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Organ coefficient information after DEHP exposure in different groups. Values are expressed as mean AE SD, n Z 6.
Source publication
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 expo...
Contexts in source publication
Context 1
... coefficient of rats after treatment Table 1 showed a significantly decrease in organ coefficients of testis, epididymis as well as seminal vesicle in the DEHP- treated group (P < 0.05) ( Table 1, Fig. 1. A, B, C and D). ...
Citations
... In times of stress, the upregulation of autophagy enables the cell to acclimate to changing surroundings and ensure its survival [41]. Nonetheless, excessive autophagy can result in the excessive consumption of proteins, harm to cell organelles, and impairment of cellular function, ultimately leading to defects in spermatogenesis and damage to the BTB [42][43][44]. This discovery implies that the status of autophagy may differ under different treatments. ...
Background
The management of male infertility continues to encounter an array of challenges and constraints, necessitating an in-depth exploration of novel therapeutic targets to enhance its efficacy. As an eight-carbon medium-chain fatty acid, octanoic acid (OCA) shows promise for improving health, yet its impact on spermatogenesis remains inadequately researched.
Methods
Mass spectrometry was performed to determine the fatty acid content and screen for a pivotal lipid component in the serum of patients with severe spermatogenesis disorders. The sperm quality was examined, and histopathological analysis and biotin tracer tests were performed to assess spermatogenesis function and the integrity of the blood-testis barrier (BTB) in vivo. Cell-based in vitro experiments were carried out to investigate the effects of OCA administration on Sertoli cell dysfunction. This research aimed to elucidate the mechanism by which OCA may influence the function of Sertoli cells.
Results
A pronounced reduction in OCA content was observed in the serum of patients with severe spermatogenesis disorders, indicating that OCA deficiency is related to spermatogenic disorders. The protective effect of OCA on reproduction was tested in a mouse model of spermatogenic disorder induced by busulfan at a dose 30 mg/kg body weight (BW). The mice in the study were separated into distinct groups and administered varying amounts of OCA, specifically at doses of 32, 64, 128, and 256 mg/kg BW. After evaluating sperm parameters, the most effective dose was determined to be 32 mg/kg BW. In vivo experiments showed that treatment with OCA significantly improved sperm quality, testicular histopathology and BTB integrity, which were damaged by busulfan. Moreover, OCA intervention reduced busulfan-induced oxidative stress and autophagy in mouse testes. In vitro, OCA pretreatment (100 µM) significantly ameliorated Sertoli cell dysfunction by alleviating busulfan (800 µM)-induced oxidative stress and autophagy. Moreover, rapamycin (5 µM)-induced autophagy led to Sertoli cell barrier dysfunction, while OCA administration exerted a protective effect by alleviating autophagy.
Conclusions
This study demonstrated that OCA administration suppressed oxidative stress and autophagy to alleviate busulfan-induced BTB damage. These findings provide a deeper understanding of the toxicology of busulfan and a promising avenue for the development of novel OCA-based therapies for male infertility.
... 18 The integrity of the bloodetestis barrier was impaired in premature rat testes after DEHP exposure. 19 Additionally, prepubertal exposure to DEHP caused apoptosis and inhibited the proliferation of both Leydig cells and Sertoli cells via the p53 signaling pathway. 20 Ferroptosis is also involved in somatic cell death in the testis. ...
... The dosage of DEHP and sample sizes of the groups were based on our previous studies. 19,22 No data points or rats were excluded. Gross morphology, western blotting, HE staining, and immunofluorescence analyses were employed to measure the main outcomes. ...
... Thus, the feedforward loop connecting P62 and Nrf2 is destroyed, the antioxidant capacity of testis is reduced, and the oxidative stress of testis is further aggravated, forming a vicious circulation (Tian et al. 2020). Autophagy causes extensive damage to the male reproductive system, such as inhibiting testicular Leydig cells, reducing serum testosterone levels (Zhao et al. 2018), inhibiting proliferation of supporting cells (Duan et al. 2016), and disrupting the integrity of the blood-testicular barrier (BTB) (Yi et al. 2018). In addition, inhibition of PI3/AKT/mTOR signaling pathway can inhibit the expression of p70S6K in sperm, resulting in sperm deformation and deformity, and can lead to reduced sperm parameters and motor activity, and even affect epididymal function (Xu et al. 2016). ...
