Effects of 1,4-dihydropyridine derivatives on cell injury and mTOR of HepG2 and 3D-QSAR study.

1,4-dihydropyridine derivatives (1,4-DHPs) are a class of drugs used to treat cardiovascular diseases, but these drugs can cause liver injury. To reveal the toxicity characteristics of these compounds, we used a series of assays, including cell viability, enzyme activity detection, and western blotting, to investigate the toxicity of seven kinds of 1,4-DHPs (0-100 µM) on HepG2 cells and establish 3D-QSAR model based on relevant toxicity data. After HepG2 cells were treated with 1,4-DHPs for 24 h, high-dose (100 µM) 1,4-DHPs decreased cell viability to varying degrees, while ROS and MDA contents were significantly increased, and ATP content was reduced. Moreover, with the concentration of 100 µM 1,4-DHPs (Nimodipine, Nitrendipine, Cilnidipine, and Manidipine) were markedly inhibited the phosphorylation levels of mTOR protein. The results of the 3D-QSAR model showed that the non-cross validation coefficient (R2) and cross validation coefficient (Q2) of the model were 0.982 and 0.652, respectively. Combined with external validation and the Williams diagram, the model showed good predictability and application domain. Based on the CoMSIA 3D contour map, the introduction of large volume and hydrogen bond receptor groups on the carbonyl oxygen side chains of the 1,4-DHPs ring 3- and 5- was beneficial for reducing the toxicity of 1,4-DHPs. The results of this study could supplement information on the cytotoxicity of 1,4-DHPs, and could provide theoretical support for predicting the toxicity of 1,4-DHPs.

Dietary exposure and risk assessment of phthalic acid esters through a total diet study in Shenzhen, South China.

Phthalic acid esters (PAEs) are typical endocrine disruptors which are ubiquitous contaminants. Human exposure to PAEs is through multiple routes of which the diet is recognised as the main source of daily intake. The aim of this study was to evaluate the dietary exposure to PAEs of residents in Shenzhen (China) through a total diet study and assess the potential health risk. A total of 16 different phthalate esters in samples of 12 composite food groups were determined by GC-MS. The main dietary sources of PAE exposure among adult residents in Shenzhen were potatoes (21%), eggs (21%), meat (15%) and aquatic products (14%). The median total dietary exposure to PAEs in Shenzhen residents was 7780 ng kg-1 bw d-1, and the hazard quotients (HQ) of dimethyl phthalate (DMP), diethyl phthalate (DEP), di-isobutyl phthalate (DIBP), dibutyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) were 0.09, 0.06, 0.07, 0.10 and 0.03, respectively. Therefore, the risks from dietary PAE exposure were low. However, with the increasing use of PAEs and their accumulation in the environment, the probability of PAEs entering the food chain is gradually increasing and, therefore, PAEs should be strictly controlled and regularly monitored.

Dose- and time-effects responses of Nonylphenol on oxidative stress in rat through the Keap1-Nrf2 signaling pathway.

Nonylphenol (NP) is a representative environmental endocrine-disrupting compound that can induce oxidative stress in organisms. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway acts an important role in preventing oxidative stress. The aim of this study was to investigate the influence of oxidative stress caused by NP on Keap1-Nrf2 pathway in rats. Rats were treated with NP (30, 90, 270 mg/kg) for different exposure time (7, 14 and 28 days). The levels of reactive oxygen species (ROS) in serum and glutathione S-transferase (GST), UDP-Glucuronosyl Transferase (UGT) in liver were detected by ELISA kits. Western blot was used to detect Keap1, Nrf2 protein expression in liver and cerebral cortex. The results showed that 28 days of NP exposure significantly increased ROS levels in NPH group. And 14 days exposure to NP significantly enhanced the levels of GST and UGT, while 28 days of exposure showed a suppressive effect. In liver, Keap1 levels was upregulated at 7, 14 and 28 days of NP exposure, while nuclear Nrf2 levels decreased at 7 and 28 days but increased at 14 days. In cerebral cortex, Keap1 and Nrf2 expression increased at 14 days but decreased at 28 days. Besides, with the prolongation of NP exposure time, the GST and UGT levels in NPM and NPH groups were increased firstly and then decreased, while Keap1 and Nrf2 protein levels were constantly decreased in liver and cerebral cortex. In conclusion, the lower dose and shorter exposure time of NP activated the Keap1-Nrf2 pathway that may reduce the damage of oxidative stress, but when further exposed to NP at higher dose and time, the pathway could be inhibited.

4-Nonylphenol and 4-tert-octylphenol induce anxiety-related behaviors through alternation of 5-HT receptors and transporters in the prefrontal cortex.

Environmental endocrine disruptors 4-nonylphenol (NP) and 4-tert-octylphenol (OP) may cast huge harm to human health. We used a rat model to observe the influence of NP or/and OP exposure on anxiety-related behaviors and the underlying mechanisms. Eighty male Sprague-Dawley (SD) rats were randomly divided into 10 groups: control group (corn oil), NP groups [30, 90, 270 mg/kg], OP groups [40, 120, 360 mg/kg] and NO groups [(mixed with the corresponding NP, OP alone exposed low, medium and high dose according to the natural environment exists NP:OP = 4:1]. The rats were orally administered every other day for 30 days. The neurobehaviors of rats were evaluated by open-field test (OFT) and elevated plus-maze test (EPM), and the concentrations of 5-HT, monoamine oxidase (MAOA), serotonin transporter (SERT), vesicular monoamine transporter 2 (VAMT2), 5-hydroxytryptamine 1A (5-HT1A), 5-hydroxytryptamine 2A (5-HT2A)，and 5-hydroxytryptamine 2C (5-HT2C) in the rat prefrontal cortex were analyzed by ELISA. OFT and EPM tests showed that NP or/and OP exposure induced anxiety-related behaviors in rats. 5-HT levels were significantly increased compared with the control group. The levels of MAOA, SERT, VAMT2, 5-HT1A, 5-HT2A, and 5-HT2C in the prefrontal cortex reduced in different degrees by high-doses NP or/and OP exposure. In summary, NP or/and OP exposure might cause anxiety-related behaviors in rats through regulating neurotransmitter 5-HT levels by altering the expression of 5-HT decomposition enzyme MAOA, transporters SERT and VMAT2, and 5-HT receptors 5-HT1A, 5-HT2A, and 5-HT2C.