January 2022 Member Publications

  1. Ferragut Cardoso AP, Banerjee M, Al-Eryani L, Sayed M, Wilkey DW, Merchant ML, Park JW, States JC. Temporal Modulation of Differential Alternative Splicing in HaCaT Human Keratinocyte Cell Line Chronically Exposed to Arsenic for up to 28 Wk. Environ Health Perspect. 2022 Jan;130(1):17011. doi: 10.1289/EHP9676. Epub 2022 Jan 24. PMID: 35072517; PMCID: PMC8785870.
    Impact Statement: The majority of human genes encode multiple protein isoforms. The isoforms are produced from mRNA isoforms edited from the primary transcripts by alternative splicing. This manuscript uses a model cell culture system to show that exposure to an inorganic arsenic compound that naturally contaminates drinking water in many parts of the world markedly disrupts the alternative splicing producing many errant mRNAs, and that the mRNA isoforms produced change over time with chronic exposure. One of the targets of the arsenic appears to be the splicing factor network itself.
  2. Ghosh S, Banerjee M, Haribabu B, Jala VR. Urolithin A attenuates arsenic-induced gut barrier dysfunction. Arch Toxicol. 2022 Feb 5. doi: 10.1007/s00204-022-03232-2. Epub ahead of print. PMID: 35122514.
    Impact Statement: Chronic exposure to inorganic arsenic leads to an increase in both the onset and progression of several human diseases targeting multiple organs (liver, kidney, bladder, skin, intestines, and central nervous system), which is referred to as ‘arsenicosis’. Gut microbial Urolithin A is derived from ellagic acid and ellagitannins (major poly phenolic components in berries and pomegranate) by gut commensal bacteria. The current study reports the beneficial effects of Urolithin A against adverse effects of trivalent arsenic on human gut epithelia, where treatment with Urolithin A protected against arsenic-induced gut epithelial damage. These studies will pave a pathway for preventive and therapeutic applications to mitigate arsenic-elicited adverse health effects, which are currently unavailable.
  3. Lorkiewicz P, Keith R, Lynch J, Jin L, Theis W, Krivokhizhina T, Riggs D, Bhatnagar A, Srivastava S, Conklin DJ. Electronic Cigarette Solvents, JUUL E-Liquids, and Biomarkers of Exposure: In Vivo Evidence for Acrolein and Glycidol in E-Cig-Derived Aerosols. Chem Res Toxicol. 2022 Jan 19. doi: 10.1021/acs.chemrestox.1c00328. Epub ahead of print. PMID: 35044764.
    Impact Statement: In this study, we identify the formation of 2 toxicants, acrolein and glycidol, from the e-cigarette solvent vegetable glycerin. This finding may improve public health via use of a potential biomarker of e-cigarette use such that e-cigarette use can be quantified. Subsequently, the amount of e-cigarette use can be associated with biomarkers of harm including those that reflect cardiorespiratory injury. Overall, this finding may allow us to better predict health risks of chronic use of e-cigarettes.
  4. Cave MC, Pinkston CM, Rai SN, Wahlang B, Pavuk M, Head KZ, Carswell GK, Nelson GM, Klinge CM, Bell DA, Birnbaum LS, Chorley BN. Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey. Environ Health Perspect. 2022 Jan;130(1):17003. doi: 10.1289/EHP9467. Epub 2022 Jan 6. PMID: 34989596; PMCID: PMC8734566.
    Impact Statement: This environmental epidemiology study determined associations between PCB pollutant exposures and liver disease in residents living near a chemical plant.
  5. Fan H, Li Y, Yuan F, Lu L, Liu J, Feng W, Zhang HG, Chen SY. Up-regulation of microRNA-34a mediates ethanol-induced impairment of neural crest cell migration in vitro and in zebrafish embryos through modulating epithelial-mesenchymal transition by targeting Snail1. Toxicol Lett. 2022 Jan 14;358:17-26. doi: 10.1016/j.toxlet.2022.01.004. Epub ahead of print. PMID: 35038560.
