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Bisphenol AF blocks Leydig cell regeneration from stem cells in male rats
2022
Yu, Yige | Xin, Xiu | Ma, Feifei | Li, Xiaoheng | Wang, Yiyan | Zhu, Qiqi | Chen, Haiqiong | Li, Huitao | Ge, Ren-shan
Bisphenol A (BPA) is a ubiquitous environmental pollutant, mainly from the manufacture and use of plastics. The use of BPA is restricted, and its new analogs (including bisphenol AF, BPAF) are being produced to replace it. However, the effect of BPAF on the male reproductive system remains unclear. Here, we report the effect of BPAF on Leydig cell regeneration in rats. Leydig cells were eliminated by ethane dimethane sulfonate (EDS, i.p., 75 mg/kg) and the regeneration began 14 days after its treatment. We gavaged 0, 10, 100, and 200 mg/kg BPAF to rats on post-EDS day 7–28. BPAF significantly reduced serum testosterone and progesterone levels at ≧10 mg/kg. It markedly reduced serum levels of estradiol, luteinizing hormone, and follicle-stimulating hormone at 100 and 200 mg/kg. BPAF significantly reduced Leydig cell number at 200 mg/kg. BPAF significantly down-regulated the expression of Cyp17a1 at doses of 10 mg/kg and higher and the expression of Insl3, Star, Hsd17b3, Hsd11b1 in Leydig cells at 100 and 200 mg/kg, while it induced a significant up-regulation of Fshr, Dhh, and Sox9 in Sertoli cells at 200 mg/kg. BPAF induced oxidative stress and reduced the level of SOD2 at 200 mg/kg. It induced apoptosis and autophagy by increasing the levels of BAX, LC3B, and BECLIN1 and lowering the levels of BCL2 and p62 at 100 and 200 mg/kg. It induced autophagy possibly via decreasing the phosphorylation of AKT1 and mTOR. BPAF also significantly induced ROS production and apoptosis at a concentration of 10 μM, and reduced testosterone synthesis in rat R2C Leydig cells at a concentration of 10 μM in vitro, but did not affect cell viability after 24 h of treatment. In conclusion, BPAF is a novel endocrine disruptor, inhibiting the regeneration of Leydig cells.
اظهر المزيد [+] اقل [-]Pubertal Bisphenol A exposure increases adult rat serum testosterone by resetting pituitary homeostasis
2022
Chen, Dan | Zhao, Xingyi | Huang, Fu | Guan, Xiaoju | Tian, Jing | Ji, Minpeng | Wen, Xin | Shao, Jingjing | Xie, Jiajia | Wang, Jiexia | Chen, Haolin
Bisphenol A (BPA) is widely used by manufacturers and in consumer products. Its release in the environment may affect male reproductive function. In this study, we examined the effect of low dose (0.1 mg/kg BW), short term exposure during puberty (PD21-35) on adult rat male reproduction. The results indicated that such exposure reset growth hormone (GH) and follicular stimulating hormone (FSH) homeostasis and resulted in a significantly higher level of serum testosterone without affecting serum luteinizing hormone level. QPCR and Western blot results showed that BPA significantly up-regulated selective genes/proteins in the Leydig cell steroidogenic pathway, including steroidogenic acute regulatory protein, cytochrome P450 11A1, cytochrome P450 17A, and low-density lipoprotein receptor. RNA-Seq analysis of testicular RNAs showed that BPA significantly affected the gene profiles of multiple testicular interstitial populations without affecting germ cells. Also, GO- and KEGG-analysis suggested that IGF1-related PI3K/AKT signaling was activated, which was confirmed by the increased phosphorylation of IRS1, AKT1 and CREB. The results indicated that a low-dose, short-term BPA exposure during puberty affected the adult male rat pituitary (GH and FSH) and testis (testosterone) homeostasis.
