Associations between metabolic syndrome and anxiety, and the mediating role of inflammation: Findings from the UK Biobank.

OBJECTIVES: To investigate the association between metabolic syndrome (MetS) and anxiety and to explore the mediating role of inflammation indicators in this relationship based on the UK Biobank prospective cohort. METHODS: This population-based retrospective cohort study analyzed data from 308,352 participants. MetS was defined according to criteria jointly developed by the American Heart Association, the National Heart, Lung, and Blood Institute, and the International Diabetes Federation. Anxiety was defined using ICD-10 codes. Cox proportional risk regression models were used to explore the hazard ratios (HRs) between MetS, components of MetS, number of MetS components, and anxiety. The mediating effect of inflammation on the association between MetS and anxiety was explored using longitudinal mediation analysis. RESULTS: A total of 308,352 participants were included in this study. Of these, 9471 (3.071 %) developed anxiety over a mean follow-up of 12.05 years. In the fully adjusted model, MetS increased the risk of anxiety by 13.6 % (HR: 1.136, 95 %CI: 1.085-1.189). All MetS components significantly increased the risk of anxiety, with HRs ranging from 1.066 to 1.165. When MetS was treated as a linear variable, the risk of anxiety increased by 6.5 % per component increment. Age-stratified results showed that the risk of MetS for anxiety was higher among those <55 years (HR: 1.23, 95 %CI: 1.13-1.33) than among those ≥55 years (HR: 1.12, 95 %CI: 1.06-1.18). The mediating effects of platelets, lymphocytes, neutrophils, C-reactive protein, leukocytes, and INFLA scores on the association between MetS and anxiety were significant, with mediating effects of 2.30 %, 7.20 %, 15.9 %, 20.7 %, 22.0 %, and 25.3 %, respectively, and a combined mediating effect of these inflammatory factors was 30.8 % (except for INFLA scores). CONCLUSIONS: MetS and its components significantly increased the risk of anxiety, which increased with the number of components. This association may be partially mediated by serum inflammatory indicators, suggesting that MetS may increase the risk of anxiety by elevating the level of chronic inflammation.

Association between prenatal exposure to per- and polyfluoroalkyl substances and neurodevelopment in children: Evidence based on birth cohort.

BACKGROUND: Although numerous studies have examined the effect of prenatal per- and polyfluoroalkyl substances (PFAS) exposure on neurodevelopment in children, findings have been inconsistent. OBJECTIVE: To better understand the effects of PFAS exposure during pregnancy on offspring neurodevelopment, we conducted a systematic review of prenatal exposure to different types of PFAS and neurodevelopment in children. METHODS: A comprehensive search was conducted in the PubMed, Web of Science, and EMBASE electronic databases up to March 2023. Only birth cohort studies that report a specific association between PFAS exposure during pregnancy and neurodevelopment were included in this review. RESULTS: 31 birth cohort studies that met the inclusion criteria were qualitatively integrated. Among these, 14 studies investigated the impact of PFAS exposure during pregnancy on cognition, 13 on neurobehavior, and 4 on both cognition and neurobehavior. Additionally, 4 studies explored the influence of PFAS on children's comprehensive development. CONCLUSION: Prenatal PFAS exposure was associated with poor neurodevelopment in children, including psychomotor development, externalizing behavior, and comprehensive development. However, conclusive evidence regarding its effects on other neurological outcomes remains limited. In addition, sex-specific effects on social behavior and sleep problems were identified.

Association of the Oxidative Balance Score and Cognitive Function and the Mediating Role of Oxidative Stress: Evidence from the National Health and Nutrition Examination Survey (NHANES) 2011-2014.

BACKGROUND: Oxidative stress is possibly related to cognitive function decline. The oxidative balance score (OBS) that combines pro- and antioxidant components from diet and lifestyle has been reported to be associated with age-related diseases. OBJECTIVES: We aimed to investigate the association between OBS and cognitive function in older adults and explore whether oxidative stress mediated this relationship. METHODS: A total of 1745 adults aged ≥60 y were included in the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Cognitive function was measured using 4 tests: the immediate recall test, delayed recall test, animal fluency test (AFT), and digital symbol substitution test (DSST). Weighted multivariate linear regression and restricted cubic splines (RCS) analyses were used to evaluate the association between OBS and cognitive function, and mediation analysis was used to test the indirect effect of oxidative stress indicators on the association. RESULTS: The OBS was positively associated with AFT, DSST, and global cognitive function in older adults, and the beta estimates (95% CI) were 0.015 (0.008, 0.034), 0.009 (0.002, 0.025), and 0.030 (0.024, 0.074), moreover, RCS results suggested an approximately linear dose-response relationship between the OBS and these 3 tests. The highest quartiles of these 3 tests were also significantly correlated with OBS. Albumin, uric acid, and serum 25(OH)D concentrations were significant mediators of the relationship between OBS and cognitive function, and the overall mediation effect proportion was 36% when included in 1 model. CONCLUSIONS: OBS was positively correlated with cognitive function in older adults, and albumin, uric acid, and serum 25(OH)D concentrations could be the driving mediators of the association. The findings emphasize the importance of a healthy, antioxidant diet and lifestyle that contribute to cognitive function. J Nutr 20xx;x:xx.