    Impact Statement: Fetal alcohol spectrum disorder (FASD) is among the most devastating consequences of the widespread use and abuse of alcohol in pregnant women. The prevalence of FASD in the United States and Western European countries is estimated to be as high as 1–5 per 100 children. The findings from this study elucidate a novel mechanism by which alcohol impairs neural crest cell migration through modulating microRNAs and epithelial-mesenchymal transition and suggests that miR- 34a may represent a novel therapeutic target for the development of approaches to ameliorate or prevent FASD.
  6. Abouleisa RRE, Salama ABM, Ou Q, Tang XL, Solanki M, Guo Y, Nong Y, McNally L, Lorkiewicz PK, Kassem KM, Ahern BM, Choudhary K, Thomas R, Huang Y, Juhardeen HR, Siddique A, Ifthikar Z, Hammad SK, El-Baz AS, Ivey KN, Conklin DJ, Satin J, Hill BG, Srivastava D, Bolli R, Mohamed TMA. Transient Cell Cycle Induction in Cardiomyocytes to Treat Subacute Ischemic Heart Failure. Circulation. 2022 Jan 21. doi: 10.1161/CIRCULATIONAHA.121.057641. Epub ahead of print. PMID: 35061545.
    Impact Statement: In this study, we gained mechanistic insights into the process of forced cardiomyocyte proliferation and advanced the clinical feasibility of this approach by minimizing the oncogenic potential of the cell cycle factors via use of a novel transient and cardiomyocyte-specific viral construct. These findings may lead to clinical interventions to repair the heart after acute heart attack and to delay or prevent progression to heart failure.
  7. Zhao J, Gomes D, Jin L, Mathis SP, Li X, Rouchka EC, Bodduluri H, Conklin DJ, O'Toole TE. Polystyrene bead ingestion promotes adiposity and cardiometabolic disease in mice. Ecotoxicol Environ Saf. 2022 Jan 27;232:113239. doi: 10.1016/j.ecoenv.2022.113239. Epub ahead of print. PMID: 35093814.
    Impact Statement: Modern society produces and uses huge amounts of plastics and a large percentage of these ultimately accumulate in water systems and landfills, where they eventually degrade into particles of smaller size. While emerging evidence has documented that these microplastics are abundant in water supplies and the food chain where their human consumption is inevitable, the health consequences of such consumption are not completely known. In this study, we supplied mice with drinking water containing different sizes and doses of polystyrene beads and found that they developed obesity and showed early signs of insulin resistance/diabetes. Thus, the consumption of microplastics may promote early cardiovascular disease.
  8. Carlisle SM, Trainor PJ, Doll MA, Hein DW. Human Arylamine N-Acetyltransferase 1 (NAT1) Knockout in MDA-MB-231 Breast Cancer Cell Lines Leads to Transcription of NAT2. Front Pharmacol. 2022 Jan 3;12:803254. doi: 10.3389/fphar.2021.803254. PMID: 35046826; PMCID: PMC8762260.
    Impact Statement: RNAseq was utilized to interrogate differential gene expression across three biological replicates of previously constructed and characterized MDA-MB-231 breast cancer cell lines expressing parental, increased, decreased, or knockout levels of N-acetyltransferase 1 (NAT1). 3,889 genes were significantly associated with NAT1 N-acetylation activity; 1,756 were positively associated and 2,133 were negatively associated with enrichment of genes involved in cell adhesion.
  9. Rayens MK, McGeeney T, Wiggins A, Bucher A, Ickes M, Huntington-Moskos L, Clark P, Hahn E. Smoke-free Ordinances and Youth Tobacco Use in Kentucky. Am J Health Promot. 2022 Jan 27:8901171211066913. doi: 10.1177/08901171211066913. Epub ahead of print. PMID: 35081759.
    Impact Statement: Nearly half of U.S. youth are not protected by smoke-free laws. This study underscores the association between comprehensive laws and decreased likelihood for both cigarette and smokeless tobacco use among high school students in a state with high use rates overall.
