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16 Publications visible to you, out of a total of 16
Integrated analysis of the blood metallome and DNA methylation, gene expression, and protein levels of immune-associated genes in residents from mining region

Abstract (Expand)

Environmental exposure to toxic and essential metals can disrupt host immune function through mechanisms involving epigenetic, transcriptional, and post-transcriptional regulation. Although numerous … studies have investigated these regulatory layers separately, integrative analyses across molecular levels in relation to metallome is missing. In this study, we performed a targeted multi-omics analysis of six immune-associated genes (NFKB1, CDKN2A, IGF2, H19, ESR1, and APOA5) and corresponding proteins in healthy residents from a long-term mining region (MRR, n = 46) and a non-mining region (NMR, n = 48). Transcriptome data were generated by mRNA sequencing, while DNA methylation data were obtained using targeted bisulfite sequencing by analyzing previously identified differentially methylated positions. Plasma protein levels were measured by enzyme-linked immunosorbent assay, and plasma metal concentrations were quantified using inductively coupled plasma mass spectrometry. We observed significantly higher plasma levels of NFKB1 and CDKN2A proteins, along with lower ESR1 transcript levels, in residents of the mining region compared to the non-mining region. NFKB1 protein levels were associated with both promoter methylation and residence in mining region, suggesting a regulatory cascade from DNA methylation to protein expression. IGF2 protein levels were higher in males and showed positive associations with age and the cumulative Z-score of essential metal mixture burden. Our results show that long-term residence in mining regions is associated with changes in NFKB1 at both the DNA methylation and protein levels, which may serve as a sensitive biomarker of metal exposure.

Authors: Yeva Bareghamyan, Arpine Minasyan, Suren Davitavyan, Anna Petrackova, Jakub Savara, Romana Nesnadna, Eva Kriegova, Jonathan Schug, Arsen Arakelyan, Ani Stepanyan

Date Published: 4th Jan 2026

Publication Type: Journal

Persistence of Western Diet-Associated Pathway Activity Profiles in Ventricular Tissues

Abstract (Expand)

The consumption of a Western diet (WD), characterized by high levels of fats and sugars, is strongly associated with adverse cardiovascular outcomes. In this case-control study, we evaluated long-term … alterations in signaling pathway activities in the left (LV) and right (RV) ventricular tissues of C57Bl/6J mice that were exposed to WD starting at 300 days of age for 125 days before switching to a normal diet (ND). LV and RV tissues were collected at 530 days and subjected to RNA sequencing. Pathway activity for 40 signaling pathways (comprising 709 pathway branches/sinks) was calculated using the topology-aware Pathway Signal Flow (PSF) algorithm, which assesses signal propagation along a pathway based on gene expression levels of its components and their interactions. We observed significant perturbations in 14 pathway branches specifically in LV tissue of male mice, 105 days after the ND switch. These alterations included the downregulation of cardioprotective VEGF signaling and the upregulation of pro-fibrotic TGF-beta signaling, suggesting lasting cardiovascular risks. Furthermore, strong signaling was detected in the cGMP-PKG and FOXO pathways linked to cardiac failure. Finally, pro- and anti-apoptotic signals were simultaneously upregulated, accompanied by the downregulation of cell cycle inhibitors. Notably, no significant gene expression changes were detected in the left ventricular tissue of females, and no significant differences were observed in right ventricular tissue in either sex. These findings suggest that the effects of a Western diet may persist even after transitioning to a healthier diet. Further studies are needed to elucidate the diet-associated risks and develop strategies to mitigate these long-term effects.

Authors: Tamara Sirunyan, Gisane Lazaryan, Siras Hakobyan, Suren Davitavyan, Ani Stepanyan, Agnieszka Brojakowska, Mary Khlgatian, Malik Bisserier, Shihong Zhang, David Goukassian, Arsen Arakelyan

Date Published: 2nd Jan 2026

Publication Type: Journal

Long-Term Impact of Western Diet on Right Ventricular Transcriptome: Uncovering Sex-Specific Patterns in C57BL/6J Mice

Abstract (Expand)

