DEHP exposure destroys blood-testis barrier (BTB) integrity of immature testes through excessive ROS-mediated autophagy

Abstract

Di-(2-ethylhexyl) phthalate (DEHP), is known to impair testicular functions and reproduction. However, its effects on immature testis Blood-testis barrier (BTB) and the underlying mechanisms remain obscure. We constructed a rat model to investigate the roles of autophagy in BTB toxicity induced by DEHP. Sprague–Dawley rats were developmentally exposed to 0, 250 and 500 mg/kg DEHP via intragastric administration from postnatal day (PND) 1 to PND 35. Testicular morphology, expressions of BTB junction proteins and autophagy related proteins were detected. In addition, expressions of oxidative stress markers were also analyzed. Our results demonstrated that developmental DEHP exposure induced decreasing organ coefficients of immature testes and severe testicular damage in histomorphology. The expressions of junctional proteins were down-regulated significantly after DEHP treatment. Intriguingly, DEHP simultaneously increased the number of autophagosomes and the levels of autophagy marker LC3-II and p62, suggesting that the accumulated autophagosomes resulted from impaired autophagy degradation. Moreover, the expressions of HO-1 and SOD levels remarkably decreased after DEHP exposure. Vitamins E and C could alleviate the DEHP-induced oxidative stress, reverse the autophagy defect and restore the BTB impairment. Taken together, DEHP exposure destroys immature testis blood-testis barrier (BTB) integrity through excessive ROS-mediated autophagy.

Autophagy Induced by ROS Aggravates Testis Oxidative Damage in Diabetes via Breaking the Feedforward Loop Linking p62 and Nrf2

“…And under a variety of pathological conditions, the relative excessive accumulation of ROS can induce autophagy [21][22][23][24]. In previous animal model studies, it has also been confirmed that in the testis, excessive production of ROS can induce autophagy [25][26][27]. Therefore, in this review, we speculate that in diabetes, excessive production of ROS can induce autophagy in the testis.…”

“…The BTB consisting of tight junctions, adherens junctions, and gap junctions between adjoining SCs plays a key role in the spermatogenesis microenvironment and is a wellknown premise of spermatogenesis [91][92][93]. Yi et al have proved that the accumulation of autophagosome affects the integrity of BTB, which finally contributes to spermatogenesis disturbance, accumulation of damaged mitochondria, and infertility [26]. Therefore, reducing autophagy induced by ROS may become an effective method for preventing male infertility in diabetic patients.…”

“…Therefore, in this review, we speculate that in diabetes, excessive production of ROS can induce autophagy in the testis. A series of studies have confirmed that abnormal autophagy can cause abnormalities in the complex and highly ordered sperm cell differentiation process, such as acrosome biogenesis and sperm differentiation defects [28,29], decreased serum testosterone levels [30], and SC apoptosis and BTB damage [26,31]. The phosphatidylinositol 3kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is a target of oxidative stress [32].…”

Cardamonin exerts a protective effect against autophagy and apoptosis in the testicles of diabetic male rats through the expression of Nrf2 via p62-mediated Keap-1 degradation

“…Autophagy is a lysosomal degradation pathway in cells, and it plays a very important role in eliminating cytotoxic protein aggregates and damaged organelles to maintain intracellular homeostasis [ 46 ]. However, previous experimental studies have confirmed that excessive testicular production of ROS can induce an abnormal increase in autophagy, which can contribute to diabetic testicular injury [ 47 - 49 ]. Consistent with Su and his coworkers’ study [ 50 ], we found that expression of the autophagic markers LC3 and beclin-1 was significantly upregulated in untreated diabetic rats.…”

Chitosan-Stabilized Selenium Nanoparticles and Metformin Synergistically Rescue Testicular Oxidative Damage and Steroidogenesis-Related Genes Dysregulation in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

“…Increased ROS in diabetes also has a major impact on sperm, because of the presence in the cell membrane of various polyunsaturated fatty acids [ 59 ]. In recent years, increasing evidence has shown that ROS release with hyperglycemia can interrupt the blood-testis barrier and worsen sperm dysfunction [ 60 , 61 ]. The negative effects of T2DM on sperm development and characteristics in the present study comply with previous studies [ 62 , 63 ].…”