  10. Kotla NG, Singh R, Baby BV, Rasala S, Rasool J, Hynes SO, Martin D, Egan LJ, Vemula PK, Jala VR, Rochev Y, Pandit A. Inflammation-specific targeted carriers for local drug delivery to inflammatory bowel disease. Biomaterials. 2022 Feb;281:121364. doi: 10.1016/j.biomaterials.2022.121364. Epub 2022 Jan 5. PMID: 35066288.
    Impact Statement: Delivering drugs directly to the inflamed intestinal sites to treat inflammatory bowel disease (IBD), particularly Crohn's and ulcerative colitis, is highly challenging. In collaboration with Drs. Kotla, Yury Rochev and Abhay Pandit from CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Ireland, we report the development of a strong anionic charged inflammation targeted nanocarriers (IT-NCs) loaded with an immunosuppressant model drug. The results suggest that IT-NCs have promising therapeutic potential as delivery carriers' in colitis management.
  11. Speer RM, Meaza I, Toyoda JH, Lu Y, Xu Q, Walter RB, Kong M, Lu H, Kouokam JC, Wise JP Sr. Particulate hexavalent chromium alters microRNAs in human lung cells that target key carcinogenic pathways. Toxicol Appl Pharmacol. 2022 Jan 28:115890. doi: 10.1016/j.taap.2022.115890. Epub ahead of print. PMID: 35101437.
    Impact Statement: microRNAs play a role in virtually all biological processes, and thus, it is essential to understand their role in human disease, in particular cancer. Our recent publication is at the forefront of understanding how hexavalent chromium-altered microRNAs contribute to environmental carcinogenesis and advances the fields of environmental toxicology, human health, and cancer research. This work provides cancer researchers valuable data to better understand pathways to target cancer treatments and risk assessors information to update safety standards to better protect public health.
  12. Faulkner CS, White CM, Manatsathit W, Lamb B, Vatsalya V, McClain CJ, Jophlin LL. Blood phosphatidylethanol (PEth) positivity associates with unfavorable waitlist-related outcomes for patients medically appropriate for liver transplant. Alcohol Clin Exp Res. 2022 Jan 31. doi: 10.1111/acer.14786. Epub ahead of print. PMID: 35102553.
    Impact Statement: Excessive alcohol use is a leading etiology of liver disease and indication for liver transplantation. This study explores the association of phosphatidylethanol (PEth) results with liver transplant waitlist-focused patient outcomes. This study reporting a comprehensive account of PEth utilization at a liver transplant center demonstrates that liver transplant waitlist-related outcomes associate with PEth test results.
  13. Oh YJ, Dent MW, Freels AR, Zhou Q, Lebrilla CB, Merchant ML, Matoba N. Antitumor activity of a lectibody targeting cancer-associated high-mannose glycans. Mol Ther. 2022 Jan 22:S1525-0016(22)00030-2. doi: 10.1016/j.ymthe.2022.01.030. Epub ahead of print. PMID: 35077861.
    Impact Statement: Aberrant protein glycosylation is a hallmark of cancer, but few drugs targeting cancer glycobiomarkers are currently available. CIEHS members assisting the lab of Nobuyuki Matoba, Ph.D. (UL Department of Pharmacology & Toxicology and Brown Cancer Center) showed that a fusion protein termed a ‘lectibody’ comprised of the high-mannose glycan-binding lectin Avaren and human immunoglobulin G1 (IgG1) Fc (AvFc) selectively recognizes a range of cell lines derived from lung, breast, colon, and blood cancers at nanomolar concentrations. Proteomics studies identified specific AvFc interaction with epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R). AvFc blocked EGFR and IGF1R signaling in cell culture models of cancer and induced potent Fc-mediated cytotoxic effects and significantly restricted A549 and H460 tumor growth in severe combined immunodeficiency (SCID) mice. These findings provided evidence that increased abundance of high-mannose glycans in the glycocalyx of cancer cells can be a druggable target, and AvFc may provide a new tool to probe and target this tumor-associated glycobiomarker.
