PD-L1 Enhanced by cis-Urocanic Acid on Langerhans Cells Inhibits Vγ4+ γδT17 Cells in Imiquimod-Induced Skin Inflammation.

Psoriasis is an IL-23/IL-17-mediated inflammatory autoimmune dermatosis, and UVB may contribute to immunosuppression and ameliorate associated symptoms. One of the pathophysiology underlying UVB therapy is the production of cis-urocanic acid (cis-UCA) by keratinocytes. However, the detailed mechanism is yet to be fully understood. In this study, we found FLG expression and serum cis-UCA levels were significantly lower in patients with psoriasis than in healthy controls. We also noted that cis-UCA application inhibited psoriasiform inflammation through the reduction of Vγ4+ γδT17 cells in murine skin and draining lymph nodes. Meanwhile, CCR6 was downregulated on γδT17 cells, which would suppress the inflammatory reaction at a distal skin site. We revealed that the 5-hydroxytryptamine receptor 2A, the known cis-UCA receptor, was highly expressed on Langerhans cells in the skin. cis-UCA also inhibited IL-23 expression and induced PD-L1 on Langerhans cells, leading to the attenuated proliferation and migration of γδT-cells. Compared to the isotype control, α-PD-L1 treatment in vivo could reverse the antipsoriatic effects of cis-UCA. PD-L1 expression on Langerhans cells was sustained through the cis-UCA-induced mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. These findings uncover the cis-UCA-induced PD-L1-mediated immunosuppression on Langerhans cells, which facilitates the resolution of inflammatory dermatoses.

Association of the consumption of common drinks with early puberty in both sexes.

Background: We examined the effect of sugar-sweetened beverages (SSB) and common drink intake on pubertal development in both sexes. Methods: Data were retrieved from Taiwan Children Health Study, which involved detailed pubertal stage assessments of 2,819 schoolchildren aged 11 years in 2011-2012. Drawings of secondary sexual characteristics and self-reported age at menarche or voice breaking were used to assess pubertal stages. Dietary intake was assessed using a detailed semi-quantitative food frequency questionnaire. Generalized estimating equation modeling was applied to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to represent the effects of each drink on early pubertal development outcomes. Results: In boys, an one cup/day increment of a SSB was associated with earlier voice breaking (ß = -0.12; 95% CI = -0.20, -0.04), whereas consuming yogurt (≥2 cups/day) was a protective factor against early puberty (OR = 0.78; 95% CI = 0.73, 0.83). In girls, SSB consumption was associated with increased risk of early puberty in a dose-response manner, and a similar protective effect of yogurt consumption and fermented probiotic drink (≥2 cups/day) against early puberty was observed (OR = 0.96; 95% CI = 0.94, 0.99). Furthermore, the intake of both total sugar and added sugar within SSBs increased risk of early puberty in girls but not in boys. Conclusions: Sugar-sweetened beverages were associated with early puberty, and probiotic drinks appeared to mitigate this link. These findings indicate that the gut-brain axis could play a crucial role in sexual maturation.

Prenatal antioxidant-enriched and pro-oxidant-contained food, IL4 and IL13 pathway genes, and cord blood IgE.

Prenatal oxidative balance might influence cord blood IgE (cIgE) levels. We aimed to explore if certain prenatal dietary sources of antioxidants and pro-oxidants are associated with cIgE elevation and if they interact with IL4 and IL13 pathway genes. A structured questionnaire was completed during the third trimester of pregnancy for 1107 full-term newborns. Surveyed antioxidant-enriched food included fish, shellfish, and fruit, whereas surveyed pro-oxidant-contained food included fried fish sticks and canned fish. Cord blood was collected for measuring cIgE levels and genotyping IL13 rs1800925, rs20541, rs848, IL4 rs2243250, and STAT6 rs324011. Fairly lean fish consumption showed protection against cIgE elevation (odds ratio [OR] 0.66; 95% CI 0.49-0.90) in the whole sample, while daily fruit (OR 0.46; 95% CI 0.27-0.79) and ≥ monthly canned fish (OR 2.81; 95% CI 1.24-6.36) exhibited associations only in genetically susceptible babies. A prenatal food protective index, comprising any fairly lean fish, daily fruit, and the absence of any canned fish, exerted dose-response protection against cIgE elevation in babies carrying the IL13 rs20541 GA or AA genotype (P for trend < 0.0001; P for interaction = 0.004). We concluded that prenatal antioxidant-enriched and pro-oxidant-contained food consumption may influence cIgE, especially in genetically susceptible babies.

