Mechanisms linked to differences in the mutagenic potential of 1,3-dinitropyrene and 1,8-dinitropyrene

Abstract

This study explores and characterizes the toxicity of two closely related carcinogenic dinitro-pyrenes (DNPs), 1,3-DNP and 1,8-DNP, in human bronchial epithelial BEAS-2B cells and mouse hepatoma Hepa1c1c7 cells. Neither 1,3-DNP nor 1,8-DNP (3–30 μM) induced cell death in BEAS-2B cells. In Hepa1c1c7 cells only 1,3-DNP (10–30 μM) induced a mixture of apoptotic and necrotic cell death after 24 h. Both compounds increased the level of reactive oxygen species (ROS) in BEAS-2B as measured by CM-H2DCFDA-fluorescence. A corresponding increase in oxidative damage to DNA was revealed by the formamidopyrimidine-DNA glycosylase (fpg)-modified comet assay. Without fpg, DNP-induced DNA damage detected by the comet assay was only found in Hepa1c1c7 cells. Only 1,8-DNP formed DNA adduct measured by 32P-postlabelling. In Hepa1c1c cells, 1,8-DNP induced phosphorylation of H2AX (γH2AX) and p53 at a lower concentration than 1,3-DNP and there was no direct correlation between DNA damage/DNA damage response (DR) and induced cytotoxicity. On the other hand, 1,3-DNP-induced apoptosis was inhibited by pifithrin-α, an inhibitor of p53 transcriptional activity. Furthermore, 1,3-DNP triggered an unfolded protein response (UPR), as measured by an increased expression of CHOP, ATF4 and XBP1. Thus, other types of damage possibly linked to endoplasmic reticulum (ER)-stress and/or UPR could be involved in the induced apoptosis. Our results suggest that the stronger carcinogenic potency of 1,8-DNP compared to 1,3-DNP is linked to its higher genotoxic effects. This in combination with its lower potency to induce cell death may increase the probability of causing mutations.

Synergetic delivery of artesunate and isosorbide 5-mononitrate with reduction-sensitive polymer nanoparticles for ovarian cancer chemotherapy

“…RNS directly caused DNA base lesions or indirectly facilitated DNA damage by hindering DNA replication progression. PSSP@ART-ISMN-treated SKOV3 cells showed a remarkable expression of γ-H2A.X, which is a marker of DNA damage response [ 39 , 40 ], which further confirmed the DNA double-strand break caused by PSSP@ART-ISMN (Fig. 3 G, Additional file 1 : Figure S9).…”

A Systematic Review of Polycyclic Aromatic Hydrocarbon Derivatives: Occurrences, Levels, Biotransformation, Exposure Biomarkers, and Toxicity

“…For instance, 1,8dinitropyrene was observed to be three times more mutagenic than B[a]P, a notably toxic PAH. 158 Evidence also suggests a correlation between lung cancer progression and NPAH particle concentrations, predominantly 1-NP, 4-nitropyrene, 1,6-dinitropyrene, 1,8-dinitropyrene, and 6-nitrochrysene. Furthermore, APAHs, such as 1-methylpyrene, 5-methylchryrene, 7-methyl-B[a]A, and 7,12-DMBA, which are from methylation of pyrene, chrysene, and B[a]A, have exhibited stronger carcinogenic potential than that of their parent compounds.…”

“…Extensive research highlights that PAH derivatives are both mutagenic and carcinogenic, some of which exhibit a greater potency than those of priority PAHs. For instance, 1,8-dinitropyrene was observed to be three times more mutagenic than B­[ a ]­P, a notably toxic PAH . Evidence also suggests a correlation between lung cancer progression and NPAH particle concentrations, predominantly 1-NP, 4-nitropyrene, 1,6-dinitropyrene, 1,8-dinitropyrene, and 6-nitrochrysene.…”

IRE-1-Targeting Caged Prodrug with Endoplasmic Reticulum Stress-Inducing and XBP-1S-Inhibiting Activities for Cancer Therapy

“…The Dns moiety can also induce ER stress once it is cleaved, leading to the increased expression of XBP-1s and ATF4. 17 Once liberated, fluorescent D-F07 can be visualized in cancer cells and potently inhibit XBP-1s expression. We have thus successfully designed and synthesized a caged prodrug, TC-D-F07, that demonstrates the possibility of delivering ER stress-inducing and XBP-1s-inhibiting activities in one entity for the treatment of cancer.…”

“…The sulfonate cage can stabilize the 1,3-dioxane protecting moiety on D-F07 and quench the fluorescence of D-F07 via its strong electron-withdrawing property. The Dns moiety can also induce ER stress once it is cleaved, leading to the increased expression of XBP-1s and ATF4 . Once liberated, fluorescent D-F07 can be visualized in cancer cells and potently inhibit XBP-1s expression.…”