The role of STAT3/p53 and PI3K-Akt-mTOR signaling pathway on DEHP-induced reproductive toxicity in pubertal male rat

Fu, Guoqing; Dai, Juan; Li, Zhen; Chen, Feng; Liu, Lemei; Yi, Lingna; Teng, Zengguang; Quan, Chao; Zhang, Ling; Zhou, Ting; Donkersley, Philip; Song, Shuo; Shi, Yuqin

doi:10.1016/j.taap.2020.115151

Cited by 48 publications

(18 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Testicular cell damage induced by DEHP is associated with the mitochondrial dysfunction in, which this contributes to the excessive generation of ROS/RNS and induction of the mitochondrial apoptotic pathways; these events may finally contribute to testicular atrophy [ 22 ]. DEHP activates P53 signaling pathway in prepubertal testes, which this effect results in the enhancement of cell apoptosis and inhibition of proliferation of Leydig cells [ 23 ]; activation of P53 may play a major role to induce testis injury and reproductive dysfunction [ 24 ]. Elevated level of DEHP-induced oxidative stress is also associated with the reduction of the expression of PI3K, p-Akt and p-mTOR proteins, leading to the activation of the downstream autophagy-related proteins including ULK1, Beclin-1, autophagy-related gene 7 (Atg7), LC3-II.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated level of DEHP-induced oxidative stress is also associated with the reduction of the expression of PI3K, p-Akt and p-mTOR proteins, leading to the activation of the downstream autophagy-related proteins including ULK1, Beclin-1, autophagy-related gene 7 (Atg7), LC3-II. Autophagy activation may protect testes from DEHP-induced reproductive damage [ 24 ]. The reduction of sperm motility induced by DEHP may result from the impairment of ATP production; DEHP inhibits the expression of subunits of oxidative phosphorylation (OXPHOS) complex II, III, IV and V, which this effect is correlated with the attenuation of ATP levels in testes [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The ameliorative effect of ellagic acid on di-(2-ethylhexyl) phthalate-induced testicular structural alterations, oxidative stress, inflammation and sperm damages in adult mice

Hosseinzadeh

Mehrzadi

Siahpoosh

et al. 2021

Reprod Biol Endocrinol

View full text Add to dashboard Cite

Background Phthalates such as di (2-ethylhexyl) phthalate (DEHP) are well known exogenous substances, disrupting reproductive system function and structure. The current research demonstrated the effect of ellagic acid (EA) on DEHP-induced testicular injury in mice. Methods Thirty-five healthy adult male mice were randomly divided to five groups; normal saline receiving group, DEHP (2 g/kg/day, dissolved in corn oil, p.o.) receiving group, DEHP (2 g/kg/day, dissolved in corn oil, p.o.) and EA receiving groups (25, 50 and 100 mg/kg/day, p.o.). Treatment duration of animals was 14 days. Body and testes weights and sperm characteristics and histological changes of testes were evaluated. Serum testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were analyzed. In the testicular tissue, oxidative/nitrosative stress markers and inflammatory cytokine levels were measured. Results Ellagic acid significantly reduced DEHP-induced reduction of body and testes weights. The DEHP-induced reduction of spermatogonia, primary spermatocyte and sertoli cells numbers as well as reduction of sperm vitality and progressive motility were reversed by EA. Furthermore, EA inhibited DEHP-induced alterations in serum hormone levels. These effects were associated with the reduction of DEHP-induced increased level of oxidative stress and inflammatory responses. Conclusions Ellagic acid considerably inhibits testicular toxicity of DEHP through reducing oxidative/nitrosative stress and inflammatory responses. Our data suggest that EA may be considered as a promising agent to inhibit male reproductive toxicity induced by endocrine disrupting chemicals such as DEHP.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The ameliorative effect of ellagic acid on di-(2-ethylhexyl) phthalate-induced testicular structural alterations, oxidative stress, inflammation and sperm damages in adult mice