Pulmonary IL-33 orchestrates innate immune cells to mediate respiratory syncytial virus-evoked airway hyperreactivity and eosinophilia.

BACKGROUND: Respiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, IL-33 is elevated and promotes immune cell activation, leading to the development of asthma. However, which immune cells are responsible for triggering airway hyperreactivity (AHR), inflammation and eosinophilia remained to be clarified. We aimed to elucidate the individual roles of IL-33-activated innate immune cells, including ILC2s and ST2+ myeloid cells, in RSV infection-triggered pathophysiology. METHODS: The role of IL-33/ILC2 axis in RSV-induced AHR inflammation and eosinophilia were evaluated in the IL-33-deficient and YetCre-13 Rosa-DTA mice. Myeloid-specific, IL-33-deficient or ST2-deficient mice were employed to examine the role of IL-33 and ST2 signaling in myeloid cells. RESULTS: We found that IL-33-activated ILC2s were crucial for the development of AHR and airway inflammation, during RSV infection. ILC2-derived IL-13 was sufficient for RSV-driven AHR, since reconstitution of wild-type ILC2 rescued RSV-driven AHR in IL-13-deficient mice. Meanwhile, myeloid cell-derived IL-33 was required for airway inflammation, ST2+ myeloid cells contributed to exacerbation of airway inflammation, suggesting the importance of IL-33 signaling in these cells. Local and peripheral eosinophilia is linked to both ILC2 and myeloid IL-33 signaling. CONCLUSIONS: This study highlights the importance of IL-33-activated ILC2s in mediating RSV-triggered AHR and eosinophilia. In addition, IL-33 signaling in myeloid cells is crucial for airway inflammation.

Consumption of betel quid contributes to sensorineural hearing impairment through arecoline-induced oxidative stress.

Betel quid is one of the most widely used psychoactive substances, and is consumed by approximately 10% of the world's population. In addition to its carcinogenicity, betel quid has also been reported to affect many organs, including the brain, heart, lungs, gastrointestinal tract, and reproductive organs. As betel quid contains several neurotoxic ingredients, we hypothesize that it also possesses ototoxicity and may lead to sensorineural hearing impairment (SNHI). In this study, we investigated the contribution of betel quid consumption to SNHI in a large clinical cohort, and validated the pathogenetic mechanisms in ex vivo tissue explants. We enrolled a total of 2364 volunteers, and determined their audiologic results based on Z-scores converted from their original frequency-specific hearing thresholds. Using generalized linear regression, we identified a positive correlation between betel quid consumption and the Z-scores across different frequencies. Subsequently, we explored the toxicity of arecoline, the main neuroactive component of betel quid, on tissue explants from murine cochleae. Arecoline reduced cell activity in the explant cultures and induced apoptosis in the hair cells, probably through the effects of oxidative stress. These findings have expanded the potential hazards of betel quid to common neurological disorders, and provide insights into preventive strategies against SNHI caused by neurotoxic substances.

Sialyl Glycan Expression on T Cell Subsets in Asthma: a correlation with disease severity and blood parameters.

