Household cleaning products and the risk of allergic dermatitis: a prospective cohort study with primary-school children.

BACKGROUND: Household cleaning products are widely used by the public, but limited data have been obtained on whether their use induces allergic dermatitis in children. OBJECTIVE: This study investigated the association between exposure to household cleaning products and allergic dermatitis in primary-school children. METHODS: A prospective cohort study of Hong Kong primary-school children was conducted between 2012 and 2014. A baseline survey was administered to 1812 students who did not have allergic dermatitis. Information on respiratory symptoms, exposure to household chemical cleaning products and other topics was collected using a self-administered questionnaire. A cumulative chemical burden (CCB) score was calculated for each student by summing the duration of exposure to 14 chemical cleaning products. Principal component analysis was used to identify patterns in the use of these cleaning products. Logistic regression was performed to calculate relative risk (RR) with 95% confidence intervals (CIs) after adjusting for potential confounders. RESULTS: Eighty-nine (4.9%) of the students surveyed had dermatitis during the follow-up. However, exposure to individual chemical cleaning products was not found to be associated with the children's allergic dermatitis (all P > 0.05). In contrast to those in the lowest tertile, neither CCB scores in the middle tertile (RR: 1.16, 95% CI: 0.67 to 2.00) nor those in the highest tertile (RR: 1.24, 95% CI: 0.73 to 2.14) were significantly associated with the risk of allergic dermatitis. The adjusted RR for every 5-unit increment in CCB score was 1.01 (95% CI: 0.98 to 1.03). Four patterns of cleaning-product use were derived, but none were found to be associated with the risk of dermatitis (all P > 0.05). CONCLUSION: The use of household chemical cleaning products is not associated with the risk of dermatitis in primary-school children.

Genome-wide expression and response to exposure-based psychological therapy for anxiety disorders.

Exposure-based psychological treatments for anxiety have high efficacy. However, a substantial proportion of patients do not respond to therapy. Research examining the potential biological underpinnings of therapy response is still in its infancy, and most studies have focussed on candidate genes. To our knowledge, this study represents the first investigation of genome-wide expression profiles with respect to treatment outcome. Participants (n=102) with panic disorder or specific phobia received exposure-based cognitive behavioural therapy. Treatment outcome was defined as percentage reduction from baseline in clinician-rated severity of their primary anxiety diagnosis at post treatment and 6 month follow-up. Gene expression was determined from whole blood samples at three time points using the Illumina HT-12v4 BeadChip microarray. Linear regression models tested the association between treatment outcome and changes in gene expression from pre-treatment to post treatment, and pre-treatment to follow-up. Network analysis was conducted using weighted gene co-expression network analysis, and change in the detected modules from pre-treatment to post treatment and follow-up was tested for association with treatment outcome. No changes in gene expression were significantly associated with treatment outcomes when correcting for multiple testing (q<0.05), although a small number of genes showed a suggestive association with treatment outcome (q<0.5, n=20). Network analysis showed no association between treatment outcome and change in gene expression for any module. We report suggestive evidence for the role of a small number of genes in treatment outcome. Although preliminary, these findings contribute to a growing body of research suggesting that response to psychological therapies may be associated with changes at a biological level.

Hyperglycemia impedes definitive endoderm differentiation of human embryonic stem cells by modulating histone methylation patterns.

Exposure to maternal diabetes during fetal growth is a risk factor for the development of type II diabetes (T2D) in later life. Discovery of the mechanisms involved in this association should provide valuable background for therapeutic treatments. Early embryogenesis involves epigenetic changes including histone modifications. The bivalent histone methylation marks H3K4me3 and H3K27me3 are important for regulating key developmental genes during early fetal pancreas specification. We hypothesized that maternal hyperglycemia disrupted early pancreas development through changes in histone bivalency. A human embryonic stem cell line (VAL3) was used as the cell model for studying the effects of hyperglycemia upon differentiation into definitive endoderm (DE), an early stage of the pancreatic lineage. Hyperglycemic conditions significantly down-regulated the expression levels of DE markers SOX17, FOXA2, CXCR4 and EOMES during differentiation. This was associated with retention of the repressive histone methylation mark H3K27me3 on their promoters under hyperglycemic conditions. The disruption of histone methylation patterns was observed as early as the mesendoderm stage, with Wnt/ß-catenin signaling being suppressed during hyperglycemia. Treatment with Wnt/ß-catenin signaling activator CHIR-99021 restored the expression levels and chromatin methylation status of DE markers, even in a hyperglycemic environment. The disruption of DE development was also found in mouse embryos at day 7.5 post coitum from diabetic mothers. Furthermore, disruption of DE differentiation in VAL3 cells led to subsequent impairment in pancreatic progenitor formation. Thus, early exposure to hyperglycemic conditions hinders DE development with a possible relationship to the later impairment of pancreas specification.

