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Guoxin Hu, Junwei Li, Yuanyuan Shan, Xiaoheng Li, Qiqi Zhu, Huitao Li, Yiyan Wang, Xiaofang Chen, Qingquan Lian, Ren-Shan Ge
Phthalate diesters, including di-(2-ethylhexyl) phthalate (DEHP) and diethyl phthalate (DEP), are chemicals to which humans are ubiquitously exposed. Humans are exposed simultaneously to multiple environmental chemicals, including DEHP and DEP. There is little information available about how each chemical may interact to each other if they were exposed at same time. The present study investigated effects of the combinational exposure of rats to DEP and DEHP on fetal Leydig cell development. The results showed that the gestational (GD12-20) exposure of DEP + DEHP resulted in synergistic and/or dose-additive effects on the development of fetal Leydig cell...
January 8, 2018: Toxicology
Yun-Fang An, Xiao-Rui Geng, Li-Hua Mo, Jiang-Qi Liu, Li-Teng Yang, Xiao-Wen Zhang, Zhi-Gang Liu, Chang-Qing Zhao, Ping-Chang Yang
BACKGROUND AND AIMS: It is recognized that the air pollution is associated with the pathogenesis of airway diseases. This study aims to elucidate the role of the 3-methyl-4-nitrophenol (PNMC), one of the components of diesel-exhaust particles, in compromising the airway epithelial barrier integrity. METHODS: A549 cells, an airway epithelial cell line, were cultured to monolayers to be used as an in vitro epithelial barrier model. BALB/c mice were treated with nasal drops containing PNMC to test the effects of PNMC on alternating the airway epithelial barrier functions...
January 4, 2018: Toxicology
Michael Aagaard Andersen, Karen Malene Wegener, Steen Larsen, Lassina Badolo, Garrick Paul Smith, Ross Jeggo, Poul Henning Jensen, Florence Sotty, Kenneth Vielsted Christensen, Annemette Thougaard
Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no existing therapeutic approach to delay or stop progression. Genetic, biochemical and pre-clinical studies have provided evidence that leucine-rich-repeat-kinase-2 (LRRK2) kinase is involved in the pathogenesis of PD, and small molecule LRRK2 inhibitors represent a novel potential therapeutic approach. However, potentially adverse target-related effects have been discovered in the lung and kidneys of LRRK2 knock-out (ko) mice and rats...
January 4, 2018: Toxicology
Peter Dornbos, John J LaPres
Humans respond to chemical exposures differently due to many factors, such as previous and concurrent stressors, age, sex, and genetic background. The vast majority of laboratory-based toxicology studies, however, have not considered the impact of population-level variability within dose-response relationships. The lack of data dealing with the influence of genetic diversity on the response to chemical exposure provides a difficult challenge for risk assessment as individuals within the population will display a wide-range of responses following toxicant challenge...
December 21, 2017: Toxicology
Paula Moyano, Mariano de Frias, Margarita Lobo, María José Anadon, Emma Sola, Adela Pelayo, María Jesús Díaz, María Teresa Frejo, Javier Del Pino
Cadmium, an environmental neurotoxic compound, produces cognitive disorders, although the mechanism remains unknown. Previously, we described that cadmium induces a more pronounced cell death on cholinergic neurons from basal forebrain (BF). This effect, partially mediated by M1 receptor blockade, triggering it through AChE splices variants alteration, may explain cadmium effects on learning and memory processes. Cadmium has been also reported to induce oxidative stress generation leading to M2 and M4 muscarinic receptors alteration, in hippocampus and frontal cortex, which are necessary to maintain cell viability and cognitive regulation, so their alteration in BF could also mediate this effect...
December 15, 2017: Toxicology
Samantha Louise Cooper, Hardip Sandhu, Afthab Hussain, Christopher Mee, Helen Maddock
The tyrosine kinase inhibitor Sunitinib is used to treat cancer and is linked to severe adverse cardiovascular events. Mitogen activated kinase kinase 7 (MKK7) is involved in the development of cardiac injury and is a component of the c-Jun N-terminal kinase (JNK) signal transduction pathway. Apoptosis signal-regulating kinase 1 (ASK1) is the upstream activator of MKK7 and is specifically inhibited by 2,7-dihydro-2,7-dioxo-3H-naphtho[1,2,3-de]quinoline-1-carboxylic acid ethyl ester (NQDI-1). This study investigates the role of ASK1, MKK7 and JNK during Sunitinib-induced cardiotoxicity...
December 14, 2017: Toxicology
Ichiro Kawahata, Tohru Yamakuni
Imidacloprid is a neonicotinoid insecticide acting as an agonist of nicotinic acetylcholine receptors (nAChRs) in the target insects. However, questions about the safety to mammals, including human have emerged. Overactivation of mammalian peripheral catecholaminergic systems leads to onset of tachycardia, hypertension, vomiting, etc., which have been observed in acutely imidacloprid-poisoned patients as well. Physiological activation of the nAChRs is known to drive catecholamine biosynthesis and secretion in mammalian adrenal chromaffin cells...