Hosseinzadeh

Mehrzadi

Siahpoosh

et al. 2021

Reprod Biol Endocrinol

View full text Add to dashboard Cite

show abstract

“…however, the potential upstream mechanism of its regulation on Gadd45a was not fully elucidated here. As one of the important downstream molecules of p53 in cell cycle regulation, Gadd45a can be regulated in a p53-dependent manner, while the expression of p53 in tumour cells can be signi cantly inhibited by the PI3K/Akt signalling pathway (30)(31)(32). Thus, given recent ndings showing that the activation of the PI3K/Akt signalling pathway is closely related to the binding of FGFRs to their ligands (33)(34)(35), we speculated that the regulation of Gadd45a by lenvatinib may rely on the upstream PI3K/Akt/p53 signalling pathway, which will be further investigated in our future work.…”

Section: Discussionmentioning

confidence: 99%

Lenvatinib Inhibits Intrahepatic Cholangiocarcinoma Growth via Gadd45a-Mediated Cell Cycle Arrest

Xia

Wang

Zhuang

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, and its 5-year survival rate is less than 10%. Fibroblast growth factor receptor (FGFR) changes have been observed in 6%-50% of ICC patients, and patients with FGFR mutations have been shown to have more inert tumour biological activity than patients with wild-type FGFRs. Thus, as a pan-FGFR inhibitor, lenvatinib is supposed to play an anti-tumour role in ICC. However, no relevant experiments have been reported.Methods: Patients derived xenograft (PDX) model and cell line derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyse the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism.Reaults: In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G0/G1 phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC.Conclusion: Our work firstly found that lenvatinib exerted excellent antitumor effect on ICC, mainly via inducing Gadd45a mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC.

show abstract

“…Many studies have shown the toxic effects of DEHP on male reproductive organs in the rodents at growth stages [9][10][11][12][13][14][15][16][17][18][19]. Although the pathogenesis of testicular atrophy by DEHP is yet unclear, this injury has been suggested to be due to oxidative stress induced by mono (2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP [20].…”

Section: Introductionmentioning

confidence: 99%

Effect of dilute Ethanol Intake on DEHP (di (2-ethylhexyl) phthalate)-induced Testicular Atrophy

Suna¹,

Jitsunari²

2022

JPPR

View full text Add to dashboard Cite

Background: Di(2-ethylhexyl) phthalate (DEHP) is the most commonly used as a plasticizer for polyvinyl chloride (PVC), but recently, concern has arisen over the DEHP which may act as a reproductive toxicant to humans. On the other hand, ethanol is the most common supplement of beverages and foods, and so many persons ingest a large quantity of ethanol in daily life. However, interactions between ethanol and DEHP toxicity are not well known. Method: To investigate the effect of dilute ethanol ingestion on the DEHP induced testicular atrophy, rats were received a 1% (w/w) DEHP diet and 2.5 or 5% (v/v) ethanol water for 7 days. Result: The rats treated with DEHP-diet alone for 7 days were observed significant testicular weight loss. On the other hand, testicular weight loss was significantly suppressed in rats treated with DEHP diet and ethanol water. A significant negative correlation between relative testicular weight (as a percentage of body weight) and testicular MEHP concentration was found among rats treated with DEHP-free diet (Control) and DEHP diet alone. Most of the data plots for the DEHP diet plus ethanol water group were scattered above the regression line. Conclusion: These results suggest that dilute ethanol may be effective in preventing DEHP testicular atrophy. However, the mechanism of prevention is unknown and further research is needed.

show abstract

The role of STAT3/p53 and PI3K-Akt-mTOR signaling pathway on DEHP-induced reproductive toxicity in pubertal male rat

Cited by 48 publications

References 65 publications

The ameliorative effect of ellagic acid on di-(2-ethylhexyl) phthalate-induced testicular structural alterations, oxidative stress, inflammation and sperm damages in adult mice

The ameliorative effect of ellagic acid on di-(2-ethylhexyl) phthalate-induced testicular structural alterations, oxidative stress, inflammation and sperm damages in adult mice

Lenvatinib Inhibits Intrahepatic Cholangiocarcinoma Growth via Gadd45a-Mediated Cell Cycle Arrest

Effect of dilute Ethanol Intake on DEHP (di (2-ethylhexyl) phthalate)-induced Testicular Atrophy

Contact Info

Product

Resources

About