siddhad

• Kannen, Vinicius; Olafsen, Ninni Elise; Das, Siddhartha; Giuliana, Paolo; Izzati, Fauzia N. & Choksi, Hani [Vis alle 16 forfattere av denne artikkelen] (2025). Loss of aryl hydrocarbon receptor reduces pancreatic tumor growth by increasing immune cell infiltration. Biochemical Pharmacology. ISSN 0006-2952. 236, s. 1–12. doi: 10.1016/j.bcp.2025.116872. Fulltekst i vitenarkiv
• Rundblad, Amanda; Das, Siddhartha; Ginos, Bigina N.R; Matthews, Jason; Holven, Kirsten Bjørklund & Voortman, Trudy [Vis alle 7 forfattere av denne artikkelen] (2025). Exposure to fine particulate matter in adults is associated with immune cell gene expression related to inflammation, the electron transport chain, and cell cycle regulation. Environmental Epigenetics. 11(1). doi: 10.1093/eep/dvaf008. Fulltekst i vitenarkiv Vis sammendrag

  Exposure to air pollution and an unhealthy built environment increase disease risk by impacting metabolic risk factors and inflammation, potentially via epigenetic modifications and effects on gene expression. We aimed to explore associations between fine particulate matter (PM2.5), black carbon, ozone, nitrogen dioxide, distance to nearest water body, normalized difference vegetation index, and impervious surface and gene expression profiles in adults. This study is a part of the LongITools project and includes cross-sectional data from the Rotterdam Study, a population-based cohort study, and NoMa, a randomized controlled trial. Environmental exposures were assigned using land-use regression (LUR) models and satellite data. Gene expression was assessed with whole blood RNA sequencing (Rotterdam Study, n = 758) and microarray analyses in peripheral blood mononuclear cells (NoMa, n = 100). We analysed transcriptomic profiles and enriched pathways associated with each of the environmental exposures. PM2.5 had the strongest gene expression associations, while only a few significant associations were observed for the other environmental exposures. In both populations, exposure to PM2.5 was associated with genes and pathways related to inflammation, oxidative stress, DNA metabolism, cell cycle regulation, histones, electron transport chain, oxidative phosphorylation, and neural signalling. This study is limited by different methods for RNA quantification, a cross-sectional design, and a small sample size. However, in both populations, exposure to PM2.5 resulted in the maximum number of associations with gene expression. In conclusion, PM2.5 is strongly associated with various gene expression profiles, which provide information about the underlying mechanisms of the detrimental health effects of exposure to PM2.5.

• Kannen, Vinicius; Rasmussen, Marit; Das, Siddhartha; Giuliana, Paolo; Izzati, Fauzia N. & Choksi, Hani [Vis alle 18 forfattere av denne artikkelen] (2025). Loss of Parp7 increases type I interferon signalling and reduces pancreatic tumour growth by enhancing immune cell infiltration. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1513595. Fulltekst i vitenarkiv Vis sammendrag

  Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and despite low incidence rates, it remains the sixth leading cause of cancer related deaths worldwide. Immunotherapy, which aims to enhance the immune system’s ability to recognize and eliminate cancer cells, has emerged as a promising approach in the battle against PDAC. PARP7, a mono-ADP-ribosyltransferase, is a negative regulator of the type I interferon (IFN-I) pathway and has been reported to reduce anti-tumour immunity.Methods: We used murine pancreatic cancer cells, CR705, CRISPR/Cas9, in vivo tumour models and spectral flow cytometry to determine the role of PARP7 in pancreatic tumour growth.Results: Loss of Parp7 elevated the levels of interferon stimulated gene factor 3 (ISGF3) and its downstream target genes, even in the absence of STING. Cancer cells knocked out for Parp7 (CR705Parp7KO) produced smaller tumours than control cells (CR705Cas9) when injected into immunocompetent mice. Transcriptomic analyses revealed that CR705Parp7KO tumours had increased expression of genes involved in immunoregulatory interactions and interferon signalling pathways. Characterization of tumour infiltrating leukocyte (TIL) populations showed that CR705Parp7KO tumours had higher proportions of natural killer cells, CD8+ T cells and a lower proportion of anti-inflammatory macrophages (M2). The overall TIL profile of CR705Parp7KO tumours was suggestive of a less suppressive microenvironment.Conclusions: Our data show that loss of Parp7 reduces PDAC tumour growth by increasing the infiltration of immune cells and enhancing anti-tumour immunity. These findings provide support to pursue PARP7 as a therapeutic target for cancer treatment.