  14. Sriwastva MK, Deng ZB, Wang B, Teng Y, Kumar A, Sundaram K, Mu J, Lei C, Dryden GW, Xu F, Zhang L, Yan J, Zhang X, Park JW, Merchant ML, Egilmez NK, Zhang HG. Exosome-like nanoparticles from Mulberry bark prevent DSS-induced colitis via the AhR/COPS8 pathway. EMBO Rep. 2022 Jan 7:e53365. doi: 10.15252/embr.202153365. Epub ahead of print. PMID: 34994476.
    Impact Statement: Proof of concept research demonstrated that exosome-like nanoparticles (MBELNs) derived from edible mulberry bark conferred protection against colitis in a mouse model through promoting heat shock protein family A (Hsp70) member 8 (HSPA8)-mediated activation of the AhR signaling pathway and induction of COP9 Constitutive Photomorphogenic Homolog Subunit 8 (COPS8). The results suggest that MBELNs represent an undescribed mode of inter-kingdom communication in the mammalian intestine and edible plant-derived ELNs may hold the potential as new agents for the prevention and treatment of gut-related inflammatory disease.
  15. Das S, Rai SN. Statistical methods for analysis of single-cell RNA-sequencing data. MethodsX.2021 Nov 17;8:101580. doi: 10.1016/j.mex.2021.101580. PMID: 35004214; PMCID: PMC8720898.
    Impact Statement: Analyzing the Single-cell RNA-sequencing (scRNA-seq) data in presence of biological confounding factors including dropout events is a challenging task. In this article, we present a novel statistical approach for various analyses of the scRNA-seq Unique Molecular Identifier (UMI) counts data, including model-based fitting of observed UMI data, cell type detection, estimation of cell capture rates, estimation of gene specific model parameters, estimation of the sample mean, and sample variance of the genes.
  16. Bhattacharyya A, Chakraborty T, Rai SN. Stochastic forecasting of COVID-19 daily new cases across countries with a novel hybrid time series model. Nonlinear Dyn. 2022 Jan 13:1-16. doi: 10.1007/s11071-021-07099-3. Epub ahead of print. PMID: 35039713; PMCID: PMC8754528.
    Impact Statement: In this paper, we develop a hybrid forecasting model that can generate real-time out-of-sample forecasts of COVID-19 outbreaks for five profoundly affected countries, namely the USA, Brazil, India, the UK, and Canada. A novel hybrid approach based on the Theta method and autoregressive neural network (ARNN) model, named Theta-ARNN (TARNN) model. Daily new cases of COVID-19 are nonlinear, non-stationary, and volatile; thus, a single specific model cannot be ideal for future prediction of the pandemic. The proposed method outperforms traditional univariate and hybrid forecasting models for the test datasets on an average.
  17. Riggs DW, Malovichko MV, Gao H, McGraw KE, Taylor BS, Krivokhizhina T, Rai SN, Keith RJ, Bhatnagar A, Srivastava S. Environmental exposure to volatile organic compounds is associated with endothelial injury. Toxicol Appl Pharmacol. 2022 Jan 16;437:115877. doi: 10.1016/j.taap.2022.115877. Epub ahead of print. PMID: 35045333.
    Impact Statement: In this study, we hypothesized that ambient exposure to VOCs amplifies cardiovascular disease (CVD) risk by depleting circulating angiogenic cells (CACs). We found that Low-level ambient exposure to VOCs is associated with CAC depletion, which could compromise endothelial repair and angiogenesis, and exacerbate CVD risk. 
  18. Jin J, Wahlang B, Thapa M, Head KZ, Hardesty JE, Srivastava S, Merchant ML, Rai SN, Prough RA, Cave MC. Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver. Acta Pharm Sin B. 2021 Dec;11(12):3806-3819. doi: 10.1016/j.apsb.2021.10.014. Epub 2021 Oct 21. PMID: 35024308; PMCID: PMC8727924.
    Impact Statement: PCB pollutant exposures activate the aryl hydrocarbon receptor and are associated with liver disease. This study used genetic mouse models to determine the role of this receptor and PCBs acting through this receptor in liver disease.