December 12, 2017: Toxicology
Sabah H Enayah, Brigitte C Vanle, Laurence J Fuortes, Jonathan A Doorn, Gabriele Ludewig
Polychlorinated biphenyls (PCB) exposure at low chronic levels is a significant public health concern. Animal and epidemiological studies indicate that low PCB body burden may cause neurotoxicity and be a risk factor for neurodegenerative diseases. In the current study, we measured the ability of two non-dioxin like PCBs, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and 2,2'3,5',6-pentachlorobiphenyl (PCB95), to alter dopamine (DA) levels and metabolism using the dopaminergic PC12 cell line. Our hypothesis is that treatment of PC12 cells with non-toxic concentrations of PCB153 or PCB95 for 12 and 24h will have different effects due to different congener structures...
December 9, 2017: Toxicology
Shuichi Hara, Masamune Kobayashi, Fumi Kuriiwa, Kazuya Ikematsu, Hajime Mizukami
Severe poisoning induced by carbon monoxide (CO) at 3000ppm, but not 1000ppm, enhances hydroxyl radical (OH) production in rat striatum, which is greatly susceptible to inhibitors of NADPH oxidase (NOX), including diphenyleneiodonium (DPI), but not xanthine oxidase. The quantitative real-time PCR confirmed the previous microarray finding that CO at 3000ppm, but not 1000ppm, enhanced mRNA expression of dual oxidase 2 (DUOX2), but not DUOX1, in rat striatum, both of which are NOX family members producing reactive oxygen species...
December 6, 2017: Toxicology
Qian Zhou, Xiaolong Fu, Xueting Wang, Qin Wu, Yuanfu Lu, Jingshan Shi, James E Klaunig, Shaoyu Zhou
Excessive environmental or occupational exposure to manganese (Mn) is associated with increased risk of neuron degenerative disorders. Oxidative stress and mitochondrial dysfunction are the main mechanisms of Mn mediated neurotoxicity. Selective removal of damaged mitochondria by autophagy has been proposed as a protective mechanism against neuronal toxicant-induced neurotoxicity. Whether autophagic flux plays a role in Mn-induced cytotoxicity remains to be fully elucidated. The present study was designed to investigate the effect of Mn exposure on autophagy, and how modulation of autophagic flux alters the sensitivities of cells to Mn-elicited cytotoxicity...
December 6, 2017: Toxicology
A José Alberto Hernández, V Liliana Reyes, Damaris Albores-García, Rocío Gómez, Emma S Calderón-Aranda
Methylmercury (MeHg) is an environmental neurotoxicant that inhibits neuronal migration. This process requires several cyclic steps involving the formation of membrane protrusions (lamellipodia and filopodia) and focal adhesion turnover. FAK and Src are critical proteins that regulate both processes. The FAK-Src complex promotes the activation of Rac1 and Cdc42, two GTPases involved in the remodeling of the actin cytoskeletal network. Here, we studied the effect of MeHg (1, 10, 100, 500 and 1000nM) on cell migration, the formation of cell protrusions, focal adhesion location and the activation of FAK, Src, Rac1 and Cdc42 using the SH-SY5Y neuroblastoma cell line stimulated with PDGF-BB (PDGF)...
November 29, 2017: Toxicology
Aritra Chowdhury, Aparajita Choudhury, Shruti Chakraborty, Arunava Ghosh, Victor Banerjee, Shinjini Ganguly, Gautam Bhaduri, Rajat Banerjee, Kalipada Das, Indu B Chatterjee
Cigarette smoking is a significant risk factor for cataract. However, the mechanism by which cigarette smoke (CS) causes cataract remains poorly understood. We had earlier shown that in CS-exposed guinea pig, p-benzoquinone (p-BQ) derived from CS in the lungs is carried by the circulatory system to distant organs and induces various smoke-related pathogeneses. Here, we observed that CS exposure caused accumulation of the p-BQ-protein adduct in the eye lens of guinea pigs. We also observed accumulation of the p-BQ-protein adduct in resected lens from human smokers with cataract...
November 28, 2017: Toxicology
J L Yao, Q Z He, M Liu, X W Chang, J T Wu, T Duan, K Wang
BACKGROUND: The deleterious effects of cannabis consumption for fertility and pregnancy outcome are recognized for years. The main psychoactive molecule of cannabis, Δ(9)-tetrahydrocannabinol (THC) is able to cross the placenta barrier and cause alterations in fetal growth, low birth weight and preterm labor. However, the effects of THC on the human placenta amnion are still unknown. METHODS: The distributions of CB1R and CB2R in human amnion tissues were observed by immunohistochemistry (IHC)...
