Here, we review present understanding of sources and trends in human exposure to poly- and perfluoroalkyl substances (PFASs) and epidemiologic evidence for impacts on cancer, immune function, metabolic outcomes, and neurodevelopment. More than 4000 PFASs have been manufactured by humans and hundreds have been detected in environmental samples. Direct exposures due to use in products can be quickly phased out by shifts in chemical production but exposures driven by PFAS accumulation in the ocean and marine food chains and contamination of groundwater persist over long timescales. Serum concentrations of legacy PFASs in humans are declining globally but total exposures to newer PFASs and precursor compounds have not been well characterized. Human exposures to legacy PFASs from seafood and drinking water are stable or increasing in many regions, suggesting observed declines reflect phase-outs in legacy PFAS use in consumer products. Many regions globally are continuing to discover PFAS contaminated sites from aqueous film forming foam (AFFF) use, particularly next to airports and military bases. Exposures from food packaging and indoor environments are uncertain due to a rapidly changing chemical landscape where legacy PFASs have been replaced by diverse precursors and custom molecules that are difficult to detect. Multiple studies find significant associations between PFAS exposure and adverse immune outcomes in children. Dyslipidemia is the strongest metabolic outcome associated with PFAS exposure. Evidence for cancer is limited to manufacturing locations with extremely high exposures and insufficient data are available to characterize impacts of PFAS exposures on neurodevelopment. Preliminary evidence suggests significant health effects associated with exposures to emerging PFASs. Lessons learned from legacy PFASs indicate that limited data should not be used as a justification to delay risk mitigation actions for replacement PFASs.

/pdf/a-review-of-the-pathways-of-human-exposure-to-poly-and-21ibeto3y1.pdf

A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects

MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

OncoLnc is a tool for interactively exploring survival correlations, and for downloading clinical data coupled to expression data for mRNAs, miRNAs, or long noncoding RNAs (lncRNAs). OncoLnc contains survival data for 8,647 patients from 21 cancer studies performed by The Cancer Genome Atlas (TCGA), along with RNA-SEQ expression for mRNAs and miRNAs from TCGA, and lncRNA expression from MiTranscriptome beta. Storing this data gives users the ability to separate patients by gene expression, and then create publication-quality Kaplan-Meier plots or download the data for further analyses. OncoLnc also stores precomputed survival analyses, allowing users to quickly explore survival correlations for up to 21 cancers in a single click. This resource allows researchers studying a specific gene to quickly investigate if it may have a role in cancer, and the supporting data allows researchers studying a specific cancer to identify the mRNAs, miRNAs, and lncRNAs most correlated with survival, and researchers looking for a novel lncRNA involved with cancer lists of potential candidates. OncoLnc is available at http://www.oncolnc.org. Subjects Bioinformatics, Computational Biology, Databases

OncoLnc: linking TCGA survival data to mRNAs, miRNAs, and lncRNAs

基因科学与亲子鉴定——国际流行病与公众健康杂志J Epidemiol Community Health

CONTEXT\nPerfluorinated compounds (PFCs) have emerged as important food contaminants. They cause immune suppression in a rodent model at serum concentrations similar to those occurring in the US population, but adverse health effects of PFC exposure are poorly understood.\n\n\nOBJECTIVE\nTo determine whether PFC exposure is associated with antibody response to childhood vaccinations.\n\n\nDESIGN, SETTING, AND PARTICIPANTS\nProspective study of a birth cohort from the National Hospital in the Faroe Islands. A total of 656 consecutive singleton births were recruited during 1997-2000, [corrected] and 587 participated in follow-up through 2008.\n\n\nMAIN OUTCOME MEASURES\nSerum antibody concentrations against tetanus and diphtheria toxoids at ages 5 and 7 years.\n\n\nRESULTS\nSimilar to results of prior studies in the United States, the PFCs with the highest serum concentrations were perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Among PFCs in maternal pregnancy serum, PFOS showed the strongest negative correlations with antibody concentrations at age 5 years, for which a 2-fold greater concentration of exposure was associated with a difference of -39% (95% CI, -55% to -17%) in the diphtheria antibody concentration. PFCs in the child's serum at age 5 years showed uniformly negative associations with antibody levels, especially at age 7 years, except that the tetanus antibody level following PFOS exposure was not statistically significant. In a structural equation model, a 2-fold greater concentration of major PFCs in child serum was associated with a difference of -49% (95% CI, -67% to -23%) in the overall antibody concentration. A 2-fold increase in PFOS and PFOA concentrations at age 5 years was associated with odds ratios between 2.38 (95% CI, 0.89 to 6.35) and 4.20 (95% CI, 1.54 to 11.44) for falling below a clinically protective level of 0.1 IU/mL for tetanus and diphtheria antibodies at age 7 years.\n\n\nCONCLUSION\nElevated exposures to PFCs were associated with reduced humoral immune response to routine childhood immunizations in children aged 5 and 7 years.

