Mitochondrion-mediated apoptosis is involved in reproductive damage caused by BPA in male rats

Wang, Peng; Luo, Chunxiong; Li, Qianyuan; Sai, Chen; Hu, Yong

doi:10.1016/j.etap.2014.10.018

Cited by 71 publications

(34 citation statements)

References 22 publications

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“…Mitochondria are critical for the maintenance of β -cell function coupling glucose stimulus to insulin release 47, 48 and are targets of BPA toxicity. 32, 49 Moreover, alterations in mitochondrial dynamics have been reported among the mechanisms underlying the development of T2D and obesity. 50 Indeed, recent studies indicated that BPA exposure could cause profound mitochondrial structural defects and decrease of mitochondrial activity in pancreatic islets.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity

et al. 2015

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Epidemiologic and experimental studies have associated changes of blood glucose homeostasis to Bisphenol A (BPA) exposure. We took a toxicogenomic approach to investigate the mechanisms of low-dose (1 × 10−9 M) BPA toxicity in ex vivo cultures of primary murine pancreatic islets and hepatocytes. Twenty-nine inhibited genes were identified in islets and none in exposed hepatocytes. Although their expression was slightly altered, their impaired cellular level, as a whole, resulted in specific phenotypic changes. Damage of mitochondrial function and metabolism, as predicted by bioinformatics analyses, was observed: BPA exposure led to a time-dependent decrease in mitochondrial membrane potential, to an increase of ROS cellular levels and, finally, to an induction of apoptosis, attributable to the bigger Bax/Bcl-2 ratio owing to activation of NF-κB pathway. Our data suggest a multifactorial mechanism for BPA toxicity in pancreatic islets with emphasis to mitochondria dysfunction and NF-κB activation. Finally, we assessed in vitro the viability of BPA-treated islets in stressing condition, as exposure to high glucose, evidencing a reduced ability of the exposed islets to respond to further damages. The result was confirmed in vivo evaluating the reduction of glycemia in hyperglycemic mice transplanted with control and BPA-treated pancreatic islets. The reported findings identify the pancreatic islet as the main target of BPA toxicity in impairing the glycemia. They suggest that the BPA exposure can weaken the response of the pancreatic islets to damages. The last observation could represent a broader concept whose consideration should lead to the development of experimental plans better reproducing the multiple exposure conditions.

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Section: Discussionmentioning

confidence: 99%

Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity

et al. 2015

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“…In studies by Wang et al . () it was found that BPA exposure (50, 100 or 200 mg of BPA kg −1 bw; in corn oil) could change the levels of apoptotic signaling, cause morphological changes in the mitochondria, and affect the function of the reproductive system in male Sprague–Dawley rats. On the other hand, Ema et al .…”

Section: Effect Of Bisphenol a On Male Reproductive Processes And Fermentioning

confidence: 99%

“…Chitra et al (2003) conducted a study on Wistar rats in which they showed that BPA (0.2, 2, 20 μg kg À1 bw per 45 day À1 ), apart from causing a decrease (P < 0.05) in testis/epididymis weight and a reduction (P < 0.05) in sperm motility (which directly translates into deterioration of semen quality), also induced an increase of oxidative stress in semen in comparison to the control group. In studies by Wang et al (2014b) it was found that BPA exposure (50, 100 or 200 mg of BPA kg À1 bw; in corn oil) could change the levels of apoptotic signaling, cause morphological changes in the mitochondria, and affect the function of the reproductive system in male Sprague-Dawley rats. On the other hand, Ema et al (2001) found no harmful activity of BPA in a twogeneration rat reproduction study using International Genetic Standard rats, which were subjected to oral administration of 0.2, 2, 20 or 200 μg kg À1 day À1 of BPA by gastric intubation.…”

Section: Effect Of Bisphenol a On Male Reproductive Processes And Fermentioning

confidence: 99%

Effect of bisphenol A on reproductive processes: A review of in vitro, in vivo and epidemiological studies