• Das, Siddhartha; Rundblad, Amanda; Marques, Irene Fontes; Soares, Ana Goncalves; Jaddoe, Vincent W. & Vrijheid, Martine [Vis alle 14 forfattere av denne artikkelen] (2024). Air pollution exposure is associated with gene expression in children. Environmental Epigenetics. 10(1). doi: 10.1093/eep/dvae025. Fulltekst i vitenarkiv Vis sammendrag

  Environmental exposures, including air pollutants and lack of natural spaces, are associated with suboptimal health outcomes in children. We aimed to study the associations between environmental exposures and gene expression in children. Associations of exposure to particulate matter (PM) with diameter <2.5 (PM2.5) and < 10 (PM10) micrometers, nitrogen dioxide, green spaces, and blue space, with whole-blood gene expression were explored in children from the Dutch Generation R Study (n = 172). Analyses were adjusted for age, sex, batch, maternal education, and area socioeconomic status. Follow-up analysis was carried out using lymphoblastoid cell line gene expression in children from the ALSPAC Study (n = 946). Gene set enrichment analysis (GSEA) using hallmark and immune gene sets from the molecular signature database was carried out to identify significantly over-represented gene sets for insights into biological mechanisms Exposure to PM2.5 was associated with expression of 86 genes in discovery analyses in the Generation R Study [false discovery rate (FDR)-adjusted P-value < .25]. Of these, PM2.5 was also associated with GNG11 expression in the same direction in follow-up analysis (FDR-adjusted P-value < .05). The remaining exposures showed much fewer associations in the discovery analyses. GSEA using PM2.5 association results for both cohorts indicated suppression of gene sets related to interferon response and response to bacterial and viral exposure. In conclusion, gene expression analysis performed in two independent cohorts suggests that PM2.5 exposure in children may be involved in interferon and microbial infection responses.

• Olafsen, Ninni Elise; Das, Siddhartha; Gorrini, Chiara & Matthews, Jason (2024). Long-term exposure to BAY2416964 reduces proliferation, migration and recapitulates transcriptional changes induced by AHR loss in PyMT-induced mammary tumor cells. Frontiers in Oncology. 14. doi: 10.3389/fonc.2024.1466658. Fulltekst i vitenarkiv Vis sammendrag

  The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor which in certain cancer types drives pro-survival processes that facilitate tumorigenesis, malignant cell migration, invasion, and metastasis. Much of AHR’s pro-tumorigenic action is due to its activation by the oncometabolite, kynurenine. Because of this AHR antagonists are being actively investigated as new anti-tumor therapy. In this study we compared the effects of treatment with the AHR antagonists, BAY2416964 and GNF351, to that of AHR knockout in PyMT murine mammary cancer cells. BAY2416964 and GNF351 effectively inhibited kynurenine-dependent increases in Cyp1a1 and Cyp1b1 mRNA levels. CRISPR/Cas9-generated PyMT AhrKO cells exhibited reduced cell proliferation compared with controls, but treatment with 1 μM BAY2416964 for 96 h had no effect on the proliferation of wildtype cells. To further examine the differences between AHR knockout and short term BAY2416964, we generated long-term BAY2416964 (LT-BAY) cells by exposing wildtype cells to 1 μM BAY2416964 for at least 6 weeks. Similar to AhrKO cells, LT-BAY cells exhibited reduced cell proliferation and migration compared with wildtype cells. No differentially expressed genes (DEGs) were identified in wildtype cells exposed to 1 μM BAY2416964 for 24 h; however, 46.4% of DEGs overlapped between AhrKO and LT-BAY cells including gene regulated cell proliferation. Our data reveal long-term pharmacological inhibition of AHR by BAY2416964 closely resembles AHR loss in a mouse model of breast cancer.