Memory T helper (Th) and regulatory T (Treg) cells play key roles in asthma. Certain sialyl carbohydrate determinants for selectins profoundly affect the migratory properties of memory Th cells, and the suppressive function of Treg cells. Previous studies have shown that the proportion of CCR4+ memory Th cells expressing sialyl 6-sulfo Lewis X (LeX) is elevated in asthma patients. We aim to investigate the roles of different sialyl glycans on T cell subsets in asthma. Using flow cytometry, we assessed the expression of three sialyl glycans, sialyl 6-sulfo LeX, cyclic sialyl 6-sulfo LeX, and sialyl LeX on memory Th and Treg cells, in the peripheral blood of asthmatic children. We also assessed the relationships between glycan-expressing cell percentages and asthma clinical parameters. Compared with controls, asthmatic children showed higher proportions of memory Th cells expressing sialyl LeX and sialyl 6-sulfo LeX. The proportions of memory Th cells with sialyl 6-sulfo LeX and cyclic sialyl 6-sulfo LeX expression in asthmatic children correlated with absolute eosinophil count and IgE level, respectively. Children with moderate-to-severe asthma had lower numbers of sialyl LeX positive Treg cells. Our study suggests that sialyl glycans on T cells may play important roles in the pathogenesis of asthma.

Sex-moderated interactions between IL4/IL13 pathway genes and prenatal environment on cord blood IgE levels.

BACKGROUND: Elevated cord blood IgE (cIgE), a predictor of atopic diseases, is influenced by genetic and environmental factors. However, gene-environment interactions on cIgE elevation and their difference by sex remain largely unexplored. OBJECTIVE: This study aimed to determine whether there are sex-moderated interactions between genetic variants in the IL4/IL13 pathway and prenatal environments on cIgE elevation. METHODS: Comprehensive information on environmental tobacco smoke (ETS), home dampness (indexed by combining mildewy odour, visible mould and water stamp on the wall) and other household environments was obtained using a structured questionnaire during the third trimester of pregnancy in 1107 full-term newborns. The cord blood was collected for measuring cIgE levels, with elevation defined as ≥0.5 IU/mL, and for genotyping of five single nucleotide polymorphisms of three candidate genes (IL-13 rs1800925, rs20541, rs848, IL-4 rs2243250 and STAT6 rs324011). RESULTS: Gene-environment interactions on cIgE elevation were observed in male but not female newborns, including those between ETS and IL13 rs20541, between home dampness and STAT6 rs324011, and between composite environmental exposure (combined ETS and the three home dampness indices) and STAT6 rs324011 (P for interaction = 0.03, 0.006, and 0.001, respectively). Male newborns carrying STAT6 rs324011 CT or TT genotype manifested with a significant dose-response association of the composite environmental exposure with cIgE elevation. CONCLUSION AND CLINICAL RELEVANCE: Sex moderates the gene-environment interactions involving IL4/IL13 pathway genes and prenatal household environments on cIgE elevation. The absence of prenatal exposure to ETS and home dampness in male neonates carrying the STAT6 rs324011 CT or TT genotype is least likely associated with cIgE elevation.

Association of Air Pollution Exposure and Interleukin-13 Haplotype with the Risk of Aggregate Bronchitic Symptoms in Children.

Interleukin-13(IL-13) might play an important role in driving aggregate bronchitic symptoms pathogenesis. However, none of the studies assessed the interaction between air pollutants exposure and IL-13 gene on the risk of aggregate bronchitic symptoms in non-asthma children. To assess the independent and joint effects of the exposure to air pollution and IL-13 haplotypes on the risk of aggregate bronchitic symptoms, we conducted a cross-sectional study and focused on non-asthma children. The study population consisted of 2944 children. The effect of each air pollutant on the risk of aggregate bronchitic symptoms was estimated as odds ratios per interquartile range (IQR) change. In the multiple logistic regressions, adjusted for confounding factors, the risk of chronic phlegm was associated with PM2.5 exposure (aOR, 1.59; 95% CI, 1.07-2.37 per 12.51µg/m3 change), O3 exposure (aOR, 1.54 95% CI, 1.05-2.27 per 8.28ppb change) and SO2 exposure (aOR, 1.19; 95% CI, 1.02-1.39 per 0.98ppb change). Our study further provides the evidence that gene-environment interactions between IL-13 haplotype and O3 exposure on chronic phlegm (95% CI for interaction, 1.01-1.38). Identifying children who are more sensitive to air pollution helps us to provide them an efficient prevention to avoid aggregate bronchitic symptoms.