اظهر المزيد [+] اقل [-]Regioselective hydroxylation of carbendazim by mammalian cytochrome P450: A combined experimental and computational study
2022
Lv, Xia | Li, Jing-Xin | Wang, Jia-Yue | Tian, Xiang-Ge | Feng, Lei | Sun, Cheng-Peng | Ning, Jing | Wang, Chao | Zhao, Wen-Yu | Li, Ya-Chen | Ma, Xiao-Chi
Carbendazim (CBZ), a broad-spectrum pesticide frequently detected in fruits and vegetables, could trigger potential toxic risks to mammals. To facilitate the assessment of health risks, this study aimed to characterize the cytochrome P450 (CYPs)-mediated metabolism profiles of CBZ by a combined experimental and computational study. Our results demonstrated that CYPs-mediated region-selective hydroxylation was a major metabolism pathway for CBZ in liver microsomes from various species including rat, mouse, minipig, dog, rabbit, guinea pig, monkey, cow and human, and the metabolite was biosynthesized and well-characterized as 6-OH-CBZ. CYP1A displayed a predominant role in the region-selective hydroxylation of CBZ that could attenuate its toxicity through converting it into a less toxic metabolite. Meanwhile, five other common pesticides including chlorpyrifos-methyl, prochloraz, chlorfenapyr, chlorpyrifos, and chlorothalonil could significantly inhibit the region-selective hydroxylation of CBZ, and consequently remarkably increased CBZ exposure in vivo. Furthermore, computational study clarified the important contribution of the key amino acid residues Ser122, and Asp313 in CYP1A1, as well as Asp320 in CYP1A2 to the hydroxylation of CBZ through hydrogen bonds. These results would provide some useful information for the metabolic profiles of CBZ by mammalian CYPs, and shed new insights into CYP1A-mediated metabolic detoxification of CBZ and its health risk assessment.
اظهر المزيد [+] اقل [-]PM2.5 induces pulmonary microvascular injury in COPD via METTL16-mediated m6A modification
2022
Guo, Xiaolan | Lin, Yuyin | Lin, Yingnan | Zhong, Yue | Yu, Hongjiao | Huang, Yibin | Yang, Jingwen | Cai, Ying | Liu, FengDong | Li, Yuanyuan | Zhang, Qian-Qian | Dai, Jianwei
Fine particulate matter (PM2.5) exposure is a significant cause of chronic obstructive pulmonary disease (COPD), but the detailed mechanisms involved in COPD remain unclear. In this study, we established PM2.5-induced COPD rat models and showed that PM2.5 induced pulmonary microvascular injury via accelerating vascular endothelial apoptosis, increasing vascular permeability, and reducing angiogenesis, thereby contributing to COPD development. Moreover, microvascular injury in COPD was validated by measurements of plasma endothelial microparticles (EMPs) and serum VEGF in COPD patients. We then performed m⁶A sequencing, which confirmed that altered N⁶-methyladenosine (m⁶A) modification was induced by PM2.5 exposure. The results of a series of experiments demonstrated that the expression of methyltransferase-like protein 16 (METTL16), an m⁶A regulator, was upregulated in PM2.5-induced COPD rats, while the expression of other regulators did not differ upon PM2.5-induction. To clarify the regulatory effect of METTL16-mediated m⁶A modification induced by PM2.5 on pulmonary microvascular injury, cell apoptosis, permeability, and tube formation, the m⁶A level in METTL16-knockdown pulmonary microvascular endothelial cells (PMVECs) was evaluated, and the target genes of METTL16 were identified from a set of the differentially expressed and m⁶A-methylated genes associated with vascular injury and containing predicted sites of METTL16 methylation. The results showed that Sulfatase 2 (Sulf2) and Cytohesin-1 (Cyth1) containing the predicted METTL16 methylation sites, exhibited higher m⁶A methylation and were downregulated after PM2.5 exposure. Further studies demonstrated that METTL16 may regulate Sulf2 expression via m⁶A modification and thereby contribute to PM2.5-induced microvascular injury. These findings not only provide a better understanding of the role played by m⁶A modification in PM2.5-induced microvascular injury, but also identify a new therapeutic target for COPD.