Caring burden of REM sleep behavior disorder - spouses' health and marital relationship.

OBJECTIVES: Idiopathic REM sleep behavior disorder (iRBD) is noxious due to the high prevalence of sleep-related injuries to patients and their bed-partners. In this study, we aimed to investigate the impact of patients' RBD symptoms on their spouses, in terms of the quality of sleep, and physical, mental and marital aspects. METHOD: A cross-sectional study comparing spouses of iRBD patients to the spouses of the age-and-sex-matched OSAS patients. RESULTS: 40 iRBD patients and their spouses (patients' age 66.6 ± 9.1, male 90%; spouses' age 62.9 ± 7.5), and 35 OSAS patients and their spouses (patients' age 67.8 ± 8.7 years old, male 80%; spouses' age 64.1 ± 9.1) were recruited. Almost all iRBD spouses (90%) reported disturbances by the nocturnal RBD behavioral symptoms of their bedpartners. About two-thirds (62.5%, N = 25) of the iRBD spouses reported a history of being injured during sleep. Spouses of both iRBD and OSAS patients reported a comparably high prevalence of insomnia, anxiety and depressive symptoms. Spouses of iRBD patients, however, reported more impaired quality of life and marital relationship. Nearly two-thirds of RBD couples continued co-sleeping, despite the risk of sleep-related injuries and nocturnal disturbances. CONCLUSIONS: Both iRBD and OSAS spouses exhibited a high prevalence of insomnia and mood problems. In particular, iRBD significantly and negatively affect the spouses' quality of life and the marital relationship. Optimization of iRBD treatment, proper diagnosis, and management of sleep and mental health aspects of spouses may help to lessen the caring burden.

Serotonin transporter [corrected] methylation and response to cognitive behaviour therapy in children with anxiety disorders.

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35-45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT.

Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain.

Epigenetic processes such as DNA methylation have been implicated in the pathophysiology of neurodevelopmental disorders including schizophrenia and autism. Epigenetic changes can be induced by environmental exposures such as inflammation. Here we tested the hypothesis that prenatal inflammation, a recognized risk factor for schizophrenia and related neurodevelopmental conditions, alters DNA methylation in key brain regions linked to schizophrenia, namely the dopamine rich striatum and endocrine regulatory centre, the hypothalamus. DNA methylation across highly repetitive elements (long interspersed element 1 (LINE1) and intracisternal A-particles (IAPs)) were used to proxy global DNA methylation. We also investigated the Mecp2 gene because it regulates transcription of LINE1 and has a known association with neurodevelopmental disorders. Brain tissue was harvested from 6 week old offspring of mice exposed to the viral analog PolyI:C or saline on gestation day 9. We used Sequenom EpiTYPER assay to quantitatively analyze differences in DNA methylation at IAPs, LINE1 elements and the promoter region of Mecp2. In the hypothalamus, prenatal exposure to PolyI:C caused significant global DNA hypomethylation (t=2.44, P=0.019, PolyI:C mean 69.67%, saline mean 70.19%), especially in females, and significant hypomethylation of the promoter region of Mecp2, (t=3.32, P=0.002; PolyI:C mean 26.57%, saline mean 34.63%). IAP methylation was unaltered. DNA methylation in the striatum was not significantly altered. This study provides the first experimental evidence that exposure to inflammation during prenatal life is associated with epigenetic changes, including Mecp2 promoter hypomethylation. This suggests that environmental and genetic risk factors associated with neurodevelopmental disorders may act upon similar pathways. This is important because epigenetic changes are potentially modifiable and their investigation may open new avenues for treatment.

Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits.

Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins.

BACKGROUND: Childhood adverse experiences are known to induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. However, the mechanisms by which these experiences shape the neuroendocrine response to stress remain unclear. Method We tested whether bullying victimization influenced serotonin transporter gene (SERT) DNA methylation using a discordant monozygotic (MZ) twin design. A subsample of 28 MZ twin pairs discordant for bullying victimization, with data on cortisol and DNA methylation, were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994-1995 cohort of families with twins. RESULTS: Bullied twins had higher SERT DNA methylation at the age of 10 years compared with their non-bullied MZ co-twins. This group difference cannot be attributed to the children's genetic makeup or their shared familial environments because of the study design. Bullied twins also showed increasing methylation levels between the age of 5 years, prior to bullying victimization, and the age of 10 years whereas no such increase was detected in non-bullied twins across time. Moreover, children with higher SERT methylation levels had blunted cortisol responses to stress. CONCLUSIONS: Our study extends findings drawn from animal models, supports the hypothesis that early-life stress modifies DNA methylation at a specific cytosine-phosphate-guanine (CpG) site in the SERT promoter and HPA functioning and suggests that these two systems may be functionally associated.