  19. Ritzenthaler JD, Torres-Gonzalez E, Zheng Y, Zelko IN, Van Berkel V, Nunley DR, Kidane B, Halayko AJ, Summer R, Watson WH, Roman J. The pro-fibrotic and senescence phenotype of old lung fibroblasts is reversed or ameliorated by genetic and pharmacological manipulation of Slc7a11 expression. Am J Physiol Lung Cell Mol Physiol. 2022 Jan 5. doi: 10.1152/ajplung.00593.2020. Epub ahead of print. PMID: 34984918.
    Impact Statement: Fibroblasts from the lungs of old mice have low expression of the transporter for the amino acid cystine and high expression of markers of senescence and genes associated with fibrosis. Restoration of the cystine transporter made the old cells look more like young cells. These findings point the way toward new therapies designed to counteract the disrepair responses typically seen in the aging lung.
  20. Xiong L, Zhou B, Young JL, Xu J, Wintergerst K, Cai L. Effects of whole-life exposure to low-dose cadmium with post-weaning high-fat diet on offspring testes in a male mouse model. Chem Biol Interact. 2022 Feb 1;353:109797. doi: 10.1016/j.cbi.2022.109797. Epub 2022 Jan 5. PMID: 34998821.
    Impact Statement: Several studies have reported testicular impairments caused by cadmium (Cd) or obesity alone, therefore, this study examined the combined effect of Cd and obesity on the testes and its underlying mechanism remains unclear. demonstrated that exposure to Cd or HFD alone significantly disrupted testicular structure and increased germ cell apoptosis at both 10 and 24 weeks. However, co-exposure to Cd and HFD did not induce the toxic effects that were induced by either alone, which was associated with the activation of the JAK/STAT pathway. These unexpected results need to be further investigated in the future study.
  21. Young JL, Cave MC, Xu Q, Kong M, Xu J, Lin Q, Tan Y, Cai L. Whole life exposure to low dose cadmium alters diet-induced NAFLD. Toxicol Appl Pharmacol. 2022 Feb 1;436:115855. doi: 10.1016/j.taap.2021.115855. Epub 2022 Jan 3. PMID: 34990729; PMCID: PMC8796138.
    Impact Statement: This study is one of the first to investigate the impact of whole life cadmium exposure (in utero throughout adulthood) on the development high fat diet-induced Nonalcoholic fatty liver disease NAFLD, taking into consideration that environmental exposures can be life-long, spanning multiple windows of susceptibility. Results confirm the multi-hit nature of NAFLD and highlight the urgent need to better understand the interaction of diet and environmental exposures, such as heavy metals, in driving disease severity and progression.
  22. Mo Y, Zhang Y, Zhang Y, Yuan J, Mo L, Zhang Q. Nickel nanoparticle-induced cell transformation: involvement of DNA damage and DNA repair defect through HIF-1α/miR-210/Rad52 pathway. J Nanobiotechnology. 2021 Nov 17;19(1):370. doi: 10.1186/s12951-021-01117-7. PMID: 34789290; PMCID: PMC8600818.
    Impact Statement: Nickel nanoparticles (Nano-Ni) are increasingly used in industry and biomedicine with the development of nanotechnology. However, the genotoxic and carcinogenic effects of Nano-Ni and the underlying mechanisms are still unclear. This study unraveled the mechanisms underlying Nano-Ni-induced cell malignant transformation. The combined effects of Nano-Ni-induced DNA damage and DNA repair defects through HIF-1α/miR-210/Rad52 pathway probably contribute to Nano-Ni-induced genomic instability and ultimately cell transformation. Our findings will provide information to further elucidate the molecular mechanisms of Nano-Ni-induced genotoxicity and carcinogenicity.
  23. Kumar A, Sundaram K, Mu J, Dryden GW, Sriwastva MK, Lei C, Zhang L, Qiu X, Xu F, Yan J, Zhang X, Park JW, Merchant ML, Bohler HCL, Wang B, Zhang S, Qin C, Xu Z, Han X, McClain CJ, Teng Y, Zhang HG. High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance. Nat Commun. 2021 Jan 11;12(1):213. doi: 10.1038/s41467-020-20500-w. PMID: 33431899; PMCID: PMC7801461.