اظهر المزيد [+] اقل [-]Dysregulation of NrF2 expression mediates testicular injury and infertility in 3-monochloro-1,2-propandiol-intoxicated rats with special reference to accessory gland–related pathology
2022
Moustafah, Yousrah | Mohammed, Faten F. | Elmosalamy, Shereef | Ibrahim, Marwa A. | F.Tohamy, Adel | Hassan, Nabiha Ramadan A.
3-Monochloropropane-1,2-diol (3-MCPD) is a food contaminant formed during acid hydrolysis of vegetable proteins. The toxicological evaluation of smaller doses of 3-MCPD is essential for safety evaluation of this compound. The present study investigates the toxicologic potential of 3-MCPD on male genital organs of rats, applies a correlation between the induced infertility and developed lesions in testes, epididymis, and accessory glands and study the possible mechanisms of 3-MCPD-induced male infertility. Forty rats were randomly divided into four main groups of ten animals each: the control untreated group and three treated groups that were orally administered 3-MCPD at different doses (3, 7.5 and 15 mg/kg b.w) daily via stomach intubation for five successive days per week. Five rats from each group were euthanized after 30 days. The remaining rats were euthanized after 90 days to establish subacute and chronic toxicity studies. Oxidative stress markers, Nrf2 gene expression, semen analysis, and histopathological examination were performed at the end of each experimental period. Results indicated that 3-MCPD induces infertility in male rat via disruption of Nrf2 expression in the testicular tissue with subsequent increased oxidative stress indicators in the testis that affect spermatogenesis and induced testicular degeneration, in addition, induction of epididymal lesions that affect sperm motility and concentration and finally possible development of hyperplastic tissue reactions in accessory glands of intoxicated rats predicting the carcinogenic potential of this compound.
اظهر المزيد [+] اقل [-]Therapeutic effect of dithiophenolato chitosan nanocomposites against carbon tetrachloride-induced hepatotoxicity in rats
2022
Shaban, Nadia Z. | Aboelsaad, Ahmed M. | Awad, Doaa | Abdulmalek, Shaymaa A. | Shaban, Shaban Y.
Our previous study showed that dithiophenolate (DTP) and its chitosan nanoparticles (DTP-CSNPs) have abilities to bind with DNA helixes. So in this study, their lethal doses (LD₅₀) and therapeutic roles against rat liver injuries induced by carbon tetrachloride (CCl₄) were evaluated. The study focused on the determination of the markers of oxidative stress (OS) and apoptosis and compare the results with those of cisplatin treatment. The results revealed that LD₅₀ values of DTP and DTP-CSNPs are 2187.5 and 1462.5 mg/kg, respectively. Treatment with DPT and DPT-CSNPs after CCl₄ administration reduced liver injuries, induced by CCl₄, and improved liver functions and architecture through the reduction of OS and apoptosis. Where the oxidant marker was decreased with elevations of antioxidant markers. Also, there was an elevation in Bcl-2 value, with decreases in caspase-8, Bax, and Bax/Bcl-2 ratio. DPT-CSNPs treatment gave preferable results than those treated with DPT. Moreover, DTP and DPT-CSNPs treatment gave better results than cisplatin treatment. The administration of healthy rats with low doses of DTP and DTP-CSNPs for 14 days had no effect. Otherwise, the study on HepG2 cell line showed that DTP and DPT-CSNPs inhibited cell growth by arresting cells in the G2/M phase and inducing cell death. In conclusion, DTP and DTP-CSNPs have antiapoptotic and anti-oxidative stress toward hepatotoxicity induced by CCl₄. Moreover, DTP and DTP-CSNPs have anticancer activity against the HepG2 cell line. Generally, DTP-CSNPs are more effective than DTP. So, they can be used in the pharmacological fields, especially DTP-CSNPs.