Tomza–Marciniak

Stępkowska

Kuba

et al. 2017

J of Applied Toxicology

117

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As bisphenol A (BPA) is characterized by a pronounced influence on human hormonal regulation, particular attention has been aimed at understanding its role in reproductive processes in males and females, as well as on fetal development. Owing to the increasing number of alarming reports on the negative consequences of the presence of BPA in human surroundings, more and more studies are being undertaken to clarify the negative effects of BPA on human reproductive processes. The aim of this work was to collect and summarize data on the influence of BPA exposure on reproductive health. Based on an analysis of selected publications it was stated that there is strong proof confirming that BPA is an ovarian, uterine and prostate toxicant at a level below the lowest observed adverse effect level (50 mg kg À1 bodyweight) as well as a level below the proposed safe level (4 μg kg À1 bodyweight). It seems there is also reliable evidence in relation to the negative effect of BPA on sperm quality and motility. Limited evidence also pertains to the case of the potential of BPA to affect polycystic ovary syndrome occurrence. Although in epidemiological studies this disease was common, in studies on animal models such results were still not confirmed. No unambiguous results of epidemiological studies and with animal models were obtained in relation to the evaluation of associations between BPA and implantation failure in women, evaluation of associations between BPA and sexual dysfunction in men, and impact of BPA on birth rate, birth weight and length of gestation.

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“…), which markedly affects the development of testicular germ cells (Wang et al. ). Hence, spermatogenesis and sperm production increase the expression of Fas, FasL and active caspase‐3, which is accompanied by an increase in the phosphorylation of JNKs/p38 MAPK and nuclear factor kappa B (NF‐κB) translocation (Qi et al.…”

Section: Discussionmentioning

confidence: 99%

Sequential testicular atrophy involves changes in cellular proliferation and apoptosis associated with variations in aromatase P450 expression levels in Irs‐2‐deficient mice

et al. 2018

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Insulin receptor substrate 2 (Irs‐2) is an intracellular protein susceptible to phosphorylation after activation of the insulin receptor. Its suppression affects testis development and its absence induces peripheral resistance to insulin. The aim of this study was to identify changes induced by the deletion of Irs‐2 in the testicular structure and by the altered expression of cytochrome P450 aromatase, a protein necessary for the development and maturation of germ cells. Adult knockout (KO) mice (Irs‐2−/−, 6 and 12 weeks old) and age‐matched wild‐type (WT) mice were used in this study. Immunohistochemistry and Western blot analyses were performed to study proliferation (PCNA), apoptosis (active caspase‐3) and P450 aromatase expression in testicular histological sections. Deletion of Irs‐2 decreased the number of epithelial cells in the seminiferous tubule and rete testis. Aberrant cells were frequently detected in the epithelia of Irs‐2−/− mice, accompanied by variations in spermatogonia, which were shown to exhibit small hyperchromatic nuclei as well as polynuclear and anuclear structures. The amount of cell proliferation was significantly lower in Irs‐2−/− mice than in WT mice, whereas apoptotic processes were more common in Irs‐2−/− mice. Aromatase P450 reactivity was higher in 6‐week‐old KO mice than in WT mice of the same age and was even higher at 12 weeks. Our results suggest that Irs‐2 is a key element in spermatogenesis because silencing Irs‐2 induces the sequential development of testicular atrophy. The effects are observed mainly in germ cells present in the seminiferous tubule, which may be due to changes in cytochrome P450 aromatase expression.

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Mitochondrion-mediated apoptosis is involved in reproductive damage caused by BPA in male rats

Cited by 71 publications

References 22 publications

Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity

Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity

Effect of bisphenol A on reproductive processes: A review of in vitro, in vivo and epidemiological studies

Sequential testicular atrophy involves changes in cellular proliferation and apoptosis associated with variations in aromatase P450 expression levels in Irs‐2‐deficient mice

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