1. Mitochondrial dysfunction and endoplasmic reticulum stress induced by activation of PPARα leaded testicular to apoptosis in SD rats explored to di-(2-ethylhexyl) phthalate (DEHP).
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Zhang, Haoyang, Ran, Maohuan, Jiang, Liping, Sun, Xiance, Qiu, Tianming, Li, Jing, Wang, Ningning, Yao, Xiaofeng, Zhang, Cong, Deng, Haoyuan, Wang, Shaopeng, and Yang, Guang
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ENDOPLASMIC reticulum ,ENDOCRINE disruptors ,MITOCHONDRIA ,PHTHALATE esters ,APOPTOSIS ,MITOCHONDRIAL pathology - Abstract
Di-2-ethylhexyl phthalate (DEHP), as a common endocrine disrupting chemicals, can induce toxicity to reproductive system. However, the mechanism remains to be explored. In our study, DEHP exposure induced testicular injury in rats. The high throughput transcriptional sequencing was performed to identify differentially expressed genes (DEGs) between the treatment and control groups. KEGG analysis revealed that DEGs were enriched in apoptosis, PPARα, and ER stress pathway. DEHP up-regulated the expression of PPARα, Bax, Bim, caspase-4. GRP78, PERK, p-PERK, eIF2α, p-eIF2α, ATF4 and CHOP. This view has also been confirmed in TM3 and TM4 cells. In vitro, after pre-treatment with GW6471 (an inhibitor of PPARα) or GSK (an inhibitor of PERK), the apoptosis was inhibited and mitochondrial dysfunction was improved. Moreover, the improvement of mitochondrial dysfunction decreased the expression of PERK pathway by using SS-31(a protective agent for mitochondrial function). Interestingly, ER stress promoted the accumulation of ROS by ERO1L (the downstream of CHOP during ER stress), and the ROS further aggravated the ER stress, thus forming a feedback loop during the apoptosis. In this process, a vicious cycle consisting of PERK, eIF2α, ATF4, CHOP, ERO1L, ROS was involved. Taken together, our results suggested that mitochondrial dysfunction and ER stress-ROS feedback loop caused by PPARα activation played a crucial role in DEHP-induced apoptosis. This work provides insight into the mechanism of DEHP-induced reproductive toxicity. [Display omitted] • DEHP induced apoptosis in rat testis. • MEHP induced apoptosis in TM3 and TM4 cells. • PPARα was activated to induce mitochondrial dysfunction through CPT1A pathway. • Apoptosis was via PPARα regulated mitochondrial disorder and ER stress interaction. • the ER stress-ROS feedback loop was discovered during apoptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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