• Das, Siddhartha; Somisetty, Venkata Satheesh; Ulven, Stine Marie & Matthews, Jason (2023). Resveratrol and 3,3′-Diindolylmethane Differentially Regulate Aryl Hydrocarbon Receptor and Estrogen Receptor Alpha Activity through Multiple Transcriptomic Targets in MCF-7 Human Breast Cancer Cells. International Journal of Molecular Sciences. ISSN 1661-6596. 24(19). doi: 10.3390/ijms241914578. Fulltekst i vitenarkiv Vis sammendrag

  Inhibitory crosstalk between estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AHR) regulates 17β-estradiol (E2)-dependent breast cancer cell signaling. ERα and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. Dietary ligands resveratrol (RES) and 3,3′diindolylmethane (DIM) also activate ERα while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and anti-inflammatory properties. Studies with genome-wide targets and AHR- and ERα-regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ERα as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2, or TCDD alone or E2+TCDD for 1 and 6 h, respectively. ERα bound sites after being DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after being DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ERα site, and 60% of the coregulated genes between DIM and E2+TCDD were common. Collectively, our data show that RES and DIM differentially regulate multiple transcriptomic targets via ERα and ERα/AHR coactivity, respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that, when both receptors are activated, ERα dominates with preferential recruitment of AHR to ERα target genes.

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• Granly, Emma Nilsen; Åhrling, Samaneh Shabani; Alvik, Karoline; Das, Siddhartha & Matthews, Jason (2025). Aryl Hydrocarbon Receptor Differentially Regulated Gene Expression Profiles in Resting and Polarized Bone Marrow-Derived Macrophages. Fulltekst i vitenarkiv
• Åhrling, Samaneh Shabani; Das, Siddhartha; Olafsen, Ninni Elise; Granly, Emma Nilsen & Matthews, Jason (2025). Differential Effects of Loss and Pharmacological Inhibition of Aryl Hydrocarbon Receptor on Mammary Tumor Growth. Fulltekst i vitenarkiv
• Olafsen, Ninni Elise; Das, Siddhartha; Gorrini, Chiara & Matthews, Jason (2024). Corrigendum: Long-term exposure to BAY2416964 reduces proliferation, migration and recapitulates transcriptional changes induced by AHR loss in PyMT-induced mammary tumor cells (Frontiers in Oncology, (2024), 14, (1466658), 10.3389/fonc.2024.1466658). Frontiers in Oncology. 14. doi: 10.3389/fonc.2024.1516633. Fulltekst i vitenarkiv
• Rundblad, Amanda; Das, Siddhartha; Matthews, Jason; Ginos, Gina; Kavousi, Maryam & Holven, Kirsten Bjørklund [Vis alle 7 forfattere av denne artikkelen] (2023). Air pollution, built environment and associations with gene expression and CVD risk markers in adults. Fulltekst i vitenarkiv
• Das, Siddhartha (2026). Environmental exposures and gene expression: Evidence from in vitro and population-based studies. Universitetet i Oslo. ISSN 9788234807886. Fulltekst i vitenarkiv Vis sammendrag

  Air pollution is a major contributor to global disease burden. Key pollutants include particulate matter and gaseous compounds. Exposure to natural green and blue spaces may mitigate the harmful effects of air pollutants. Environmental pollutants can alter gene expression by regulating transcription factors. The aryl hydrocarbon receptor (AHR) is a nuclear receptor activated by organic pollutants such as TCDD. AHR is also modulated by dietary ligands, including activation by 3,3’-diindolylmethane (DIM) and inhibition by resveratrol. In Paper I, we investigated genome-wide AHR binding and gene expression regulation after treatment with TCDD, E2, DIM, and resveratrol. Both TCDD and DIM activated AHR; however, DIM-induced AHR binding was enriched at estrogen response elements and regulated developmental genes, whereas TCDD primarily affected metabolic genes. These findings highlight that distinct environmental exposures can differentially regulate AHR activity, to influence chronic disease risk. Papers II and III examined associations between air pollution, natural spaces, and gene expression in population-based children and adult cohorts. In children, PM2.5 exposure was associated with expression levels of 86 genes (FDR < 0.25), including GFI1B, TSC22D1, and GNG11. Gene set enrichment showed negative associations between PM2.5 and interferon alpha and gamma pathway genes. In adults, the exposure to PM2.5 was also associated with the expression of the highest number of differentially expressed genes. Negatively associated genes were enriched for cell cycle, DNA repair, and metabolism as well as oxidative phosphorylation. Green space within 300 meters of residence was negatively associated with adaptive immune response genes in both child and adult cohorts. Overall, PM2.5 showed the most consistent gene expression associations across age groups. Green space may exert protective effects through modulation of immune gene expression. Additionally, dietary ligands can directly regulate pollutant activated transcription factors such as AHR.

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