The Western diet (WD) has been linked to various structural and functional alterations in the left ventricle (LV), but the molecular response of the right ventricle (RV) remains largely unknown. Given … the RV’s distinct anatomical and functional characteristics, it is crucial to understand how long-term WD exposure affects RV gene expression, especially in a sex-specific context. Our objective was to perform gene expression profiling of the RV late responses to WD in wild-type mice. Male and female C57BL/6J mice were fed a WD for 125 days from 300 to 425 days of age, and RV tissues were collected at 530 and 640/750 (female/male) days. mRNA sequencing was performed on RV tissues to identify differentially expressed genes (DEGs) between WD-fed and normal diet (ND)-fed groups. Data processing and analysis were conducted using the STAR aligner and DESeq2. WD-induced RV transcriptomic changes were characterized by differential expression of genes associated with cardiac remodeling and transcriptional regulation in both sexes. In females, additional genes showing altered expression were associated with immune response, whereas in males, changes were more limited, primarily involving genes related to circadian rhythm and cardiac remodeling. Echocardiography revealed modest, sex-specific differences: WD-fed females showed a decrease in right-ventricular internal diameter in diastole and a trend toward increased pulmonary trunk diameter, whereas males showed no notable changes. These exploratory results suggest that WD is associated with modest transcriptomic changes in the RV in both sexes, with only minor structural differences observed in females, indicating subtle sex-specific effects after a switch to normal chow.

Authors: Ani Stepanyan, Siras Hakobyan, Agnieszka Brojakowska, Malik Bisserier, Roksana Zakharyan, Suren Davitavyan, Tamara Sirunyan, Gisane Khachatryan, Mary K. Khlgatian, Shihong Zhang, Ania Baghoomian, Susmita Sahoo, Lahouaria Hadri, Venkata Naga Srikanth Garikipati, Arsen Arakelyan, David A. Goukassian

Date Published: 26th Dec 2025

Publication Type: Journal

Long-term Pathway Activation in Cardiac Ventricular Tissues after Gamma and simGCRsim Irradiation.

Abstract (Expand)

Space radiation represents a significant health risk for deep-space exploration, yet its long-term effects on cardiovascular function remain poorly understood. While our previous studies have highlighted … persistent transcriptional changes in left ventricular (LV) and right ventricular (RV) tissues after a single whole-body irradiation in mice, a systems-level understanding of pathway activity deregulation is lacking. To address this gap, we applied the Pathway Signal Flow (PSF) algorithm to analyze long-term pathway activity alterations in LV and RV tissues of C57Bl/6J mice exposed to gamma radiation (100 cGy 137Cs) or the simplified Galactic Cosmic Ray simulation (simGCRsim, 50 cGy 500 MeV/n) composition of ion beams. RNA sequencing data were analyzed to assess pathway activity changes, sex-specific effects, and ventricular differences 440 days post-irradiation. We observed marked sex- and ventricle-specific differences in pathway deregulation. Left ventricular tissues in females exhibited broad signaling pathway alterations after simGCRsim exposure, particularly in immune response, cytoskeletal remodeling, and survival-related pathways (e.g., NF-κB, VEGF, and MAPK). In contrast, male RV tissues demonstrated higher pathway deregulation than LV, particularly in PPAR, NF-κB, and HIF-1 pathways, implicating metabolic disruption and survival adaptations. Furthermore, simGCRsim exposure induced greater long-term pathway perturbations than gamma rays. Our findings suggest that sex-dependent and ventricle-specific signaling alterations contribute to long-term cardiovascular risks following space irradiation. Notably, VEGF and NF-κB signaling emerge as key regulators of cardiac adaptation in females. Future studies in larger cohorts, incorporating early-stage molecular responses and broader pathway analyses, are needed to refine cardiovascular risk assessments for space travel.

Authors: Gisane Khachatryan, Tamara Sirunyan, Siras Hakobyan, Suren Davitavyan, Roksana Zakharyan, Ani Stepanyan, Agnieszka Brojakowska, Mary K Khlgatian, Malik Bisserier, Shihong Zhang, David A Goukassian, Arsen Arakelyan

Date Published: 25th Sep 2025

Publication Type: Journal

The effects of space radiation on the transcriptome of heart right ventricle tissue

Abstract (Expand)

Deep space represents a challenging environment for human exploration and can be accompanied by harmful health-related risks. We aimed to assess the effect of simplified galactic cosmic ray simulated … (simGCRsim) and gamma (γ) ionizing radiation (IR) on transcriptome changes in right ventricular (RV) tissue after a single low dose (0.5 Gy, 500 MeV/nucleon) full body exposure in C57BL/6J male and female mice. In females, no differentially expressed genes (DEGs) and only 2 upregulated genes in males exposed to γ-IR were revealed. In contrast, exposure to simGCRsim-IR resulted in 4 DEGs in females and 371 DEGs in males, suggesting longer-lasting and sex-biased DEGs after simGCRsim-IR. Overrepresentation analysis of DEGs in simGCRsim-IR males revealed significant enrichment in pathways related to muscle contraction, hypertrophic cardiomyopathy, oxytocin release, the regulation of cytoskeleton, and genes associated with Alzheimer’s, Huntington’s, and Parkinson’s diseases. Our results suggested the RV transcriptome exhibits distinct responses after exposure based on both the IR and sex.