November 27, 2017: Toxicology
Min-Seok Kim, Sung-Hwan Kim, Doin Jeon, Hyeon-Young Kim, Kyuhong Lee
Inhalation of polyhexamethylene guanidine (PHMG) causes irreversible pulmonary injury, such as pulmonary fibrosis. However, the mechanism underlying PHMG-induced lung injury is unclear. In this study, we compared the difference in time-dependent lung injury between PHMG- and bleomycin (BLM)-treated mice and determined cytokines involved in inducing lung injury by performing cytokine antibody array analysis. Mice were treated once with 1.8mg/kg BLM or 1.2mg/kg PHMG through intratracheal instillation and were sacrificed on days 7 and 28...
November 22, 2017: Toxicology
Chaowei Wang, Yi Zhou, Xiaoxu Guan, Mengfei Yu, Huiming Wang
Caffeine negatively mediates bone homeostasis to cause bone loss and even osteoporosis. This phenomenon occurs in postmenopausal women with estrogen deficiency but not in healthy young women. In this study, we determined whether the effects of caffeine on bone homeostasis were antagonized by estrogen and the underlying mechanisms. In particular, because high levels of cAMP, an important second messenger, have been observed in postmenopausal women suffering from osteoporosis, we examined the role of cAMP in the effects of caffeine on bone homeostasis...
November 15, 2017: Toxicology
Lisa M Prince, Matthew D Rand
Methylmercury (MeHg) is a ubiquitous environmental toxicant, best known for its selective targeting of the developing nervous system. MeHg exposure has been shown to cause motor deficits such as impaired gait and coordination, muscle weakness, and muscle atrophy, which have been associated with disruption of motor neurons. However, recent studies have suggested that muscle may also be a target of MeHg toxicity, both in the context of developmental myogenic events and of low-level chronic exposures affecting muscle wasting in aging...
November 15, 2017: Toxicology
Simone G J van Breda, Sandra M H Claessen, Marcel van Herwijnen, Daniël H J Theunissen, Danyel G J Jennen, Theo M C M de Kok, Jos C S Kleinjans
Valproic acid (VPA) is a very potent anti-cancer and neuro-protective drug probably by its HDAC inhibiting properties, which may cause steatosis in the liver. The present study investigates the effect of repetitive VPA treatment of primary human hepatocytes (PHH) on whole genome gene expression-, DNA methylation-, and miRNA changes, using microarrays and integrated data analyses. PHH were exposed to a non-cytotoxic dose of VPA for 5days daily which induced lipid accumulation. Part of the PHH was left untreated for 3days for studying the persistence of 'omics' changes...
November 14, 2017: Toxicology
José Teixeira, Ricardo Amorim, Katia Santos, Pedro Soares, Sandipan Datta, Gino A Cortopassi, Teresa L Serafim, Vilma A Sardão, Jorge Garrido, Fernanda Borges, Paulo J Oliveira
Menadione, also known as vitamin K3, is a 2-methyl-1,4 naphthoquinone with a potent cytotoxic activity mainly resulting from its quinone redox-cycling with production of reactive oxygen species (ROS). Although increased ROS generation is considered a relevant mechanism in cancer cell death, it may not be sufficiently effective to kill cancer cells due to phenotypic adaptations. Therefore, combining ROS-generating agents with other molecules targeting important cancer cell phenotypes can be an effective therapeutic strategy...
November 12, 2017: Toxicology
Hua Xu, Zhongcai Gao, Peng Wang, Bin Xu, Yajiao Zhang, Long Long, Cheng Zong, Lei Guo, Weijian Jiang, Qinong Ye, Lili Wang, Jianwei Xie
Sulphur mustard (2,2'-dichloroethyl sulfide; SM) is a vesicant chemical warfare agent whose mechanism of acute or chronic action is not known with any certainty and to date there is no effective antidote. SM accumulation in adipose tissue (AT) has been originally verified in our previous study. To evaluate the biological effect caused by the presence of abundant SM in adipocyte and assess the biological role of AT in SM poisoning, in vitro and in vivo experiments were performed. High content analysis revealed multi-cytotoxicity in SM exposed cells in a time and dose dependent manner, and adipocytes showed a relative moderate damage compared with non-adipocytes...
November 10, 2017: Toxicology
Tomoka Ozaki, Junki Matsuoka, Maho Tsubota, Shiori Tomita, Fumiko Sekiguchi, Takeshi Minami, Atsufumi Kawabata
Cav3.2 T-type Ca(2+) channel activity is suppressed by zinc that binds to the extracellular histidine-191 of Cav3.2, and enhanced by H2S that interacts with zinc. Cav3.2 in nociceptors is upregulated in an activity-dependent manner. The enhanced Cav3.2 activity by H2S formed by the upregulated cystathionine-γ-lyase (CSE) is involved in the cyclophosphamide (CPA)-induced cystitis-related bladder pain in mice. We thus asked if zinc deficiency affects the cystitis-related bladder pain in mice by altering Cav3...
November 10, 2017: Toxicology
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