Comprehensive determinants of growth trajectories and body composition in school children: A longitudinal cohort study.

OBJECTIVE: To fully explain the dynamic and comprehensive etiology of the trajectory associated with adiposity indices. METHODS: This study involved data of 5572 children, aged 6-11 years, as part of the Taiwan Children Health Study (TCHS). The present study introduced four distinct BMI trajectories, identified previously among children: persistently healthy weight; late-onset overweight or obesity; persistent overweight or obesity; and declining BMI class. Logistic regression was used to examine the effect of non-modifiable factors on BMI trajectory classes. Generalized estimating equations were used to examine the effect of dynamically modifiable factors on either BMI trajectory classes or adiposity indices. RESULTS: Compared with class 1 (persistently healthy weight), class 2 exhibited a significantly increased risk of weight gain and fat mass, affected by lower family incomes and poor-quality sleep. Class 3 had a higher risk of persistent obesity and abdominal obesity, affected by higher birthweight and sedentary lifestyle. Class 4 approached a healthy weight due to increased physical activity, which was associated with a decrease in body fat and central obesity. CONCLUSIONS: We found crucially non-modifiable and modifiable factors that could describe each high BMI growth pattern, and calculated their modifiable contributions to adiposity indices. Modifiable factors that focus on those crucially dynamic factors are recommended for preventing obese growth trajectories.

Perfluoroalkyl substance exposure and urine CC16 levels among asthmatics: A case-control study of children.

BACKGROUND: Studies have reported an association between serum perfluoroalkyl substances (PFASs) and asthma. However, few studies have examined the possible associations between PFASs and the 16-kDa club cell secretory protein (Clara) (CC16) level, a prominent biomarker of asthma, among adolescents. METHODS: We recruited a total of 231 asthmatic children and 225 non-asthmatic controls in the Genetic and Biomarkers study for Childhood Asthma (GBCA) in northern Taiwan from 2009 to 2010. Structured questionnaires were administered by face-to-face interview. Urine CC16 was determined by an enzyme-link immunoassay kit. Multiple general linear models were employed to examine the associations between PFASs and urinary CC16 levels. RESULTS: Asthmatic participants had significantly higher serum PFAS concentrations overall than the healthy controls. After adjusting for confounding factors, urinary CC16 was significantly, negatively associated with PFASs, especially PFOS, PFOA, PFDA and PFNA, and especially among males, as follows: PFOS (ß = -0.003, 95% confidence interval [CI]: -0.004, -0.002), PFOA (ß = -0.045, 95% CI: -0.086, -0.004), and PFHxA (ß = -0.310, 95% CI: -0.455, -0.165) among asthmatic boys, and PFDA (ß = -0.126, 95%CI: -0.241, -0.012) and PFNA (ß = -0.329, 95% CI: -0.526, -0.132) among non-asthmatic boys. Among girls, PFDA (ß = -0.088, 95% CI: -0.172, -0.004), was the only PFAS significantly associated with CC16. Significant interaction effects (p < 0.15) on CC16 levels were found between asthma and PFOS, PFOA, PFBS and PFHxA in all participants. CONCLUSION: Our overall results showed that serum PFASs were significantly, inversely associated with CC16 levels. Associations were stronger among males.

Interaction effects of polyfluoroalkyl substances and sex steroid hormones on asthma among children.

