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Cadmium-induced immune abnormality is a key pathogenic event in human and rat models of preeclampsia
2016
Zhang, Qiong | Huang, Yinping | Zhang, Keke | Huang, Yanjun | Yan, Yan | Wang, Fan | Wu, Jie | Wang, Xiao | Xu, Zhangye | Chen, Yongtao | Cheng, Xue | Li, Yong | Jiao, Jinyu | Ye, Duyun
With increased industrial development, cadmium is an increasingly important environmental pollutant. Studies have identified various adverse effects of cadmium on human beings. However, the relationships between cadmium pollution and the pathogenesis of preeclampsia remain elusive. The objective of this study is to explore the effects of cadmium on immune system among preeclamptic patients and rats. The results showed that the cadmium levels in the peripheral blood of preeclamptic patients were significantly higher than those observed in normal pregnancy. Based on it, a novel rat model of preeclampsia was established by the intraperitoneal administration of cadmium chloride (CdCl2) (0.125 mg of Cd/kg body weight) on gestational days 9–14. Key features of preeclampsia, including hypertension, proteinuria, placental abnormalities and small foetal size, appeared in pregnant rats after the administration of low-dose of CdCl2. Cadmium increased immunoglobulin production, mainly angiotensin II type 1-receptor-agonistic autoantibodies (AT1-AA), by increasing the expression of activation-induced cytosine deaminase (AID) in B cells. AID is critical for the maturation of antibody and autoantibody responses. In addition, angiotensin II type 1-receptor-agonistic autoantibody, which emerged recently as a potential pathogenic contributor to PE, was responsible for the deposition of complement component 5 (C5) in kidneys of pregnant rats via angiotensin II type 1 receptor (AT1R) activation. C5a is a fragment of C5 that is released during C5 activation. Selectively interfering with C5a signalling by a complement C5a receptor-specific antagonist significantly attenuated hypertension and proteinuria in Cd-injected pregnant rats. Our results suggest that cadmium induces immune abnormalities that may be a key pathogenic contributor to preeclampsia and provide new insights into treatment strategies of preeclampsia.
Show more [+] Less [-]Toxicity assessment of perfluorooctane sulfonate using acute and subchronic male C57BL/6J mouse models
2016
Xing, Jiali | Wang, Gang | Zhao, Jichun | Wang, Eryin | Yin, Boxing | Fang, Dongsheng | Zhao, Jianxin | Zhang, Hao | Chen, Yong Q. | Chen, Wei
Perfluorooctane sulfonate (PFOS) is a principal representative and the final degradation product of several commercially produced perfluorinated compounds. However, PFOS has a high bioaccumulation potential and therefore can exert toxicity on aquatic organisms, animals, and cells. Considering the widespread concern this phenomenon has attracted, we examined the acute and subchronic toxic effects of varying doses of PFOS on adult male C57BL/6 mice. The acute oral LD50 value of PFOS in male C57BL/6J mice was 0.579 g/kg body weight (BW). Exposure to the subchronic oral toxicity of PFOS at 2.5, 5, and 10 mg PFOS/kg BW/day for 30 days disrupted the homeostasis of antioxidative systems, induced hepatocellular apoptosis (as revealed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay), triggered liver injury (as evidenced by the increased serum levels of aspartate aminotransferase, alanine amino transferase, alkaline phosphatase, and gamma-glutamyl transpeptidase and by the altered histology), and ultimately increased the liver size and relative weight of the mice. PFOS treatment caused liver damage but only slightly affected the kidneys and spleen of the mice. This study provided insights into the toxicological effects of PFOS.
Show more [+] Less [-]Excessive apoptosis and defective autophagy contribute to developmental testicular toxicity induced by fluoride
2016
Zhang, Shun | Niu, Qiang | Gao, Hui | Ma, Rulin | Lei, Rongrong | Zhang, Cheng | Xia, Tao | Li, Pei | Xu, Chunyan | Wang, Chao | Chen, Jingwen | Dong, Lixing | Zhao, Qian | Wang, Aiguo
Fluoride, a ubiquitous environmental contaminant, is known to impair testicular functions and fertility; however the underlying mechanisms remain obscure. In this study, we used a rat model to mimic human exposure and sought to investigate the roles of apoptosis and autophagy in testicular toxicity of fluoride. Sprague–Dawley rats were developmentally exposed to 25, 50, or 100 mg/L sodium fluoride (NaF) via drinking water from pre-pregnancy to post-puberty, and then the testes of offspring were excised on postnatal day 56. Our results demonstrated that developmental NaF exposure induced an enhanced testicular apoptosis, as manifested by a series of hallmarks such as caspase-3 activation, chromatin condensation and DNA fragmentation. Further study revealed that fluoride exposure elicited significant elevations in the levels of cell surface death receptor Fas with a parallel increase in cytoplasmic cytochrome c, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. Intriguingly, fluoride treatment also simultaneously increased the number of autophagosomes and the levels of autophagy marker LC3-II but not Beclin1. Unexpectedly, the expression of p62, a substrate that is degraded by autophagy, was also significantly elevated, suggesting that the accumulated autophagosomes resulted from impaired autophagy degradation rather than increased formation. Importantly, these were associated with marked histopathological lesions including spermatogenic failure and germ cell loss, along with severe ultrastructural abnormalities in testes. Taken together, our findings provide deeper insights into roles of excessive apoptosis and defective autophagy in the aggravation of testicular damage, which could contribute to a better understanding of fluoride-induced male reproductive toxicity.