Authors: Roksana Zakharyan, Siras Hakobyan, Agnieszka Brojakowska, Malik Bisserier, Shihong Zhang, Mary K. Khlgatian, Amit Kumar Rai, Suren Davitavyan, Ani Stepanyan, Tamara Sirunyan, Gisane Khachatryan, Susmita Sahoo, Venkata Naga Srikanth Garikipati, Arsen Arakelyan, David A. Goukassian

Date Published: 21st Jul 2025

Publication Type: Journal

Transcriptome alterations in long-term mining region residents: Insights into immune response and molecular pathways.

Abstract (Expand)

Pollution with metals and metalloids is a global problem that adversely affects human health and environment. Although several studies have reported gene expression changes in response to human exposures … to metals, there are a limited number of studies exploring the effect of long-term residence in mining areas. The evidence of increased levels of several essential and non-essential metals in soil, water, and plants in Kapan mining area (Armenia) has been previously demonstrated in several environmental studies. Our study investigated the impact of long-term residence in this mining area on the transcriptome state of human peripheral blood mononuclear cells and the possible association of transcriptome changes with the blood metallome. In total, 58 participants including 27 mining region residents (MRR) and 31 non-mining region residents (NMR) were selected for our study. Transcriptomic analysis of peripheral blood mononuclear cells was performed by mRNA sequencing. Differential expression analyses were conducted using generalized linear modeling, optimized for participant demographics, cell types, and sequencing technical factors, followed by pathway analysis. The study revealed that long-term residence in a mining area is correlated with alterations in the blood transcriptome, with responses varying by sex. The identified transcriptome changes were enriched for pathways related to immune response and RNA translation. These changes correlated with higher blood levels of a mixture of non-essential metals, including arsenic, antimony, nickel, thallium, and beryllium. Additionally, the study identified differences in the transcriptome response between male and female MRR. While females exhibited a stronger immune response, males show dysregulation in ion transport and epigenetic modifications. Our findings contribute to understanding the effects of long-term residence in mining regions and can aid in developing more effective risk assessment and mitigation approaches in target populations.

Authors: A. Stepanyan, A. Arakelyan, J. Schug

Date Published: 24th Mar 2025

Publication Type: Journal

Long-lasting sex-specific alteration in left ventricular cardiac transcriptome following gamma and simGCRsim radiation

Abstract (Expand)

Space irradiation (IR) is an important health risk for deep-space missions. We reported heart failure with preserved ejection fraction like cardiac phenotype 660-days following exposure to a single-dose … of a simplified galactic cosmic ray simulation (simGCRsim) only in males with functional and structural impairment in left ventricular (LV) function. This sex-based dichotomy prompted us to investigate sex-specific changes in the LV transcriptome in three-month-old male and female mice exposed to 137Cs-γ- or simGCRsim-IR. Non-IR male and female (10 each) mice served as controls. LVs were collected at 440/660- and 440/550-days post-IR, male and female, respectively. RNA sequencing, differential gene expression, and functional annotation were performed on tissues from 5 mice/group. Sex and post-IR time points had the greatest influence on gene expression, surpassing the IR-type effects. SimGCRsim-IR showed more persistent transcriptome changes than γ-IR. We suggest that the single IR effects can persist up to 550-660 days, with overwhelmingly sex-biased responses at individual gene expression level.

Authors: Roksana Zakharyan, Siras Hakobyan, Agnieszka Brojakowska, Suren Davitavyan, Ani Stepanyan, Tamara Sirunyan, Gisane Khachatryan, Mary K. Khlgatian, Malik Bisserier, Shihong Zhang, Susmita Sahoo, Lahouaria Hadri, Venkata Naga Srikanth Garikipati, Arsen Arakelyan, David A. Goukassian

Date Published: 18th Feb 2025

Publication Type: Journal

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