To evaluate the interactions between polyfluoroalkyl substances (PFASs) and reproductive hormones and associated asthma, a total of 231 asthmatic and 225 non-asthmatic adolescents were selected from northern Taiwan in the Genetic and Biomarkers study for Childhood Asthma from 2009-2010. The interaction between PFASs and reproductive hormones on asthma was analyzed with a two-level binary logistic regression model. The results showed that, among asthmatics, PFASs were positively associated with estradiol levels and negatively associated with testosterone levels. However, only significant association was identified for PFNA and estradiol in control group. After controlling for hormone levels, associations between PFAS exposure and asthma were consistently stronger among children with higher than lower estradiol, with odds ratios (OR) for asthma ranging from 1.25 for PFOS (95% Confidence Interval [CI]: 0.90, 1.72) to 4.01 for PFDA (95% CI: 1.46, 11.06) among boys and 1.25 for PFOS (95% CI: 0.84, 1.86) to 4.16 for PFNA (95% CI: 1.36, 12.73) among girls. Notably, the interactions between estradiol and PFASs were significant for PFOS (p = 0.026) and PFNA (p = 0.043) among girls. However, testosterone significantly attenuated the association between PFOS and asthma across sex. In conclusions, our findings suggested that reproductive hormones amplify the association between PFASs and asthma among adolescents.

Association of perfluoroalkyl substances exposure with impaired lung function in children.

Previous studies have demonstrated associations between serum levels of perfluoroalkyl substances (PFASs) and asthma or asthma related-biomarkers. However, no studies have reported a possible relationship between PFASs exposure and lung function among children. The objective of the present study is to test the association between PFASs exposure and lung function in children from a high exposure area by using a cross-sectional case-control study, which included 132 asthmatic children and 168 non-asthmatic controls recruited from 2009 to 2010 in the Genetic and Biomarkers study for Childhood Asthma. Structured questionnaires were administered face-to-face. Lung function was measured by spirometry. Linear regression models were used to examine the influence of PFASs on lung function. The results showed that asthmatics in our study had significantly higher serum PFAS concentrations than healthy controls. Logistic regression models showed a positive association between PFASs and asthma, with adjusted odds ratios (ORs) ranging from 0.99 (95% confidence interval [CI]: 0.80-1.21) to 2.76 (95% CI: 1.82-4.17). Linear regression modeling showed serum PFASs levels were significantly negatively associated with three pulmonary function measurements (forced vital capacity: FVC; forced expiratory volume in 1s: FEV1; forced expiratory flow 25-75%: FEF25-75) among children with asthma, the adjusted coefficients between lung function and PFASs exposure ranged from -0.055 (95%CI: -0.100 to -0.010) for FVC and perfluorooctane sulfonate (PFOS) to -0.223 (95%CI: -0.400 to -0.045) for FEF25-75 and perfluorooctanoic acid (PFOA). PFASs were not, however, significantly associated with pulmonary function among children without asthma. In conclusion, this study suggests that serum PFASs are associated with decreased lung function among children with asthma.

Newborn genetic screening for hearing impairment: a population-based longitudinal study.

PURPOSE: The feasibility of genetic screening for deafness-causing mutations in newborns has been reported in several studies. The aim of this study was to investigate the long-term results in those who screened positive for deafness mutations; these results are crucial to determine the cost-effectiveness to justify population-wide genetic screening. METHODS: We performed simultaneous hearing screening and genetic screening targeting four common deafness mutations (p.V37I and c.235delC of GJB2, c.919-2A>G of SLC26A4, and the mitochondrial m.1555A>G) in 5173 newborns at a tertiary hospital between 2009 and 2015. Serial audiometric results up to 6 years old were then analyzed in children with conclusive genotypes. RESULTS: Newborn genetic screening identified 82 (1.6%) babies with conclusive genotypes, comprising 62 (1.2%) with GJB2 p.V37I/p.V37I, 16 (0.3%) with GJB2 p.V37I/c.235delC, and 4 (0.1%) with m.1555A>G. Of these, 46 (56.1%) passed hearing screening at birth. Long-term follow-up demonstrated progressive hearing loss in children with the GJB2 p.V37I/p.V37I and p.V37I/c.235delC genotypes; this hearing loss deteriorated by approximately 1 decibel hearing level (dBHL) per year. CONCLUSIONS: We delineated the longitudinal auditory features of the highly prevalent GJB2 p.V37I mutation on a general population basis and confirmed the utility of newborn genetic screening in identifying infants with late-onset or progressive hearing impairment undetectable by newborn hearing screening.Genet Med 19 1, 6-12.

