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Global N6-methyladenosine profiling of cobalt-exposed cortex and human neuroblastoma H4 cells presents epitranscriptomics alterations in neurodegenerative disease-associated genes
2020
Tang, Jianping | Zheng, Chunyan | Zheng, Fuli | Li, Yuqing | Wang, Yuanliang | Aschner, Michael | Guo, Zhenkun | Yu, Guangxia | Wu, Siying | Li, Huangyuan
Excessive exposure to cobalt (Co) is known to make adverse impact on the nervous system, but its detailed mechanisms of neurotoxicity have yet to be determined. In this study, C57BL/6 mice (0, 4, 8, 16 mg/kg CoCl₂, 30 days) and human neuroblastoma H4 cells (0, 100, 400, 600 μM CoCl₂) were used as in vivo and in vitro models. Our results revealed that CoCl₂ intraperitoneal injection caused significant impairments in learning and memory, as well as pathological damage in the nervous system. We further certificated the alteration of m⁶A methylation induced by CoCl₂ exposure. Our findings demonstrate for the first time, significant differences in the degree of m⁶A modification, the biological function of m⁶A-modified transcripts between cortex and H4 cell samples. Specifically, MeRIP-seq and RNA-seq elucidate that CoCl₂ exposure results in differentially m⁶A-modified and expressed genes, which were enriched in pathways involving synaptic transmission, and central nervous system (CNS) development. Mechanistic analyses revealed that CoCl₂ remarkably changed m⁶A modification level by affecting the expression of m⁶A methyltransferase and demethylase, and decreasing the activity of demethylase. We observed variation of m⁶A modification in neurodegenerative disease-associated genes upon CoCl₂ exposure and identified regulatory strategy between m⁶A and potential targets mRNA. Our novel findings provide novel insight into the functional roles of m⁶A modification in neurodegenerative damage caused by environmental neurotoxicants and identify Co-mediated specific RNA regulatory strategy for broadening the epigenetic regulatory mechanism of RNA induced by heavy metals.
Show more [+] Less [-]N6-methyladenosine mediates arsenite-induced human keratinocyte transformation by suppressing p53 activation
2020
Zhao, Tianhe | Sun, Donglei | Zhao, Manyu | Lai, Yanhao | Liu, Yuan | Zhang, Zunzhen
N⁶-methyladenosine (m⁶A), the most abundant and reversible RNA modification, plays critical a role in tumorigenesis. However, whether m⁶A can regulate p53, a leading antitumor protein remains poorly understood. In this study, we explored the regulatory role of m⁶A on p53 activation using an arsenite-transformed keratinocyte model, the HaCaT-T cell line. We created the cell line by exposing human keratinocyte HaCaT cells to 1 μM arsenite for 5 months. We found that the cells exhibited an increased m⁶A level along with an aberrant expression of the methyltransferases, demethylase, and readers of m⁶A. Moreover, the cells exhibited decreased p53 activity and reduced p53 phosphorylation, acetylation, and transactivation with a high nucleus export rate of p53. Knockdown of the m⁶A methyltransferase, METTL3 significantly decreased m⁶A level, restoring p53 activation and inhibiting cellular transformation phenotypes in the arsenite-transformed cells. Further, using both a bioinformatics analysis and experimental approaches, we demonstrated that m⁶A downregulated the expression of the positive p53 regulator, PRDM2, through the YTHDF2-promoted decay of PRDM2 mRNAs. We showed that m⁶A upregulated the expression of the negative p53 regulator, YY1 and MDM2 through YTHDF1-stimulated translation of YY1 and MDM2 mRNA. Taken together, our study revealed the novel role of m⁶A in mediating arsenite-induced human keratinocyte transformation by suppressing p53 activation. This study further sheds light on the mechanisms of arsenic carcinogenesis via RNA epigenetics.
