Effects of deletion of the transcription factor Nrf2 and benzo [a]pyrene treatment on ovarian follicles and ovarian surface epithelial cells in mice

Lim, Jinhwan; Ortíz, Laura Velasco; Nakamura, Brooke N.; Hoang, Yvonne D.; Banuelos, Jésus; Flores, Victoria N.; Chan, Julia Y.; Luderer, Ulrike

doi:10.1016/j.reprotox.2015.07.080

Cited by 34 publications

(22 citation statements)

References 72 publications

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“…A previous study showed that the inhibition of Nrf2 increased B[a]P toxicity and decreased the expression of several GSTs [72]. To confirm that silymarin regulates the Nrf2 signaling pathway, which is related to the attenuation of BPDE-DNA adduct formation, we demonstrated that knockdown of Nrf2 expression by RNA interference abolishes the inhibition of BPDE-DNA adduct formation by silymarin ( Figure 5B).…”

Section: Discussionsupporting

confidence: 52%

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

Jee

Kim

Sung

2020

IJMS

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Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon, is a group 1 carcinogen that introduces mutagenic DNA adducts into the genome. In this study, we investigated the molecular mechanisms underlying the involvement of silymarin in the reduction of DNA adduct formation by B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), induced by B[a]P. B[a]P exhibited toxicity in HepG2 cells, whereas co-treatment of the cells with B[a]P and silymarin reduced the formation of BPDE-DNA adducts, thereby increasing cell viability. Determination of the level of major B[a]P metabolites in the treated cells showed that BPDE levels were reduced by silymarin. Nuclear factor erythroid 2-related factor 2 (Nrf2) and pregnane X receptor (PXR) were found to be involved in the activation of detoxifying genes against B[a]P-mediated toxicity. Silymarin did not increase the expression of these major transcription factors, but greatly facilitated their nuclear translocation. In this manner, treatment of HepG2 cells with silymarin modulated detoxification enzymes through NRF2 and PXR to eliminate B[a]P metabolites. Knockdown of Nrf2 abolished the preventive effect of silymarin on BPDE-DNA adduct formation, indicating that activation of the Nrf2 pathway plays a key role in preventing B[a]P-induced genotoxicity. Our results suggest that silymarin has anti-genotoxic effects, as it prevents BPDE-DNA adduct formation by modulating the Nrf2 and PXR signaling pathways.

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Section: Discussionsupporting

confidence: 52%

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

Jee

Kim

Sung

2020

IJMS

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“…We assume that in order to avoid B[a]P-induced toxicity, the low level of ROS molecules activates signaling networks such as transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) hypoxia-inducible factor (HIF)1α and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), which are involved in maintaining cell homeostasis 43 , 44 . Once activated, Nrf2 binds to antioxidant response elements (ARE) of antioxidant genes including genes for NADPH production, glutathione homeostasis/utilization and of phase I and II enzymes 45 , 46 .…”

Section: Discussionmentioning

confidence: 99%

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Verma

Pink

Boland

et al. 2017

Sci Rep

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Benzo[a]pyrene (B[a]P), a well-known polyaromatic hydrocarbon, is known for its lung carcinogenicity, however, its role in bladder cancer development is still discussed. Comparative two-dimensional blue native SDS-PAGE analysis of protein complexes isolated from subcellular fractions of 0.5 µM B[a]P-exposed cells indicated a differential regulation of proteins involved in carbohydrate, fatty acid, and nucleotide metabolism, suggesting a possible metabolic flux redistribution. It appeared that B[a]P exposure led to a repression of enzymes (fructose-bisphosphate aldolase A, glucose-6-phosphate isomerase, lactate dehydrogenase) involved in glycolysis, and an up-regulation of proteins (glucose-6-phosphate 1-dehydrogenase, 6-phosphogluconolactonase) catalyzing the pentose phosphate pathway and one carbon metabolism (10-formyltetrahydrofolate dehydrogenase, bifunctional purine biosynthesis protein). Untargeted metabolomics further supported the proteomic data, a lower concentration of glycolytic metabolite was observed as compared to glutamine, xylulose and fatty acids. The analysis of the glutathione and NADPH/NADP+ content of the cells revealed a significant increase of these cofactors. Concomitantly, we did not observe any detectable increase in the production of ROS. With the present work, we shed light on an early phase of the metabolic stress response in which the urothelial cells are capable of counteracting oxidative stress by redirecting the metabolic flux from glycolysis to pentose phosphate pathway.

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“…The transcription factor NRF2 stimulates the expression of detoxifying and antioxidant genes thus preserving the homeostasis of the primordial follicle pool. Indeed, null Nrf2 mice exposed to the toxicant benzo-a-pyrene (BaP) display an accelerated ovarian follicle depletion by middle-age [ 89 ]. The rate-limiting step of GSH synthesis is catalyzed by the heterodimeric enzyme glutamate cysteine ligase, composed of a modifier ( Gclm ) and a catalytic ( Gclc ) subunit.…”

Section: Origin Of Female Cancersmentioning

confidence: 99%

Oxidative stress in female cancers

et al. 2018

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Breast, cervical and ovarian cancers are highly prevalent in women worldwide. Environmental, hormonal and viral-related factors are especially relevant in the development of these tumors. These factors are strongly related to oxidative stress (OS) through the generation of reactive oxygen species (ROS). The OS is caused by an imbalance in the redox status of the organism and is literally defined as “an imbalance between ROS generation and its detoxification by biological system leading to impairment of damage repair by cell/tissue”. The multistep progression of cancer suggests that OS is involved in cancer initiation, promotion and progression. In this review, we described the role of OS and the interplay with environmental, host and viral factors related to breast, cervical and ovarian cancers initiation, promotion and progression. In addition, the role of the natural antioxidant compound curcumin and other compounds for breast, cervical and ovarian cancers prevention/treatment is discussed.

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Effects of deletion of the transcription factor Nrf2 and benzo [a]pyrene treatment on ovarian follicles and ovarian surface epithelial cells in mice

Cited by 34 publications

References 72 publications

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Oxidative stress in female cancers

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