Male infertility is a physiological phenomenon in which a man is unable to impregnate a fertile woman during a 12-month period of continuous, unprotected sexual intercourse. A growing body of clinical and epidemiological evidence indicates that the increasing incidence of male reproductive problems, especially infertility, shows a very similar trend to the incidence of diabetes within the same age range. In addition, a large number of previous in vivo and in vitro experiments have also suggested that the complex pathophysiological changes caused by diabetes may induce male infertility in multiple aspects, including hypothalamic-pituitary–gonadal axis dysfunction, spermatogenesis and maturation disorders, testicular interstitial cell damage erectile dysfunction. Based on the above related mechanisms, a large number of studies have focused on the potential therapeutic association between diabetes progression and infertility in patients with diabetes and infertility, providing important clues for the treatment of this population. In this paper, we summarized the research results of the effects of diabetes on male reproductive function in recent 5 years, elaborated the potential pathophysiological mechanisms of male infertility induced by diabetes, and reviewed and prospected the therapeutic measures.
... Consistent with previous studies [36,37], we found that HS impaired testicular function as indicated by the testis index, sperm count and motility, histologic injury, and impaired BTB function in our HS mouse model. The BTB, which contains tight junction, gap junction, and adherens junction proteins, plays a crucial role in spermatogenesis by maintaining the testicular microenvironment [38,39]. Similar to previous studies [40,41], HS decreased the expression of tight junction proteins (occludin and ZO-1), indicating that HS disrupts BTB integrity. ...
... However, the mechanisms associated with infertility are not completely understood. Spermatogenesis and male reproductive health require a stable testicular microenvironment (Yi et al., 2018). The blood-testes barrier (BTB) between neighbouring Sertoli cells is composed of tight junctions (TJ), gap junctions (GJ), and basal ectoplasmic specializations (ES). ...
Background: Aflatoxins are food-contaminating metabolites that can intoxicate and damage multiple organs. This study compared the effects of aflatoxin powder (AFB) and aflatoxin liquid (AFS) administrations on the testes and lungs of rats and elaborated their potential activity mechanisms.Methods: Fifteen rats were equally divided into 3 groups. The AFB and AFS groups were orally administered with aflatoxin B1 powder (0.5 mg/kg) and aflatoxin B1 liquid (0.5 mg/kg) for 21 days. The control group was fed on a basal pellet diet and water. The body weights of the rats were measured at the beginning of the trial and on the 7th, 14th, and 21st days. Blood samples were withdrawn at the end of the experiments and examined for complete blood count (CBC) [red blood cells (RBCs), hemoglobin content, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), white blood cells (WBCs), and platelet, neutrophil, monocyte, lymphocyte, basophil, and eosinophil counts]. The levels of oxidative stress biomarkers, e.g. malonaldehyde (MDA) and nitric oxide (NO), and serum testosterone were determined. Testes and lungs were examined under a light microscope to assess the aflatoxin B1-induced histopathological changes.Results: The weight gain and its percentages were significantly high in the AFS group than AFB group (P <0.050). Neutrophil, lymphocyte, monocyte, and basophil counts were also significantly increased in AFB and AFS groups in comparison to the controls. A significant increase in eosinophil count was noted in the AFB group as compared to controls whereas lymphocyte count remained significantly high in the AFS group than AFB group. Testosterone serum levels significantly decreased in both groups (AFB and AFS) as compared to the control group. MDA and NO serum levels were also significantly high in the AFS group than the AFB group whereas the levels of both groups (AFB and AFS) were higher than in controls. Histological examinations of the testes revealed severe testicular damage, loss of the spermatogenesis process, necrosis, degeneration, shrinkage, and atrophy of seminiferous tubules in both AFB and AFS groups. Histological observations of the lungs depicted large numbers of inflammatory cells, mast cell infiltration, dilated alveolar sacs with exudates, and marked hemorrhages in both groups (AFB and AFS). The histological damages of the testes and lungs were more prominent in the AFS group than AFB group.Conclusion: The results demonstrated elevated oxidative stress markers and reduced serum testosterone levels in AFB and AFS-treated rats. Both studied organs (testes and lung) were severely damaged with more obvious changes in AFS treated group than in AFB treated group.