Growth trajectories and asthma/rhinitis in children: a longitudinal study in Taiwan.

Studies have reported the effect of body weight in early childhood on asthma. However, the effect of growth patterns during school age on asthma and rhinitis has yet to be explored. We sought to investigate whether various growth patterns predict incident asthma and rhinitis.We conducted a nationwide longitudinal study (Taiwan Children Health Study) in 14 Taiwanese communities. Body mass index (BMI) z-scores of 4422 children aged 6-11 years were collected annually and distinct growth trajectory classes were identified using a latent generalised mixture model. Pulmonary function and exhaled nitric oxide fraction (FeNO) levels were also measured. Whether different growth trajectory classes predict incident asthma and rhinitis at age 12, 15 and 18 years was determined using a discrete time hazard model.Four growth trajectory classes were identified. Persistently overweight children exhibited significantly increased risks of asthma and rhinitis at age 12 years. Furthermore, being persistently overweight had a long-term effect on incident asthma (hazard ratio 2.47, 95% CI 1.18-5.12) and rhinitis (hazard ratio 1.44, 95% CI 1.12-1.84) in adolescence and early adulthood. Children in high BMI classes exhibited significantly lower pulmonary functions compared with normal growth children. FeNO levels were lower in children in the high BMI classes and higher in children showing declining obesity compared with normal growth children.Persistently overweight children exhibited incident asthma and rhinitis in adolescence and early adulthood.

Associations between Respiratory Diseases and Dietary Patterns Derived by Factor Analysis and Reduced Rank Regression.

BACKGROUND/AIMS: The study aims to identify children's dietary patterns and explore the relationship between dietary patterns and respiratory diseases. METHODS: Subjects were 2,397 fourth graders in 14 Taiwanese communities who participated in the Taiwan Children Health Study. This study is based on an evaluation of dietary patterns, performed from April until June 2011. Information pertaining to respiratory disease was obtained by The International Study of Asthma and Allergies in Childhood questionnaire, and dietary intake data obtained by food frequency questionnaire. Factor analysis and reduced rank regression (RRR) were both used to analyze dietary patterns. RESULTS: Using factor analysis, it was found that children on a high-protein, high-fat, Western diet had a significantly higher risk of allergic rhinitis (OR 1.10, 95% CI 1.01-1.20). Lower ORs were noted for current wheezing, ever asthma and bronchitis in children eating a healthy diet than those on a high-protein, high-fat, Western diet. Using RRR, it was found that children on a high-protein, high-fat diet had significantly higher risks of allergic rhinitis (OR 1.17, 95% CI 1.07-1.27), current wheezing (OR 1.23, 95% CI 1.04-1.45) and bronchitis (OR 1.26, 95% CI 1.09-1.46). CONCLUSIONS: A diet rich in fat and protein may increase the risk of respiratory disease in children.

Associations between allergic diseases and attention deficit hyperactivity/oppositional defiant disorders in children.