Show more [+] Less [-]Associations of annual ambient PM2.5 components with DNAm PhenoAge acceleration in elderly men: The Normative Aging Study
2020
Wang, Cuicui | Koutrakis, Petros | Gao, Xu | Baccarelli, Andrea | Schwartz, Joel
Current studies indicate that long-term exposure to ambient fine particulate matter (PM₂.₅) is related with global mortality, yet no studies have explored relationships of PM₂.₅ and its species with DNAm PhenoAge acceleration (DNAmPhenoAccel), a new epigenetic biomarker of phenotypic age. We identified which PM₂.₅ species had association with DNAmPhenoAccel in a one-year exposure window in a longitudinal cohort. We collected whole blood samples from 683 elderly men in the Normative Aging Study between 1999 and 2013 (n = 1254 visits). DNAm PhenoAge was calculated using 513 CpGs retrieved from the Illumina Infinium HumanMethylation450 BeadChip. Daily concentrations of PM₂.₅ species were measured at a fixed air-quality monitoring site and one-year moving averages were computed. Linear mixed-effect (LME) regression and Bayesian kernel machine (BKM) regression were used to estimate the associations. The covariates included chronological age, body mass index (BMI), cigarette pack years, smoking status, estimated cell types, batch effects etc. Benjamini-Hochberg false discovery rate at a 5% false positive threshold was used to adjust for multiple comparison. During the study period, the mean DNAm PhenoAge and chronological age in our subjects were 68 and 73 years old, respectively. Using LME model, only lead and calcium were significantly associated with DNAmPhenoAccel. For example, an interquartile range (IQR, 0.0011 μg/m³) increase in lead was associated with a 1.29-year [95% confidence interval (CI): 0.47, 2.11] increase in DNAmPhenoAccel. Using BKM model, we selected PM₂.₅, lead, and silicon to be predictors for DNAmPhenoAccel. A subsequent LME model showed that only lead had significant effect on DNAmPhenoAccel: 1.45-year (95% CI: 0.46, 2.46) increase in DNAmPhenoAccel following an IQR increase in one-year lead. This is the first study that investigates long-term effects of PM₂.₅ components on DNAmPhenoAccel. The results demonstrate that lead and calcium contained in PM₂.₅ was robustly associated with DNAmPhenoAccel.
Show more [+] Less [-]microRNAs expression in relation to particulate matter exposure: A systematic review
2020
MicroRNAs (miRNAs) are a class of small, non-coding RNAs with a post-transcriptional regulatory function on gene expression and cell processes, including proliferation, apoptosis and differentiation. In recent decades, miRNAs have attracted increasing interest to explore the role of epigenetics in response to air pollution. Air pollution, which always contains kinds of particulate matters, are able to reach respiratory tract and blood circulation and then causing epigenetics changes. In addition, extensive studies have illustrated that miRNAs serve as a bridge between particulate matter exposure and health-related effects, like inflammatory cytokines, blood pressure, vascular condition and lung function. The purpose of this review is to summarize the present knowledge about the expression of miRNAs in response to particulate matter exposure. Epidemiological and experimental studies were reviewed in two parts according to the size and source of particles. In this review, we also discussed various functions of the altered miRNAs and predicted potential biological mechanism participated in particulate matter-induced health effects. More rigorous studies are worth conducting to understand contribution of particulate matter on miRNAs alteration and the etiology between environmental exposure and disease development.
Show more [+] Less [-]Genome-wide DNA methylation analysis reveals significant impact of long-term ambient air pollution exposure on biological functions related to mitochondria and immune response
2020
Wang, Maiqiu | Zhao, Junsheng | Wang, Yan | Mao, Ying | Chao, Shin-Yi | Huang, Peng | Liu, Qiang | Ma, Yunlong | Yao, Yinghao | Yang, Zhongli | Yuan, Wenji | Cui, Wenyan | Payne, Thomas J. | Li, Ming D.
Exposure to long-term ambient air pollution is believed to have adverse effects on human health. However, the mechanisms underlying these impacts are poorly understood. DNA methylation, a crucial epigenetic modification, is susceptible to environmental factors and likely involved in these processes. We conducted a whole-genome bisulfite sequencing study on 120 participants from a highly polluted region (HPR) and a less polluted region (LPR) in China, where the HPR had much higher concentrations of five air pollutants (PM₂.₅, PM₁₀, SO₂, NO₂, and CO) (fold difference 1.6 to 6.6 times; P value 1.80E-07 to 3.19E-23). Genome-wide methylation analysis revealed 371 DMRs in subjects from the two areas and these DMRs were located primarily in gene regulatory elements such as promoters and enhancers. Gene enrichment analysis showed that DMR-related genes were significantly enriched in diseases related to pulmonary disorders and cancers and in biological processes related to mitochondrial assembly and cytokine production. Further, HPR participants showed a higher mtDNA copy number. Of those identified DMRs, 15 were significantly correlated with mtDNA copy number. Finally, cytokine assay indicated that an increased plasma interleukin-5 level was associated with greater air pollution. Taken together, our findings suggest that exposure to long-term ambient air pollution can lead to alterations in DNA methylation whose functions relate to mitochondria and immune responses.