... Reproductive damage brought on by environmental pollution is significantly influenced by oxidative stress [46]. It has been reported that ROS can disrupt the integrity of BTB and lead to reproductive toxicity [47]. In addition, it has been investigated that some environmental toxicants, such as DEHP, PM2. 5, can cause oxidative stress, which increases ROS, to activate the p38 MAPK signaling pathway, which directly impairs the integrity of BTB [48]. ...
Nickel (Ni) is an essential common environmental contaminant, it is hazardous to male reproduction, but the precise mechanisms are still unknown. Blood-testis barrier (BTB), an important testicular structure consisting of connections between sertoli cells, is the target of reproductive toxicity caused by many environmental toxins. In this study, ultrastructure observation and BTB integrity assay results indicated that NiCl2 induced BTB damage. Meanwhile, BTB-related proteins including the tight junction (TJ), adhesion junction (AJ) and the gap junction (GJ) protein expression in mouse testes as well as in sertoli cells (TM4) were significantly decreased after NiCl2 treatment. Next, the antioxidant N-acetylcysteine (NAC) was co-treated with NiCl2 to study the function of oxidative stress in NiCl2-mediated BTB deterioration. The results showed that NAC attenuated testicular histopathological damage, and the expression of BTB-related proteins were markedly reversed by NAC co-treatment in vitro and vivo. Otherwise, NiCl2 activated the p38 MAPK signaling pathway. And, NAC co-treatment could significantly inhibit p38 activation induced by NiCl2 in TM4 cells. Furthermore, in order to confirm the role of the p38 MAPK signaling pathway in NiCl2-induced BTB impairment, a p38 inhibitor (SB203580) was co-treated with NiCl2 in TM4 cells, and p38 MAPK signaling inhibition significantly restored BTB damage induced by NiCl2 in TM4 cells. These results suggest that NiCl2 treatment destroys the BTB, in which the oxidative stress-mediated p38 MAPK signaling pathway plays a vital role.
... The DEHP metabolite mono(2-ethylhexyl) phthalate (MEHP) is a potent oxidative stress factor and is thought to be an active toxicant involved in testicular damage [18][19][20][21][22]. For this reason, free-radical scavenging agents which protects the testis against inflammation and reactive oxygen species generation are considered to be effective as prophylactic agent. ...
... Most orally administered DEHP is hydrolyzed in the gastrointestinal tract of rats [24] and distributed as MEHP in the body. MEHP, a potent oxidative stressor, damages Sertoli cells after reaching the testis and induces germ cell apoptosis [18][19][20][21][22][23]. This results in testicular atrophy. ...
Contamination with the plasticizer di(2-ethylhexyl) phthalate (DEHP) is widespread worldwide. DEHP has been found to have testicular toxicity in animal experiments, and is suspected to be reproductively toxic to mammals, including humans. Therefore, it is important to explore the effects of prophylaxis on DEHP-induced reproductive toxicity, such as testicular atrophy. The DEHP metabolite mono(2-ethylhexyl) phthalate (MEHP) is a potent oxidative stress factor and is thought to be an active toxicant involved in testicular damage. For this reason, free radical scavengers that protect the testis from inflammation and generation of reactive oxygen species are considered to be effective prophylactic agent. The authors discuss the efficacy of several free radical scavengers in preventing testicular atrophy. The efficacy of these free radical scavengers was revealed in a DEHP mixed diet exposure experiment. Examples include nicotinic acid, caffeine, ethanol, and the rare sugar D-allulose.