Show more [+] Less [-]Comparison of in vitro digestion model with in vivo relative bioavailability of BDE-209 in indoor dust and combination of in vitro digestion/Caco-2 cell model to estimate the daily intake of BDE-209 via indoor dust
2016
Pan, Weijian | Kang, Yuan | Zeng, Lixuan | Zhang, Qiuyun | Luo, Jiwen | Wong, Ming Hung
There is limited information on the BDE-209 relative bioavailability (RBA) of indoor dust and the absorption of BDE-209 after in vitro digestion was seldom studied. In the present study, BDE-209 RBA in 6 household dust samples measured using an in vivo mouse model was compared to BDE-209 bioaccessibility determined using physiologically based extraction test (PBET) and solubility bioaccessibility research consortium method (SBRC) assays. BDE-209 RBA obtained ranged from 45.9 ± 16.1 to 96.0 ± 17.4% and exhibited a significant relationship with PBET gastric phase (r2 = 0.578, p = 0.080), small intestinal phase (r2 = 0.728, p = 0.031) and total BDE-209 bioaccessibility (r2 = 0.728, p = 0.031), which indicated PBET assay can serve as a surrogate to predict BDE-209 RBA to refine human health exposure. In addition, the absorption of BDE-209 by Caco-2 cell line was assessed. With the consideration of the corresponding bioaccessibility and absorption of BDE-209 by Caco-2 cell line, the human daily intake of BDE-209 via dust ingestion for adults and children was much lower than that estimated by total concentration.
Show more [+] Less [-]Neurobehavioral deficits and brain oxidative stress induced by chronic low dose exposure of persistent organic pollutants mixture in adult female rat
2016
Lahouel, Asma | Kebieche, Mohamed | Lakroun, Zohra | Rouabhi, Rachid | Fetoui, Hamadi | Chtourou, Yassine | Djamila, Zama | Soulimani, Rachid
Persistent organic pollutants (POPs) are long-lived organic compounds that are considered one of the major risks to ecosystem and human health. Recently, great concerns are raised about POPs mixtures and its potential toxicity even in low doses of daily human exposure. The brain is mostly targeted by these lipophilic compounds because of its important contain in lipids. So, it would be quite interesting to study the effects of exposure to these mixtures and evaluate their combined toxicity on brain cells. The present study was designed to characterize the cognitive and locomotors deficits and brain areas redox status in rat model. An orally chronic exposure to a representative mixture of POPs composed of endosulfan (2.6 μg/kg), chlorpyrifos (5.2 μg/kg), naphthalene (0.023 μg/kg) and benzopyrane (0.002 μg/kg); the same mixture with concentration multiplied by 10 and 100 was also tested. Exposed rats have shown a disturbance of memory and a decrease in learning ability concluded by Morris water maze and the open field tests results and anxiolytic behaviour in the test of light/dark box compared to control. Concerning brain redox homeostasis, exposed rats have shown an increased malondialdehyde (MDA) amount and an alteration in glutathione (GSH) levels in both the brain mitochondria and cytosolic fractions of the cerebellum, striatum and hippocampus. These effects were accompanied by a decrease in levels of cytosolic glutathione S-transferase (GST) and a highly significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in both cytosolic and mitochondrial fractions. The current study suggests that environmental exposure to daily even low doses of POPs mixtures through diet induces oxidative stress status in the brain and especially in the mitochondria with important cognitive and locomotor behaviour variations in the rats.
Show more [+] Less [-]Probabilistic integrated risk assessment of human exposure risk to environmental bisphenol A pollution sources
2016
Fu, Keng-Yen | Cheng, Yi-Hsien | Chio, Chia-Pin | Liao, Chung-Min
Environmental bisphenol A (BPA) exposure has been linked to a variety of adverse health effects such as developmental and reproductive issues. However, establishing a clear association between BPA and the likelihood of human health is complex yet fundamentally uncertain. The purpose of this study was to assess the potential exposure risks from environmental BPA among Chinese population based on five human health outcomes, namely immune response, uterotrophic assay, cardiovascular disease (CVD), diabetes, and behavior change. We addressed these health concerns by using a stochastic integrated risk assessment approach. The BPA dose-dependent likelihood of effects was reconstructed by a series of Hill models based on animal models or epidemiological data. We developed a physiologically based pharmacokinetic (PBPK) model that allows estimation of urinary BPA concentration from external exposures. Here we showed that the daily average exposure concentrations of BPA and urinary BPA estimates were consistent with the published data. We found that BPA exposures were less likely to pose significant risks for infants (0–1 year) and adults (male and female >20 years) with <10⁻⁶-fold increase in uterus weight and immune response outcomes, respectively. Moreover, our results indicated that there was 50 % risk probability that the response outcomes of CVD, diabetes, and behavior change with or without skin absorption would increase 10⁻⁴–10⁻²-fold. We conclude that our approach provides a powerful tool for tracking and managing human long-term BPA susceptibility in relation to multiple exposure pathways, and for informing the public of the negligible magnitude of environmental BPA pollution impacts on human health.
