Several studies have reported an association between residential surrounding particulate matter with an aerodynamic diameter ≤2.5 μm (PM₂.₅) and coronary heart disease (CHD). However, the underlying biological mechanism remains unclear. To fill this research gap, this study enrolled a residentially stable sample of 942 patients with CHD and 1723 controls. PM₂.₅ concentration was obtained from satellite-based annual global PM₂.₅ estimates for the period 1998–2019. MicroRNA microarray and pathway analysis of target genes was performed to elucidate the potential biological mechanism by which PM₂.₅ increases CHD risk. The results showed that individuals exposed to high PM₂.₅ concentrations had higher risks of CHD than those exposed to low PM₂.₅ concentrations (odds ratio = 1.22, 95% confidence interval: 1.00, 1.47 per 10 μg/m³ increase in PM₂.₅). Systolic blood pressure mediated 6.6% of the association between PM₂.₅ and CHD. PM₂.₅ and miR-4726-5p had an interaction effect on CHD development. Bioinformatic analysis demonstrated that miR-4726-5p may affect the occurrence of CHD by regulating the function of RhoA. Therefore, individuals in areas with high PM₂.₅ exposure and relative miR-4726-5p expression have a higher risk of CHD than their counterparts because of the interaction effect of PM₂.₅ and miR-4726-5p on blood pressure.

Perfluorooctane sulfonate (PFOS), a hepatic toxicant and a potential hepatocarcinogen, is commonly used in industrial products. The widespread contamination of PFOS in human maternal and cord blood has raised concerns about its potential risks to the fetus. It is believed that adverse environmental exposure during the critical period of embryo development can have long-lasting consequences in later life. In this report, we used transcriptome sequencing, followed by bioinformatics analysis, to elucidate the potential hepatotoxic and hepatocarcinogenic effects of prenatal PFOS exposure in the fetus. Our results demonstrated that prenatal PFOS exposure could activate the synthesis and metabolism of fatty acids and lipids, leading to liver damage and interference with liver development in the fetus. In addition, a number of cancer-promoting signaling pathways, including Wnt/β-catenin, Rac, and TGF-β, were found to be activated in the fetal liver. More importantly, hepatic transaminase activity, including aspartate aminotransferase and alanine transaminase activity, was induced in the liver of mice offspring after prenatal PFOS exposure. For the first time, our results demonstrate that the hepatotoxic effects of prenatal exposure to PFOS may predispose to a long-term liver disorder in the offspring.

Genome fragment enrichment (GFE) method was applied to identify host-specific bacterial genetic markers that differ among different fecal metagenomes. To enrich for swine-specific DNA fragments, swine fecal DNA composite (n = 34) was challenged against a DNA composite consisting of cow, human, goat, sheep, chicken, duck and goose fecal DNA extracts (n = 83). Bioinformatic analyses of 384 non-redundant swine enriched metagenomic sequences indicated a preponderance of Bacteroidales-like regions predicted to encode metabolism-associated, cellular processes and information storage and processing. After challenged against fecal DNA extracted from different animal sources, four sequences from the clone libraries targeting two Bacteroidales- (genes 1–38 and 3–53), a Clostridia- (gene 2–109) as well as a Bacilli-like sequence (gene 2–95), respectively, showed high specificity to swine feces based on PCR analysis. Host-specificity and host-sensitivity analysis confirmed that oligonucleotide primers and probes capable of annealing to select Bacteroidales-like sequences (1–38 and 3–53) exhibited high specificity (>90%) in quantitative PCR assays with 71 fecal DNAs from non-target animal sources. The two assays also demonstrated broad distributions of corresponding genetic markers (>94% positive) among 72 swine feces. After evaluation with environmental water samples from different areas, swine-targeted assays based on two Bacteroidales-like GFE sequences appear to be suitable quantitative tracing tools for swine fecal pollution.

With the continued increase of global ammonia emission, the damage to human or animal caused by ammonia pollution has attracted wide attention. The noncoding RNAs have been reported to regulate a variety of biological processes under different environmental stimulation via ceRNA (competing endogenous RNA) networks. Autophagy is a hallmark of tissue damage from air pollution. However, the specific role of circular RNAs (circRNAs) in the injury of intestinal tissue caused by autophagy remains unclear. Here, we established 42-days old ammonia-exposed broiler models and observed that autophagy flux in broiler jejunum was activated under ammonia exposure. Meanwhile, a total of eight significantly dysregulated expressed circRNAs were obtained and a circRNAs-miRNAs-genes interaction networks were constructed by bioinformatics analysis. Furthermore, an axis named circRNA-IGLL1/miR-15a/RNF43 was predicted to participate in the excessive autophagy by targeting RNF43. The target relationship was proved by dual-luciferase reporter assay in vitro. Mechanistically, downregulated circRNA-IGLL1 could suppress the expression of RNF43 in ammonia-exposed jejunum and the Wnt/β-catenin pathway was activated. Inhibition of miR-15a reversed autophagy caused by downregulated circRNA-IGLL1. CircRNA-IGLL1 could competitively bind miR-15a to regulate RNF43 expression, thus modulating the occurrence of autophagy. Taken together, our results showed that circRNA-IGLL1/miR-15a/RNF43 axis is involved in ammonia-induced intestinal autophagy in broilers.