BACKGROUND: We aim to investigate the detailed associations between allergic diseases with attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) among children. METHODS: Clinical information from 2,896 children enrolled in the Taiwan Children Health Study was obtained for analyses. Allergic diseases, including atopic dermatitis, asthma, and allergic rhinitis, have been evaluated based on the questions adjusted from International Study of Asthma and Allergies in Childhood. The Swanson, Nolan, and Pelham questionnaire was used to assess symptoms of ADHD and ODD. Symptoms of depression, stress, and poor sleep quality were evaluated as the interactive risk factors. RESULTS: Children having symptoms of allergic diseases within the past 1 y were associated with having all dimensions of symptoms of ADHD and ODD. Children with ever having a physician-diagnosed atopic dermatitis were associated with inattentive and hyperactive-impulsive symptoms of ADHD. Ever diagnosed asthma was associated with ADHD and ODD. Ever diagnosed allergic rhinitis was associated with inattentive and combined symptoms of ADHD and ODD. CONCLUSION: Children with allergic diseases, such as atopic dermatitis, asthma, and allergic rhinitis, were associated with exhibiting ADHD and ODD.

Association of perfluoroalkyl substances exposure with reproductive hormone levels in adolescents: By sex status.

Polyfluoroalkyl substances (PFASs) are a group of common chemicals that ubiquitously exist in wildlife and humans. However, few studies have researched the effect of PFASs on reproductive hormones in adolescents. To provide information in this regard, we recruited 225 Taiwanese adolescents aged 13-15years from 2009 to 2010 to investigate the relationship between serum PFASs (PFOS, PFOA, PFBS, PFDA, PFDoA, PFHxA, PFHxS, PFNA and PFTA) and reproductive hormone concentrations using a cross-sectional study design. Results showed PFOS and PFTA levels were highest among the PFASs, with a median concentrations of 29.9 (interquartile range: 13.0-43.8) ng/mL and 6.0 (0.6-25.9) ng/mL in males, and a median concentrations of 28.8 (14.8-42.6) ng/mL and 4.5 (0.3-18.4) ng/mL in females. After adjustment for confounding factors, nonsignificant associations between PFASs and reproductive hormone were found except for PFNA with ln(estradiol) (ß=0.2060, 95%CI: 0.0016, 0.4105). When stratified by sex, more significant associations were found in males than in females. Among males, PFASs were negatively associated with ln(testosterone) level for PFOS (ß=-0.0029, 95%CI: -0.0055, -0.0003), PFDA (ß=-0.2565, 95%CI: -0.4135, -0.0994), PFHxA (ß=-0.3095, 95%CI: -0.5942, -0.0248), and PFNA (ß=-0.4233, 95%CI: -0.6998, -0.1467). Furthermore, male participant ln(estradiol) levels were positively associated with PFOA (ß=0.0921, 95%CI: 0.0186, 0.1656), and PFHxS (ß=0.0462, 95%CI: 0.0020, 0.0905). Among females, a significant relationship was found only for PFDoA with ln(testosterone) (ß=-0.0119, 95%CI: -0.0227, -0.0010). In conclusion, this study showed higher levels of PFASs coincide with lower testosterone and higher estradiol levels, and more significant associations of PFASs with reproductive hormone were found in males than in females.

Smoking-related microRNAs and mRNAs in human peripheral blood mononuclear cells.

Teenager smoking is of great importance in public health. Functional roles of microRNAs have been documented in smoke-induced gene expression changes, but comprehensive mechanisms of microRNA-mRNA regulation and benefits remained poorly understood. We conducted the Teenager Smoking Reduction Trial (TSRT) to investigate the causal association between active smoking reduction and whole-genome microRNA and mRNA expression changes in human peripheral blood mononuclear cells (PBMC). A total of 12 teenagers with a substantial reduction in smoke quantity and a decrease in urine cotinine/creatinine ratio were enrolled in genomic analyses. In Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA), differentially expressed genes altered by smoke reduction were mainly associated with glucocorticoid receptor signaling pathway. The integrative analysis of microRNA and mRNA found eleven differentially expressed microRNAs negatively correlated with predicted target genes. CD83 molecule regulated by miR-4498 in human PBMC, was critical for the canonical pathway of communication between innate and adaptive immune cells. Our data demonstrated that microRNAs could regulate immune responses in human PBMC after habitual smokers quit smoking and support the potential translational value of microRNAs in regulating disease-relevant gene expression caused by tobacco smoke.