scholarly journals Use of dose-dependent absorption into target tissues to more accurately predict cancer risk at low oral doses of hexavalent chromium

2015 ◽  
Vol 71 (1) ◽  
pp. 93-100 ◽  
Author(s):  
J. Haney
2021 ◽  
Vol 22 ◽  
Author(s):  
Liyuan Zhang ◽  
Zhaohua Liu ◽  
Yunrui Zhang ◽  
Yuewu Xie ◽  
Jie Xing

Background: Hepatocellular damage has been reported for the antimalarial piperaquine (PQ) in the clinic after cumulative doses. Objectives: The role of metabolism in PQ toxicity was evaluated, and the mechanism mediating PQ hepatotoxicity was investigated. Method: The toxicity of PQ and its major metabolite (PQ N-oxide; M1) in mice was evaluated in terms of serum biochemical parameters. The role of metabolism in PQ toxicity was investigated in mice pretreated with an inhibitor of CYP450 (ABT) and/or FMO enzyme (MMI). The dose-dependent pharmacokinetics of PQ and M1 were studied in mice. Histopathological examination was performed to reveal the mechanism mediating PQ hepatotoxicity. Results: Serum biochemical levels (ALT and BUN) increased significantly (P < 0.05) in mice after three-day oral doses of PQ (> 200 mg/kg/day), indicating hepatotoxicity and nephrotoxicity of PQ at a high dose. Weaker toxicity was observed for M1. Pretreatment with ABT and/or MMI did not increase PQ toxicity. PQ and M1 showed linear pharmacokinetics in mice after a single oral dose, and multiple oral doses led to their cumulative exposures. Histopathological examination showed that a high dose of PQ (> 200 mg/kg/day for three days) could induce hepatocyte apoptosis. The mRNA levels of targets in NF-κB and p53 pathways could be up-regulated by 2-30-fold in mice by PQ or M1. Conclusions: PQ metabolism led to detoxification of PQ, but there was a low possibility of altered toxicity induced by metabolism inhibition. The hepatotoxicity of PQ and its N-oxidation metabolite was partly mediated by NF-κB inflammatory pathway and p53 apoptosis pathway.


Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2205
Author(s):  
Mohamed S. Ahmed ◽  
Ahmed H. Massoud ◽  
Aly S. Derbalah ◽  
Ashraf Al-Brakati ◽  
Mohsin A. Al-Abdawani ◽  
...  

Evaluating potential adverse health impacts caused by pesticides is an important parameter in human toxicity. This study focuses on the importance of subchronic toxicity assessment of cymoxanil fungicide in rats with special reference to target biochemical enzymes and histopathological changes in different tissues. In this regard, a 21-day toxicity study with repeated cymoxanil oral doses was conducted. It has been shown that low doses (0.5 mg/kg) were less effective than medium (1 mg/kg) and high (2 mg/kg) doses. Moreover, high dose dose-treated rats showed piecemeal necrosis in the liver, interstitial nephritis and tubular degeneration in the kidneys, interstitial pneumonia and type II pneumocyte hyperplasia in the lungs, gliosis, spongiosis, and malacia in the brain, and testicular edema and degeneration in the testes. Cymoxanil significantly increased AST, ALT, and ALP in serum and liver, indicating tissue necrosis and possible leakage of these enzymes into the bloodstream. Creatinine levels increased, indicating renal damage. Similarly, significant inhibition was recorded in brain acetylcholinesterase, indicating that both synaptic transmission and nerve conduction were affected. Importantly, these histopathological and biochemical alterations were dose-dependent. Taken together, our study reported interesting biochemical and histopathological alterations in different rat tissues following repeated toxicity with oral doses of cymoxanil. Our study suggests future studies on different pesticides at different concentrations that would help urge governments to create more restrictive regulations concerning these compounds’ levels.


1992 ◽  
Vol 43 (3) ◽  
pp. 277-281 ◽  
Author(s):  
J. Sjövall ◽  
G. Alván ◽  
J. E. Åkerlund ◽  
J. O. Svensson ◽  
G. Paintaud ◽  
...  

Lung Cancer ◽  
2014 ◽  
Vol 86 (2) ◽  
pp. 137-143 ◽  
Author(s):  
Ming-Ju Tsai ◽  
Chih-Jen Yang ◽  
Ya-Ting Kung ◽  
Chau-Chyun Sheu ◽  
Yu-Ting Shen ◽  
...  

2020 ◽  
Author(s):  
Lin Peng-Chan ◽  
Hui-O Chen ◽  
Chih-Jung Lee ◽  
Yu-Min Yeh ◽  
Meng-Ru Shen ◽  
...  

Abstract Background Functional disruptions by large germline genomic structural variants in susceptible genes are known risks for cancer. Few studies have used deletion structural variants (DSVs) to predict cancer risk with neural networks or studied the relationship between DSVs and immune gene expression to stratify prognosis.Methods Whole-genome sequencing (WGS) data was analyzed with the blood samples of 192 cancer and 499 noncancer subjects with or without family cancer history (FCH). Ninety-nine colorectal cancer (CRC) patients had immune response gene expression data. To build the cancer risk predictive model and identify DSVs in familial cancer, we used joint calling tools and attention-weighted model. The survival support vector machine (survival-SVM) was used to select prognostic DSVs. Results We identified 671 DSVs that could predict cancer risk. The area under the curve (AUC) of receiver operating characteristic curve (ROC) of attention-weighted model was 0.71. The 3 most frequent DSV genes observed in cancer patients were identified as ADCY9, AURKAPS1, and RAB3GAP2 (p < 0.05). We identified 65 immune-associated DSV markers for assessing cancer prognosis (P < 0.05). The functional protein of MUC4 DSV gene interacted with MAGE1expresssion, according to the STRING database. The causal inference model showed that deleting the CEP72 DSV gene could affect the recurrence-free survival (RFS) of IFIT1 expression. Conclusions We established an explainable attention-weighted model for cancer risk prediction and used the survival-SVM for prognostic stratification by using DSV and immune gene expression datasets. It can provide the genetic landscape of cancer patients and help predict the clinical outcome.


2019 ◽  
Vol 192 (2) ◽  
pp. 244-251 ◽  
Author(s):  
Mehmet Ates ◽  
Servet Kizildag ◽  
Oguz Yuksel ◽  
Ferda Hosgorler ◽  
Zeynep Yuce ◽  
...  

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