Show more [+] Less [-]Environmental temperature and human epigenetic modifications: A systematic review
2020
Xu, Rongbin | Li, Shuai | Guo, Shuaijun | Zhao, Qi | Abramson, Michael J. | Li, Shanshan | Guo, Yuming
The knowledge about the effects of environmental temperature on human epigenome is a potential key to understand the health impacts of temperature and to guide acclimation under climate change. We performed a systematic review on the epidemiological studies that have evaluated the association between environmental temperature and human epigenetic modifications. We identified seven original articles on this topic published between 2009 and 2019, including six cohort studies and one cross-sectional study. They focused on DNA methylation in elderly people (blood sample) or infants (placenta sample), with sample size ranging from 306 to 1798. These studies were conducted in relatively low temperature setting (median/mean temperature: 0.8–13 °C), and linear models were used to evaluate temperature-DNA methylation association over short period (≤28 days). It has been reported that short-term ambient temperature could affect global human DNA methylation. A total of 15 candidate genes (ICAM-1, CRAT, F3, TLR-2, iNOS, ZKSCAN4, ZNF227, ZNF595, ZNF597, ZNF668, CACNA1H, AIRE, MYEOV2, NKX1-2 and CCDC15) with methylation status associated with ambient temperature have been identified. DNA methylation on ZKSCAN4, ICAM-1 partly mediated the effect of short-term cold temperature on high blood pressure and ICAM-1 protein (related to cardiovascular events), respectively. In summary, epidemiological evidence about the impacts of environment temperature on human epigenetics remains scarce and limited to short-term linear effect of cold temperature on DNA methylation in elderly people and infants. More studies are needed to broaden our understanding of temperature related epigenetic changes, especially under a changing climate.
Show more [+] Less [-]Assessing potential mechanisms of arsenic-induced skin lesions and cancers: Human and in vitro evidence
2020
Zeng, Qibing | Zhang, Aihua
Environmental exposure to arsenic is a major public health challenge worldwide. In detailing the hallmark signs of chronic arsenic exposure, previous studies have shown that epigenetic and immune dysfunction are associated with arsenic-induced skin lesions; however, knowledge regarding interactions between the mechanisms listed above is limited. In this study, a total of 106 skin samples were collected over the past 20 years. Based on the presence or absence of high arsenic exposure, the participants were divided into arsenic exposure (72) and reference (34) groups. Additionally, the arsenic exposure group was further divided into the non-cancer group (31, including skin hyperpigmentation and hyperkeratosis) and the skin cancer group (41, including Bowen’s disease, basal cell carcinoma and squamous cell carcinoma) according to a skin histopathological examination. First, the associations among miR-155, NF-AT1 with immunological dysfunction and arsenic-induced skin lesions and carcinogenesis were confirmed using these skin samples. In the arsenic-exposed group, miR-155–5p, keratin 1(Krt1), keratin 10 (Krt10), and keratin 6c (Krt6c) were significantly increased in the skin (p < 0.05), while NF-AT1, interleukin-2 (IL-2), and interferon-γ (IFN-γ) were significantly decreased (p < 0.05). Clear correlations were observed among these factors (p < 0.05). In immortalized human keratinocytes, silencing and overexpression of NF-AT1 could alter the expression and secretion of immunological dysfunction indicators (IL-2 and IFN-γ) that are induced by arsenic exposure (p < 0.05); however, miR-155–5p levels did not change significantly (p > 0.05). The miR-155–5p mimic and inhibitor could regulate the NF-AT1-mediated immunological dysfunction caused by arsenic (p < 0.05). Our study provides some limited evidence that miR-155–5p regulates the NF-AT1-mediated immunological dysfunction that is involved in the pathogenesis and carcinogenesis of arsenic. The second major finding was that Krt1 and Krt10 are markers of hyperkeratosis caused by arsenic, and Krt6c is a potential biomarker that can reflect arsenic carcinogenesis.