PM₂.₅ (particles matter smaller aerodynamic diameter of 2.5 μm) exposure, a major environmental risk factor for the global burden of diseases, is associated with high risks of respiratory diseases. Heme-oxygenase 1 (HMOX1) is one of the major molecular antioxidant defenses to mediate cytoprotective effects against diverse stressors, including PM₂.₅-induced toxicity; however, the regulatory mechanism of HMOX1 expression still needs to be elucidated. In this study, using PM₂.₅ as a typical stressor, we explored whether microRNAs (miRNAs) might modulate HMOX1 expression in lung cells. Systematic bioinformatics analysis showed that seven miRNAs have the potentials to target HMOX1 gene. Among these, hsa-miR-760 was identified as the most responsive miRNA to PM₂.₅ exposure. More importantly, we revealed a “non-conventional” miRNA function in hsa-miR-760 upregulating HMOX1 expression, by targeting the coding region and interacting with YBX1 protein. In addition, we observed that exogenous hsa-miR-760 effectively elevated HMOX1 expression, reduced the reactive oxygen agents (ROS) levels, and rescued the lung cells from PM₂.₅-induced apoptosis. Our results revealed that hsa-miR-760 might play an important role in protecting lung cells against PM₂.₅-induced toxicity, by elevating HMOX1 expression, and offered new clues to elucidate the diverse functions of miRNAs.

In humans and animal models, the kidneys and cardiovascular systems are negatively affected by BPA from the environment. It is considered that BPA have some potential estrogen-like and non-hormone-like properties. In this study, RNA-sequencing and its-related bioinformatics was used as the basic strategy to clarify the characteristic mechanisms of kidney–heart axis remodeling and dysfunction in diabetic male rats under BPA exposure. We found that continuous BPA exposure in diabetic rats aggravated renal impairment, and caused hemodynamic disorders and dysfunctions. There were 655 and 125 differentially expressed genes in the kidney and heart, respectively. For the kidneys, functional annotation and enrichment, and gene set enrichment analyses identified bile acid secretion related to lipid synthesis and transport, and MAPK cascade pathways. For the heart, these bioinformatics analyses clearly pointed to MAPKs pathways. A total of 12 genes and another total of 6 genes were identified from the kidney tissue and heart tissue, respectively. Western blotting showed that exposure to BPA activated MAPK cascades in both organs. In this study, the exacerbated remodeling of diabetic kidney–heart axis under BPA exposure and diabetes might occur through hemodynamics, metabolism disorders, and the immune-inflammatory response, as well as continuous estrogen-like stimulation, with focus on the MAPK cascades.

Ambient fine particulate matter (PM₂.₅) is a worldwide environmental problem and is posing a serious threat to human health. Until now, the molecular toxicological mechanisms and the crucial toxic components of PM₂.₅ remain to be clarified. This study investigated the whole transcriptomic changes in THP-1 derived macrophages treated with different types of PM₂.₅ extracts using RNA sequencing technique. Bioinformatics analyses covering biological functions, signal pathways, protein networks and node genes were performed to explore the candidate pathways and critical genes, and to find the potential molecular mechanisms. Results of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), and protein-protein interaction (PPI) networks revealed that water extracts (WEs) of PM₂.₅ obviously influenced genes and molecular pathways responded to oxidative stress and inflammation. Dichloromethane extracts (DEs) specifically affected genes and signal cascades related to cell cycle progress process. Furthermore, compared with WEs collected in heating season, non-heating season WEs induced much higher expression levels of Ca-associated genes (including phosphodiesterase 4B and cyclooxygenase-2), which may consequently result in more severe inflammatory responses. While, for DEs exposure, the heating season (DH) group showed extensive induction of deferentially expressed genes (DEGs) related to cell cycle pathway, which may be caused by the higher polycyclic aromatic hydrocarbons (PAHs) contents in DH samples than those from non-heating season. In conclusion, the oxidative stress and inflammation response are closely correlated with cellular responses in THP-1 derived macrophages induced by water soluble components of PM₂.₅, and cell cycle dysregulation may play an important role in biological effects induced by organic components. The different transcriptomic changes induced by seasonal PM₂.₅ extracts may partially depend on the contents of PAHs and metal ions, respectively.