Show more [+] Less [-]Role of Spirulina in mitigating hemato-toxicity in Swiss albino mice exposed to aluminum and aluminum fluoride
2016
Sharma, Shweta | Sharma, K. P. | Sharma, Subhasini
Aluminum is ingested through foods, water, air, and even drugs. Its intake is potentiated further through foods and tea prepared in aluminum utensils and Al salt added in the drinking water for removal of suspended impurities and also fluoride in the affected areas. The ameliorating role of a blue green alga Spirulina is well documented to various pollutants in the animal models. We, therefore, examined its protective role (230 mg/kg body weight) on the hematology of male Swiss albino mice treated with aluminum (sub-acute = 78.4 mg/kg body weight for 7 days, sub-chronic = 7.8 mg/kg body weight for 90 days) and aluminum fluoride (sub-acute = 103 mg/kg body weight, sub-chronic = 21 mg/kg body weight), along with their recovery after 90 days of sub-chronic exposure. This study revealed significant reduction in the values of RBC (5–18 %), Hb (15–17 %), PCV (8–14 %), and platelets (26–36 %), and increase in WBC (54–124 %) in the treated mice, particularly after sub-acute exposure. Aluminum fluoride was comparatively more toxic than aluminum. Further, Spirulina supplement not only alleviated toxicity of test chemicals in Swiss albino mice but also led to their better recovery after withdrawal.
Show more [+] Less [-]Toxicity of different forms of graphene in a chicken embryo model
2016
Szmidt, Maciej | Sawosz, Ewa | Urbańska, Kaja | Jaworski, Sławomir | Kutwin, Marta | Hotowy, Anna | Wierzbicki, Mateusz | Grodzik, Marta | Lipińska, Ludwika | Chwalibog, A. (André)
In the present work, the toxicity of three forms of graphene: pristine graphene (pG), graphene oxide (GO), and reduced graphene oxide (rGO) was investigated using a chicken embryo model. Fertilized chicken eggs were divided into the control group and groups administered with pG, GO, and rGO, in concentrations of 50, 500, and 5000 μg/ml. The experimental solutions were injected in ovo into the eggs, and at day 18 of incubation, the embryo survival, body and organ weights, the ultrastructure of liver samples, and the concentration of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the livers were measured. Survival of embryos decreased significantly after treatment with all types of graphene, but not in a dose-dependent manner. The body weights were only slightly affected by the highest doses of graphene, while the organ weights were not different among treatment groups. In all experimental groups, atypical hepatocyte ultrastructure and mitochondrial damage were observed. The concentration of the marker of DNA damage 8-OHdG in the liver significantly decreased after pG and rGO treatments. Further in vivo studies with different animal models are necessary to clarify the level of toxicity of different types of graphene and to estimate the concentrations appropriate to evaluate their biomedical applications and environmental hazard.
Show more [+] Less [-]Biological properties of Alsidium corallinum and its potential protective effects against damage caused by potassium bromate in the mouse liver
2016
Ben Saad, Hajer | Kharrat, Nadia | Krayem, Najeh | Boudawara, Ons | Boudawara, Tahia | Zeghal, Najiba | Ben Amara, Ibtissem
In the course of searching for hepatoprotective agents from natural sources, the protective effect of chemical constituents of the marine red alga Alsidium corallinum (A. corallinum) against potassium bromate (KBrO₃)-induced liver damage in adult mice was investigated. The in vitro antioxidant and antibacterial properties of A. corallinum were firstly investigated. Then, A. corallinum was tested in vivo for its potential protective effects against damage caused by KBrO₃ in mice models divided into four groups: controls, KBrO₃, KBrO₃ + A. corallinum, and A. corallinum. Our results demonstrated the rich composition of A. corallinum in antioxidant compounds like phenolics, flavonoids, anthocyanins, polysaccharides, chlorophyll and carotenoids. Its antioxidant activity was also confirmed using β-carotene bleaching by linoleic acid assay, reducing sugar test and trolox equivalent antioxidant capacity. The ethanolic extract of A. corallinum also showed good inhibition of the tested bacteria. The coadministration of the red alga associated to the KBrO₃ alleviated hepatotoxicity as monitored by the improvement of hepatic oxidative stress biomarkers and plasma biochemical parameters, when compared to the KBrO₃-treated mice. These results were confirmed by the improvement of histological and molecular changes. Treatment with A. corallinum prevented liver damage induced by KBrO₃, thus protecting the body against free radicals and reducing inflammation and hypercholesterolemia risks.
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