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9419489 
Journal Article 
The role of STAT3/p53 and PI3K-Akt-mTOR signaling pathway on DEHP-induced reproductive toxicity in pubertal male rat 
Fu, G; Dai, J; Li, Z; Chen, F; Liu, L; Yi, L; Teng, Z; Quan, C; Zhang, L; Zhou, T; Donkersley, P; Song, S; Shi, Y 
2020 
1 
Toxicology and Applied Pharmacology
ISSN: 0041-008X
EISSN: 1096-0333 
Academic Press Inc. 
SAN DIEGO 
404 
115151 
English 
32710958 
WOS:000566798000011 
Di (2-ethylhexyl) phthalate (DEHP) is a known environmental endocrine disruptor that impairs development of testis and spermatogenesis. This study aims to explore the effects of STAT3/p53 and PI3K-Akt-mTOR signaling pathway on DEHP-induced reproductive toxicity in pubertal male rat. 24 6-week-old male Sprague-Dawley rats were randomly divided into 4 groups (Control, low-dose, middle-dose and high-dose group) and were treated with increasing concentration of DEHP (0, 250, 500, 1000 mg/kg/day) respectively for 28 consecutive days by intragastric administration. Our results showed that DEHP exposure induced obvious morphological changes of testis, decreased organ coefficient of testis and sperm count, and increased testicular cell apoptosis in the 500 and 1000 mg/kg/day DEHP groups (p < .05). The serum testosterone decreased in a dose-dependent manner after treatment with DEHP. Furthermore, the exposure of DEHP elevated the levels of oxidative stress accompanied by upregulated expression of p53 and reduced expression of STAT3. In addition, compared with the control group, the expression of PI3K, p-Akt and p-mTOR proteins significantly decreased, whereas the downstream autophagy-related proteins phosphorylated ULK1, Beclin-1, Atg7, LC3-II obviously increased in the 250 mg/kg/day DEHP group (p < .05). The expression of p62 was reduced in DEHP-treated groups. Our data indicated that autophagy could be activated to protect testes from DEHP-induced reproductive damage by inhibiting PI3K-Akt-mTOR signaling pathway in the 250 mg/kg/day DEHP group. STAT3/p53-mediated mitochondrial apoptosis pathway might play a major role to cause testis injury and reproductive dysfunction in the 500 and 1000 mg/kg/day DEHP groups. 
Di (2-ethylhexyl) phthalate; PI3K-Akt-mTOR; Puberty; Reproductive toxicology; STAT3/p53; autophagy related protein 7; beclin 1; caspase 3; caspase 9; cytochrome c; lc3 ii protein; mammalian target of rapamycin; phosphatidylinositol 3 kinase; phthalic acid bis(2 ethylhexyl) ester; protein; protein kinase B; protein p53; sequestosome 1; serine threonine protein kinase ULK1; STAT3 protein; testosterone; unclassified drug; glutathione peroxidase; malonaldehyde; mTOR protein, rat; phosphatidylinositol 3 kinase; phthalic acid bis(2 ethylhexyl) ester; protein kinase B; protein p53; STAT3 protein; Stat3 protein, rat; superoxide dismutase; target of rapamycin kinase; Akt signaling; animal tissue; apoptosis; apoptosis rate; Article; autolysosome; autophagosome; cell vacuole; controlled study; enzyme activity; Leydig cell; male; mitochondrial membrane; nonhuman; oxidative stress; protein expression; puberty; rat; reproductive toxicity; signal transduction; spermatocyte; spermatogonium; spermatozoon; spermatozoon count; testis injury; testis tissue; testosterone blood level; transmission electron microscopy; TUNEL assay; upregulation; animal; dose response; drug effect; genetics; metabolism; sexual maturation; Sprague Dawley rat; testis; Animals; Diethylhexyl Phthalate; Dose-Response Relationship, Drug; Glutathione Peroxidase; Male; Malondialdehyde; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Sexual Maturation; STAT3 Transcription Factor; Superoxide Dismutase; Testis; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53