Oxidative balance scores and depressive symptoms: Mediating effects of oxidative stress and inflammatory factors.

BACKGROUND: Few studies have examined the combined effects of dietary and lifestyle factors on depressive symptoms. This study aimed to evaluate the association between oxidative balance score (OBS) and depressive symptoms and the underlying mechanisms. METHODS: A total of 21,283 adults from the 2007 to 2018 National Health and Nutrition Examination Survey (NHANES) were included. Depressive symptoms were defined as a total score of ≥10 on the Patient's Health Questionnaire (PHQ-9). Twenty dietary and lifestyle factors were selected to calculate the OBS. Multivariable logistic regression analyses were used to evaluate the association between OBS and depression risk. Mediation analyses were conducted to explore the roles of oxidative stress and inflammatory markers. RESULTS: In multivariate model, a significant negative association was found between OBS and depression risk. Compared with those in OBS tertile 1, participants in tertile 3 had lower odds of developing depressive symptoms (OR:0.50; 95 % CI:0.40-0.62; P < 0.001). Restricted cubic splines showed a linear relationship between OBS and depression risk (P for nonlinearity = 0.67). Moreover, higher OBS was found to be associated with lower depression scores (ß = -0.07; 95 % CI:-0.08, -0.05; P < 0.001). GGT concentrations and WBC counts mediated the association between OBS and depression scores by 5.72 % and 5.42 %, respectively (both P < 0.001), with a joint mediated effect of 10.77 % (P < 0.001). LIMITATIONS: This study was a cross-sectional design making it difficult to infer a causal association. CONCLUSIONS: OBS is negatively associated with depression, which may be mediated in part by oxidative stress and inflammation.

Association of urinary heavy metals co-exposure and adult depression: Modification of physical activity.

OBJECTIVE: This study aimed to evaluate the association between urinary heavy metal mixture exposure and depression, and the modifying role of physical activity in the effects of heavy metal mixture on depression risk was also considered. METHODS: Data of this study were derived from the National Health and Nutrition Examination Survey 2011-2016. Depression was measured by the Patient Health Questionnaire. We first selected 6 (cadmium, cobalt, tin, antimony, thallium, and mercury) from 14 heavy metals through elastic net regression for further analysis. Then binomial logistic regression, generalized additive model, environment risk score (ERS), and weighted quantile sum (WQS) regression were adopted to assess the effects of six metals individual and cumulative exposure on depression risk. Finally, we also examined whether physical activity could mitigate the effects of heavy metal co-exposure on depression risk. RESULTS: Totally, 4212 participants were included and 7.40% of subjects were with depression. We found urinary tin and antimony were separately associated with increased odds of depression (Sb: OR = 1.285, 95% CI: 1.064-1.553; Sn: OR = 1.281, 95% CI: 1.097-1.495), and a linear dose-response relationship between tin and depression was also noticed (P < 0.05). Meanwhile, urinary heavy metals co-exposure was positively related to depression risk (ERSQ4: OR = 2.691, 95% CI: 1.399-5.174; WQSpositive: OR = 1.465, 95% CI: 1.063-2.021), in which tin, antimony, and cadmium were identified with greater contributions to the overall mixture effect. In both ERS and WQS models, the significant positive association between the metal mixture and depression risk remained only in those who were inactive in physical activity. CONCLUSION: Our study concluded the detrimental effect of heavy metals in combined exposure on the risk of depression, which might be attenuated by physical activity.

Association between pyrethroid exposure and risk of depressive symptoms in the general US adults.

This study aimed to investigate the association between pyrethroid exposure and the risk of depressive symptoms in adults in the USA. Data of participants aged ≥20 years (n = 6455) from the National Health and Nutrition Examination Survey (NHANES, 2007-2014) were included. 3-Phenoxybenzoic acid (3-PBA), an adequately detected pyrethroid metabolite, was used as a biomarker to assess pyrethroid exposure. Depressive symptoms were defined as the Patient's Health Questionnaire (PHQ-9) total score ≥10 or use of antidepressant. Multivariable logistic regression analyses were performed to examine the association between urinary 3-PBA levels and the risk of depressive symptoms. In this study, 1150 participants (weighted frequency, 18.45%) developed depressive symptoms. Participants in the highest tertile have a higher risk of depressive symptoms than those in the lowest tertile of urinary 3-PBA and weighted OR of 1.28 (95% CI, 1.00-1.63, P=0.019). There was a nonlinear association between urinary 3-PBA and depressive symptoms (P for nonlinearity = 0.034). Mediation analysis showed the mediating effect of trouble sleeping on the association of urinary 3-PBA with depressive symptoms was 28.8% (P = 0.006). Our findings indicate that pyrethroid exposure is associated with the increased risk of depressive symptoms, and trouble sleeping may mediated this association. Further studies should be conducted to validate our findings and elucidate their underlying mechanisms.