اظهر المزيد [+] اقل [-]The effectiveness of vitamin C on quinalphos ileal toxicity: a study of histological, ultrastructural, and oxidative stress markers
2022
Zaki, Mohamed Samir Ahmed | El-kott, Attalla F. | AlGwaiz, Hussah I. M. | Sideeg, Abulqasim M. | Andarawi, Mohamed | Eid, Refaat A.
There is a significant hazard of human exposure to the organophosphates which is a constant threat, and they are responsible for numerous cases of poisoning and mammalian toxicity annually in non-target wildlife. The antioxidants, including the vitamin C (Vit C), have a protective effect on some organophosphorus compounds-induced organ damage. Quinalphos (QP) is one of these compounds. The investigation’s objective is to see if there was any effect of QP on the rat ileum which could be rectified by using Vit C. Three groups of 24 animals were created. As a control, the first group was given pure water. Second group subjected to oral gavages of QPs. Third group rats were given oral gavages of Vit C plus QPs for 10 days. The reaction of ileal enterocytes to food-borne QPs was marked by poorly organized microvilli, numerous vacuoles within them, disrupted nuclei with chromatin margination, disoriented mitochondria, and an expanded intercellular space. The absorptive columnar cell illustrated many vacuoles inside with herniation of microvilli, and normal goblet cells were also seen. Many Paneth cells towards the lumen of intestinal gland contained secretory granules of different sizes and shapes. The histological architecture of the ileal mucosa in the QP plus Vit C group was found to be close to those of healthy controls. The outcomes of this study suggest that administering Vit C in rats treated with QPs protects them from ill dysfunction caused by QP.
اظهر المزيد [+] اقل [-]Lead Nitrate Induces Inflammation and Apoptosis in Rat Lungs Through the Activation of NF-κB and AhR Signaling Pathways [Erratum: September 2022, v.29(43), p.64971]
2022
Attafi, Ibraheem M. | Bakheet, Saleh A. | Ahmad, Sheikh F. | Belali, Osamah M. | Alanazi, Fawaz E. | Aljarboa, Suliman A. | AL-Alallah, Ibrahim A. | Korashy, Hesham M.
Lead (Pb) is one of the most frequent hazardous air contaminants, where the lungs are particularly vulnerable to its toxicity. However, the Pb distribution and its impact on lung inflammation/apoptosis and particularly the involvement of nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways in Pb-induced lung toxicity have not yet been fully investigated. Adult male Wistar albino rats were exposed to Pb nitrate 25, 50, and 100 mg/kg b.w. orally for 3 days. The histopathological changes of several rat organs were analyzed using hematoxylin and eosin staining. The concentrations of Pb ion in different organ tissues were quantified using inductive coupled plasma mass spectrometry, while gas chromatography-mass spectrometry was used to identify organic compounds. The changes in the mRNA and protein expression levels of inflammatory and apoptotic genes in response to Pb exposure were quantified by using RT-PCR and Western blot analyses, respectively. Treatment of rats with Pb for three consecutive days significantly increased the accumulation of Pb in lung tissues causing severe interstitial inflammation. Pb treatment also increased the percentage of lung apoptotic cells and modulated apoptotic genes (Bc2, p53, and TGF-α), inflammatory markers (IL-4, IL-10, TNF-α), and oxidative stress biomarkers (iNOS, CYP1A1, EphX) in rat lung tissues. These effects were associated with a significant increase in organic compounds, such as 3-nitrotyrosine and myeloperoxidase, and some inorganic elements, such as selenium. Importantly, the Pb-induced lung inflammation and apoptosis were associated with a proportional increase in the expression of NF-κB and AhR mRNAs and proteins. These findings clearly show that Pb induces severe inflammation and apoptosis in rat lungs and suggest that NF-κB and AhR may play a role in Pb-induced lung toxicity.