[Commentary on] Serum vaccine antibody concentrations in children exposed to perfluorinated compounds

Background
The importance of gene-gene and gene-environment interactions on asthma is well documented in literature, but a systematic analysis on the interaction between various genetic and environmental factors is still lacking.

Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach.

Associations of serum perfluoroalkyl acid levels with T-helper cell-specific cytokines in children: By gender and asthma status.

Background Childhood asthma comprises different phenotypes with complex pathophysiology. Different asthma phenotypes evoke various clinical symptoms and vary in their responses to treatments. Methods We applied k-means clustering algorithm of twelve objective laboratory tests among 351 asthmatic children enrolled in the Taiwanese Consortium of Childhood Asthma Study (TCCAS). We constructed gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with different asthma phenotypes. Results Five distinct phenotypes of childhood asthma were identified and can be characterized by either eosinophil-predominant or neutrophil-predominant inflammatory characteristics. In the gene expression profile analysis, significant differences were noted for neutrophil-predominant asthma, compared with samples from all the other asthma phenotypes. The vast majority of the differentially expressed genes in neutrophil-predominant asthma was associated with corticosteroid response. From an independent inhaled corticosteroid (ICS) response cohort, we also found neutrophils could be activated in this severe asthma phenotype and neutrophil-predominant asthma may be associated with corticosteroid nonresponsiveness. Conclusion Phenotype clustering of childhood asthma can be helpful to identify clinically relevant patients and reveal different inflammatory characteristics in asthmatic children. Neutrophil-predominant asthma is the most severe asthma phenotype with poor corticosteroid response. Gene expression profile of different asthma phenotypes not only improve our knowledge of childhood asthma, but also can guide asthma precision medicine.

Childhood asthma clusters reveal neutrophil-predominant phenotype with distinct gene expression

Background
There are limited studies on the role of interaction between exposure to ambient air pollution and glutathione-S-transferase (GST) P1 on the risk of asthma/wheezing among children, which provided suggestive, but inconclusive results.

/pdf/fine-particle-ozone-exposure-and-asthma-wheezing-effect-25k2s2bgin.pdf

Fine particle, ozone exposure, and asthma/wheezing: effect modification by glutathione S-transferase P1 polymorphisms.

Background Previous studies have defined transcriptomic subtypes of adult asthma using samples of induced sputum and bronchial epithelium; however, those procedures are not readily applicable in the clinic, especially for childhood asthma. Objective We aim to dissect the transcriptomic clusters of childhood asthma using highly variably expressed genes of peripheral blood mononuclear cells (PBMC) among patients. Methods Gene expression of PBMC from 133 asthmatic children and 11 healthy controls was measured with Illumina microarrays. We applied the k-means clustering algorithm of 2048 genes to assign asthmatic children into clusters. Genes with differential expression between asthma clusters and healthy controls were used to investigate whether they could identify severe asthma of children and adults. Results We identified 3 asthma clusters with distinct inflammatory profiles in peripheral blood. Cluster 1 had the highest eosinophil count. Cluster 2 showed lower counts of both eosinophils and neutrophils. Cluster 3 had the highest neutrophil count and the poorest treatment control. Compared with other patients, Cluster 3 exhibited a unique gene expression pattern which was associated with changes in the glucocorticoid signalling and activation of the T helper 1/T helper 17 (TH 1/TH 17) immune pathways. In the validation studies, an 84-gene signature could identify severe asthma in children on leucocytes, as well as severe asthma in adults on CD8+ T cells. Conclusions and clinical relevance Gene expression profiling of PBMC is useful for the identification of TH 1/TH 17-mediated asthma with poor treatment control. PBMC and CD8+ T cells could be important targets for the investigation and identification of severe asthma.

Ming-Wei Su

Papers

Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach.

Associations of serum perfluoroalkyl acid levels with T-helper cell-specific cytokines in children: By gender and asthma status.

Childhood asthma clusters reveal neutrophil-predominant phenotype with distinct gene expression

Fine particle, ozone exposure, and asthma/wheezing: effect modification by glutathione S-transferase P1 polymorphisms.

Genetic profiles of transcriptomic clusters of childhood asthma determine specific severe subtype