It is known that Di (2-ethylhexyl) phthalate (DEHP) may impact mammalian reproduction and that in females one target of the drug’s action is follicle assembly. Here we revisited the phthalate’s action on the ovary and from bioinformatics analyses of the transcriptome performed on newborn mouse ovaries exposed in vitro to DEHP, up-regulation of PDE3A, as one of the most important alterations caused by DEHP on early folliculogenesis, was identified. We obtained some evidence suggesting that the decrease of cAMP level in oocytes and the parallel decrease of PKA expression, consequent on the PDE3A increase, were a major cause of the reduction of follicle assembly in the DEHP-exposed ovaries. In fact, Pde3a RNAi on cultured ovaries reducing cAMP and PKA decrease counteracted the primordial follicle assembly impairment caused by the compound. Moreover, RNAi normalized the level of Kit, Nobox, Figla mRNA and GDF9, BMP15, CX37, γH2AX proteins in oocytes, and KitL transcripts in granulosa cells as well as their proliferation rate altered by DEHP exposure. Taken together, these results identify PDE3A as a new critical target of the deleterious effects of DEHP on early oogenesis in mammals and highlight cAMP-dependent pathways as major regulators of oocyte and granulosa cell activities crucial for follicle assembly. Moreover, we suggest that the level of intracellular cAMP in the oocytes may be an important determinant for their capability to repair DNA lesions caused by DNA damaging compounds including DEHP.

Cigarette smoke extract (CSE), a complex mixture of compounds, contributes to a range of eye diseases; however, the underlying pathophysiological responses to tobacco smoke remain ambiguous. The purpose of the present study was to evaluate the cigarette smoke-induced phenotypic and transcriptomic changes in the corneal epithelium with a view to elucidating the likely underlying mechanism. Accordingly, for the first time, we characterized the genome-wide effects of CSE on the corneal epithelium. The ocular surface of the mice in the experimental groups was exposed to CSE for 1 h per day for a period of one week, while mice in the control group were exposed to preservative-free artificial tears. Corneal fluorescein staining, in vivo confocal microscopy and scanning electron microscopy were performed to examine the corneal ultrastructure. Transcriptome sequencing and bioinformatics analysis were performed followed by RT-qPCR to validate gene expression changes. The results indicate that CSE exposure disrupted the structural integrity of the superficial epithelium, decreased the density of microvilli, and compromised the corneal epithelial barrier intactness. RNA-seq revealed 667 differentially expressed genes, and functional analysis highlighted the enhancement of several biological processes such as antioxidant activity and the response to oxidative stress. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that glutathione metabolism and drug metabolism cytochrome P450 were the most relevant pathways contributing to the effects of CSE on the corneal epithelium. Protein–protein interaction (PPI) network analysis illustrated that GCLC, NQO1, and HMOX1 were the most relevant nodes. In conclusion, the present study indicates that CSE exposure induces changes in the phenotype and genotype of the corneal epithelium. The antioxidant response element is essential for counteracting the effects of cigarette smoke on this tissue layer. These results shed novel insights into how cigarette smoke damages this ocular surface.

Bisphenol A (BPA) is a classical chemical contaminant in food, and the mode of action (MOA) of BPA remains unclear, constraining the progress of risk assessment. This study aims to assess the potential MOAs of BPA regarding reproductive/developmental toxicity, neurological toxicity, and proliferative effects on the mammary gland and the prostate potentially related to carcinogenesis by using the Comparative Toxicogenomics Database (CTD)-based bioinformatics analysis and the quantitative weight of evidence (QWOE) approach on the basis of the principles of Toxicity Testing in the 21st Century. The CTD-based bioinformatics analysis results showed that estrogen receptor 1, estrogen receptor 2, mitogen-activated protein kinase (MAPK) 1, MAPK3, BCL2 apoptosis regulator, caspase 3, BAX, androgen receptor, and AKT serine/threonine kinase 1 could be the common target genes, and the apoptotic process, cell proliferation, testosterone biosynthetic process, and estrogen biosynthetic process might be the shared phenotypes for different target organs. In addition, the KEGG pathways of the BPA-induced action might involve the estrogen signaling pathway and pathways in cancer. After the QWOE evaluation, two potential estrogen receptor-related MOAs of BPA-induced testis dysfunction and learning-memory deficit were proposed. However, the confidence and the human relevance of the two MOAs were moderate, prompting studies to improve the MOA-based risk assessment of BPA.