اظهر المزيد [+] اقل [-]In vitro toxic interaction of arsenic and hyperglycemia in mitochondria: an important implication of increased vulnerability in pre-diabetics
2022
Kalo, Mersad Bagherpour | Rezaei, Mohsen
Environmental pollutants and lifestyle both contribute to the rapidly increasing prevalence of type 2 diabetes mellitus (T2DM) worldwide. Evidence suggests that exposure to environmental contaminants such as arsenic is associated with impaired glucose metabolism and insulin signaling. In the present study, isolated rat liver mitochondria (1 mg/ml) were co-exposed to low concentration of arsenic trioxide (ATO) (IC₂₅ = 40 µM) and hyperglycemic condition (20, 40, 80, 160 mM glucose or 20, 40, 80, 160 mM pyruvate (PYR)). Mitochondrial dehydrogenase activity (complex II), glutathione content (GSH), reactive oxygen species (ROS), lipid peroxidation, mitochondrial membrane potential (ΔΨ), and mitochondrial swelling were then evaluated in the presence of ATO 40 µM and PYR 40 mM. Unexpectedly, glucose alone (20, 40, 80, 160 mM) had no toxic effect on mitochondria, even at very high concentrations and even when combined with ATO. Interestingly, PYR at low concentrations (≤ 10 mM) has a protective effect on mitochondria, but at higher concentrations (≥ 40 mM) with ATO, it decreased the complex II activity and increased mitochondrial ROS production, lipid peroxidation, GSH depletion, mitochondrial membrane damage, and swelling (p < 0.05). In conclusion, PYR but not glucose increased ATO mitochondrial toxicity even at low concentrations. These results suggest that pre-diabetics with non-clinical hyperglycemia, who are inevitably exposed to low concentrations of arsenic through food and water, may develop mitochondrial dysfunction that accelerates their progression to diabetes over time.
اظهر المزيد [+] اقل [-]Effect of PM2.5 exposure on gestational hypertension, fetal size in preeclampsia-like rats
2022
Gao, Jie | Luo, Mei | Zhao, Shuo | Wang, Hailing | Li, Xuan | Xu, Pili | Ma, Wei | Liu, Chongdong
Studies have shown intriguing associations between gestational PM₂.₅ exposure and preeclampsia (PE), as well as fetal growth restriction (FGR). This study investigated the impact of PM₂.₅ exposure on gestational hypertension and fetal outcome in a preeclampsia-like rat model. Pregnant Sprague Dawley rats were exposed to either filtered (FA) or PM₂.₅-contaminated air during the whole pregnancy period. A PE-like rat model was established by intraperitoneal injection of L-NAME (300 mg/kg) from gestational day (GD) 12 to until GD20. Systolic blood pressure (SBP), weight gain, pup weight and placental weight were measured. The percentages of rat Treg/Th17 cells and Th17-related cytokines were examined by flow cytometry. Gene expression profiles were analyzed by microarray, and the expression of differentially expressed genes was validated by qRT-PCR. The results showed that maternal PM₂.₅ exposure had no effect on SBP but was associated with low birth weight (LBW) and a higher labyrinth/basal zone ratio. The percentages of splenic Th17 cells from the PM₂.₅ group of PE-like rats were higher than those from the FA or PM₂.₅ groups of healthy controls. A significantly decreased Treg/Th17 cell ratio was found in the PM₂.₅ group of PE-like rats. The mRNA expression of Foxp3 was downregulated, while the mRNA expression of RORα and RORγτ was upregulated after PM₂.₅ exposure. Furthermore, we observed that both the mRNA and protein levels of TNF-a, CCL2, CCL3 and CCR1 increased in the PM₂.₅ groups. Our study suggested that systemic inflammation may contribute to the development of FGR associated with PM₂.₅ exposure throughout pregnancy.
اظهر المزيد [+] اقل [-]