Associations between urinary caffeine and caffeine metabolites and cognitive function in older adults.

BACKGROUND: The effects of caffeine on cognitive impairment have not been conclusively determined. This study aimed to objectively assess the correlation between the urinary caffeine and caffeine metabolites and cognitive decline in older adults. METHODS: Data on urinary caffeine and caffeine metabolites and the cognitive performance of participants aged 60 years and older were extracted from the National Health and Nutrition Examination Surveys 2011-2014. Binary logistic regression and restricted cubic splines (RCS) analyses were used to evaluate the association between urinary caffeine and caffeine metabolites and cognitive performance. RESULTS: Eight hundred twenty-seven individuals were enrolled in this cross-sectional study. We observed that 1-methylxanthine, 3-methylxanthine, 7-methylxanthine, 1,3-dimethylxanthine, 1,7-dimethylxanthine, and 3,7-dimethylxanthine levels were significantly and inversely associated with cognitive decline. The RCS results suggested an approximately linear dose-response relationship between the aforementioned metabolites and cognitive performance. Moreover, the effects of urinary caffeine and caffeine metabolites on cognitive function assessed using the AFT were more evident in men. CONCLUSIONS: Our study suggested that urinary caffeine and caffeine metabolite levels were associated with a reduced risk of cognitive impairment in a linear manner, especially in men.

MEF2C gene variations are associated with ADHD in the Chinese Han population: a case-control study.

Myocyte enhancer factor 2C (MEF2C) is associated with hyperactivity and might be a novel risk gene for susceptibility to attention deficit hyperactivity disorder (ADHD). Therefore, this study aimed to explore the association between MEF2C genetic variants and ADHD in the Chinese Han population. A total of 215 patients with ADHD and 233 controls were recruited for this study. The Swanson, Nolan, and Pelham version IV questionnaire was used to evaluate the clinical features of ADHD. In silico analysis was used to annotate the biological functions of the promising single nucleotide polymorphisms. Our findings indicated that MEF2C rs587490 was significantly associated with ADHD in the multiplicative model (OR = 0.640, p = 0.002). Participants with the rs587490 TT allele exhibited less hyperactivity/impulsivity than those with the rs587490 CC allele. Furthermore, the expression quantitative trait loci analysis suggested that rs587490 could regulate the gene expression of MEF2C in the hippocampus, putamen, thalamus, and frontal white matter. Our study concluded that the MEF2C rs587490 T allele is significantly associated with a reduced risk of ADHD in the Chinese Han population, which provides new insight into the genetic etiology of ADHD.

Systemic inflammatory regulators and 7 major psychiatric disorders: A two-sample Mendelian randomization study.

Systemic inflammation has been thought to play a considerable part in psychiatric disorders. However, the causal relationships between systemic inflammation and psychiatric disorders and the directions of the causal effects remain elusive and need further investigation. By leveraging the summary statistics of genome-wide association studies, the standard inverse variance weighted method was applied to assess the causal associations among 41 systemic inflammatory regulators and 7 major psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), autism spectrum disorder (ASD), bipolar disorder (BIP), major depression disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia (SCZ), within a two-sample bidirectional Mendelian randomization analysis. Additionally, the weighted median test and the Mendelian randomization pleiotropy residual sum and outlier test were conducted for sensitivity analyses. The results suggested a total of 15 unique systemic inflammatory regulators might be causally associated with disease risk, including 2 for ADHD, 4 for AN, 2 for ASD, 2 for MDD, 2 for OCD, and 5 for SCZ. Among them, the genetically predicted concentration of basic fibroblast growth factor was significantly related to AN at the Bonferroni-corrected threshold (Odds ratio = 0.403, 95% confidence interval = (0.261, 0.622), P = 4.03 × 10-5). Furthermore, the concentrations of 9 systemic inflammatory regulators might be influenced by neuropsychiatric disorders, including 2 by ADHD, 2 by BIP, 3 by MDD, and 2 by SCZ, and the causal effects of ASD, AN, and OCD need to be further assessed when more significant genetic variants are identified in the future. Overall, this study provides additional insights into the relationships between systemic inflammation and psychiatric disorders and may provide new clues regarding the aetiology, diagnosis and treatment of psychiatric disorders.