... Moderate doses were selected by looking at the Ld50 values and also by reading literature where these doses were reported in several studies [23][24][25] . Desired dose (500 mg/kg of body weight) of DEHP (provided by Sigma-Aldrich (99%)) was prepared in corn oil. ...
... Therefore, controlling the p62 protein levels may provide a potential target for therapeutic intervention against symptoms of schizophrenia [22]. Interestingly, Di-(2-ethylhexyl) phthalate (DEHP) could simultaneously increase the number of autophagosomes and the levels of autophagy marker p62, which is known to impair testicular functions and reproduction [25]. DEHP has the ability to cross the blood-placenta and blood-brain barriers, which could increase the proliferation of astrocytes [26]. ...
Neuropsychiatric disorders are globally public-health concern, in which diagnosis might be based on symptoms that often vary across individuals. Schizophrenia is one of the major neuropsychiatric disorders, which may affect millions worldwide. Detection of predictive biomarkers is the most intensively developing approach for the disease. However, the biochemical alterations have not been comprehensively distinguished up to the present time. In addition, there is less confidence of finding a specific biomarker for neuropsychiatric disorders including schizophrenia, but rather a specific characteristic behavioral pattern. Maternal immune activation has been considered to be one of the important factors for the development of neuropsychiatric disorders. Here, the mouse model of neuropsychiatric disorders has been built, in which poly-I:C, sodium dextran sulfate (DSS) and κ-carrageenan (CGN) were used for the maternal immune activation during the pregnancy of individuals. Subsequently, we challenged to link some of biochemical changes of p62 and GLAST in the offspring mice brain to the alteration of several pathological behaviors. Consequently, it has been shown that autophagy might be involved in the development of neuropsychiatric disorders including schizophrenia. To our knowledge, this is the first report of the significant correlation between pathological behavior and the biochemical alterations in neuropsychiatric disorder model animals. The relative ease of conducting these evaluation-tasks would make them useful for testing novel therapeutics designed to ameliorate the symptoms of several psychiatric disorders.
... Autophagy regulated the BTB's structure and barrier function; di-(2-ethylhexyl) phthalate (DEHP) exposure destroyed rats' BTB integrity, down-regulated junctional proteins, and induced the number of autophagosomes and the levels of autophagy markers LC3-II and p62. Inhibition of autophagy by CQ and 3-MA was sufficient to reduce the effects of DEHP on BTB [39]. Our findings showed that E and M induced autophagy formation ( Figure 4A) but impeded autophagy flux ( Figure 4B). ...
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disrupts the blood-testis barrier (BTB), resulting in alterations in spermatogenesis. However, whether BTB-related proteins (such as ZO-1, claudin11, N-cadherin, and CX43) are targeted by SARS-CoV-2 remains to be clarified. BTB is a physical barrier between the blood vessels and the seminiferous tubules of the animal testis, and it is one of the tightest blood-tissue barriers in the mammalian body. In this study, we investigated the effects of viral proteins, via ectopic expression of individual viral proteins, on BTB-related proteins, the secretion of immune factors, and the formation and degradation of autophagosomes in human primary Sertoli cells. Our study demonstrated that ectopic expression of viral E (envelope protein) and M (membrane protein) induced the expressions of ZO-1 and claudin11, promoted the formation of autophagosomes, and inhibited autophagy flux. S (spike protein) reduced the expression of ZO-1, N-cadherin, and CX43, induced the expression of claudin11, and inhibited the formation and degradation of autophagosomes. N (nucleocapsid protein) reduced the expression of ZO-1, claudin11, and N-cadherin. All the structural proteins (SPs) E, M, N, and S increased the expression of the FasL gene, and the E protein promoted the expression and secretion of FasL and TGF-β proteins and the expression of IL-1. Blockage of autophagy by specific inhibitors resulted in the suppression of BTB-related proteins by the SPs. Our results indicated that SARS-CoV-2 SPs (E, M, and S) regulate BTB-related proteins through autophagy.
