fear conditioning (AFC) in posttraumatic stress disorder (PTSD). However, it is still unclear how it acts on neurons. We aimed to investigate whether the activation of the ß-adrenergic receptor (ß-AR) improves AFC by sensitization of the prelimbic (PL) cortex at the animal, cellular, and molecular levels. In vivo single-cell electrophysiological recording was used to characterize the changes in neurons in the PL cortex after AFC. Then, PL neurons were locally administrated by the ß-AR agonist isoproterenol (ISO), the GABAaR agonist muscimol, or intervened by optogenetic method, respectively. Western blotting and immunohistochemistry were finally used to assess molecular changes. Noise and low-frequency tones induced similar AFC. The expression of ß-ARs in PL cortex neurons was upregulated after fear conditioning. Microinjection of muscimol into the PL cortex blocked the conformation of AFC, whereas ISO injection facilitated AFC. Moreover, PL neurons can be distinguished into two types, with type I but not type II neurons responding to conditioned sound and being regulated by ß-ARs. Our results showed that ß-ARs in the PL cortex regulate conditional fear learning by activating type I PL neurons.