Show more [+] Less [-]The intergenerational toxic effects on offspring of medaka fish Oryzias melastigma from parental benzo[a]pyrene exposure via interference of the circadian rhythm
2020
Yin, Xiaohan | Liu, Yong | Zeb, Rabia | Chen, Fangyi | Chan, Wai-wan | Wang, Ke-Jian
Benzo[a]pyrene (BaP), a widely existed polycyclic aromatic hydrocarbon pollutant in aquatic environment, has toxic effects on marine animals and their generations, but the intergenerational immunotoxic mechanism underlying has not been clearly understood. In the study, the offspring of marine medaka (oryzias melastigma) which were exposed to 0.5 μg L⁻¹ BaP suffered from circadian rhythm oscillation disorders and severe DNA damage. Many clock-associated genes like per1 were significantly modulated in offspring, both per1 and p53 were significantly inhibited that altered the progression of cell cycle and inhibited DNA repair, which possibly resulted in the increased mortality of offspring. The hypermethylation of the per1 promotor and abnormal levels of N⁶-methyladenosine (m⁶A) suggested that the underlying mechanism was probably related to the epigenetic modification. Moreover, the offspring from paternal BaP exposure had more severe DNA damage and a higher degree of hypermethylation than those from maternal exposure. F1 larvae from BaP-exposed parents were more sensitive to BaP exposure, showing that the expression of immune and metabolism-related genes were significantly up-regulated. Taken together, the parental toxicity induced by BaP could be passed to F1 generation and the mechanism underlying was probably associated with a characteristic circadian rhythm disorder.
Show more [+] Less [-]Profiling epigenetic changes in human cell line induced by atrazine exposure
2020
Sánchez, Oscar F. | Lin, Li | Bryan, Chris J. | Xie, Junkai | Freeman, Jennifer L. | Yuan, Chongli
How environmental chemicals can affect and exert their toxic effect at a molecular level has gained significant interest in recent years, not only for understanding their immediate health implications over exposed individuals, but also for their subsequent progeny. Atrazine (ATZ) is a commonly used herbicide in the U.S. and a long-suspected endocrine disrupting chemical. The molecular mechanism conferring long-term adverse health outcomes, however, remain elusive. Here, we explored changes in epigenetic marks that arise after exposure to ATZ at selected doses using image-based analysis coupled with data clustering. Significant decreases in methylated CpG (ᵐᵉCpG) and histone 3 lysine 9 tri-methylated (H3K9me3) were observed in the selected human cell line with a clear spatial preference. Treating cells with ATZ leads to the loss of a subpopulation of cells with high ᵐᵉCpG levels as identified in our clustering and histogram analysis. A similar trend was observed in H3K9me3 potentially attributing to the cross-talking between ᵐᵉCpG and H3K9me3. Changes in ᵐᵉCpG are likely to be associated with alterations in epigenetic enzyme expression levels regulating ᵐᵉCpG and persist after the removal of ATZ source which collectively provide a plausible mechanism for long-term ATZ-induced toxicity.
Show more [+] Less [-]The role of Hipk2-p53 pathways in arsenic-induced autistic behaviors: A translational study from rats to humans
2020
Zhou, Hao | Lin, Yan | Zhao, Weiqing | Teng, Yanbo | Cui, Yuxia | Wang, Tianqi | Li, Chunpei | Jiang, Yong-hui | Zhang, Junfeng (Jim) | Wang, Yi
Previous studies have associated the risk of autism spectrum disorder (ASD) with increased exposures to metals and metalloids such as arsenic. In this study, we used an animal-to-human translational strategy to identify key molecular changes that potentially mediated the effects of arsenic exposures on ASD development. In a previously established rat model, we have induced autistic behaviors in rat pups with gestational arsenic exposures (10 and 45 μg/L As₂O₃ in drinking water). Neuronal apoptosis and the associated epigenetic dysregulations in frontal cortex were assayed to screen potential mediating pathways, which were subsequently validated with qPCR, western blotting, and immunohistochemistry analyses. Furthermore, the identified pathway, along with serum levels of 26 elements including arsenic, were characterized in a case-control study with 21 ASD children and 21 age-matched healthy controls. In animals, we found that arsenic exposures caused difficulties of social interaction and increased stereotypic behaviors in a dose-dependent manner, accompanied by increased neuronal apoptosis and upregulation of Hipk2-p53 pathway in the frontal cortex. In humans, we found that serum levels of Hipk2 and p53 were 24.7 (95%CI: 8.5 to 43.4) % and 23.7 (95%CI: 10.5 to 38.5) % higher in ASD children than in healthy controls. ASD children had significantly higher serum levels of 15 elements, among which arsenic, silicon, strontium, and vanadium were positively associated with both Hipk2 and p53. Results from both the rat arsenic exposure and human case-control studies suggest a likely role of Hipk2-p53 pathway in ASD development induced by exposures to environmental pollutants such as arsenic.
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