A novel genetic variant potentially altering the expression of MANBA in the cerebellum associated with attention deficit hyperactivity disorder in Han Chinese children.

OBJECTIVES: To obtain additional insight into the genetic factors of attention deficit hyperactivity disorder (ADHD). METHODS: First, we performed a transcriptome-wide association study (TWAS) integrating human cerebellum-specific variant-expression/splicing correlations to identify ADHD susceptibility genes. Then, the associations between expression/splicing quantitative trait loci (eQTLs/sQTLs) of the transcriptome-wide significant genes and ADHD were observed in a case-control study of Han Chinese children. Furthermore, dual luciferase reporter gene assays were performed to validate the regulatory function of ADHD risk variants. Additionally, the transcription level of target genes in blood was detected by real-time quantitative polymerase chain reaction (RT-qPCR) assay. RESULTS: TWAS identified that the genetically regulated expression of MANBA in the cerebellum was significantly associated with ADHD risk. Furthermore, we observed a higher risk of ADHD and more severe clinical symptoms in subjects harbouring heterozygous (TC) or mutant homozygous (TT) genotypes of MANBA rs1054037 than CC carriers. The dual luciferase reporter gene assay revealed that the mutation of rs1054037(C > T) potentially upregulated MANBA expression by eliminating the binding site for hsa-miR-5591-3P. Finally, RT-qPCR showed that MANBA expression in blood samples of patients was significantly higher than that of controls. CONCLUSIONS: Taken together, these results suggest a role of MANBA in the development of ADHD.

A novel cis-regulatory variant modulating TIE1 expression associated with attention deficit hyperactivity disorder in Han Chinese children.

BACKGROUND: The genetic factors of attention deficit hyperactivity disorder (ADHD) are far from fully elucidated. This study aims to get additional insight into the genetic structure of ADHD. METHODS: First, a transcriptome-wide association study and summary data-based Mendelian randomization analysis were performed to identify ADHD susceptibility genes. Then, genetic variants influencing the expression of the identified susceptibility genes were tested for association with ADHD risk in a sample of Han Chinese children (543 cases and 560 controls). Dual-luciferase reporter gene assays and electrophoretic mobility shift assays were performed to verify the transcriptional regulatory functions of the identified ADHD-associated variants. Additionally, real-time quantitative polymerase chain reaction was applied to quantify the expression levels of target genes in blood samples. RESULTS: Both TIE1 and MED8 were identified as ADHD susceptibility genes. Furthermore, we first found the G allele of rs3768046 was significantly associated with an increased risk of ADHD (recessive model: GG vs AA+AG, OR= 1.659, 95% CI= (1.262, 2.181); additive model: GG vs GA vs AA, OR= 1.493, 95% CI= (1.179, 1.890)). Additionally, in vitro functional experiments revealed that rs3768046 might alter TIE1 expression by affecting the binding sites of transcription factors. Moreover, the expression level of TIE1 in the blood samples of patients was significantly higher than that of controls. LIMITATIONS: Given the moderate statistical power of this study, it is necessary to verify our findings in other larger samples. CONCLUSIONS: Together, this study presents the first systematic evidence of TIE1 with potential implications for the genetic basis of ADHD.

Transcriptomics and metabonomics analyses of maternal DEHP exposure on male offspring.

The objectives of this study were to evaluate the effect of maternal Di-2-ethylhexyl phthalate (DEHP) exposure on male offspring and to explore the mechanism of changes with the metabolic alterations and differential genes. Pregnant female Sprague-Dawley (SD) rats were intragastrically administered with 600 mg/kg body weight of DEHP or corn oil (CON) throughout pregnancy and lactation. The growth of male offspring was investigated until 14 weeks old, the indices of blood were detected, and mechanism was studied using metabonomics and transcriptomics. Compared with the CON group, body weight, body length, food intake, body fat weight, Lee's index, organ coefficient, blood lipids, and oral glucose tolerance test (OGTT) of male offspring were not significantly changed in maternal DEHP group. However, serum biochemical indexes such as alanine transaminase (ALT), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), and creatinine (CREA) were markedly reduced in maternal DEHP group (p < 0.05). In addition, insulin level was elevated and catalase (CAT) level was decreased notably in maternal DEHP group compared with the CON group (p < 0.05). Furthermore, thyroxine (T4) level was lower and thyroid stimulating hormone (TSH) level was higher in maternal DEHP group (p < 0.05). Metabonomics revealed seven principal metabolites were identified, including increased L-allothreonine, creatine, uric acid, retinyl ester, L-palmitoylcarnitine, and decreased glycocholic acid and LysoPC (18:3). Transcriptomics displayed 35 differential genes were involved in the mechanism of maternal DEHP exposure. Therefore, this research confirms the effect of a certain dose of maternal DEHP exposure on male offspring and understands exactly the mechanism of these changes with metabonomics and transcriptomics.