Exposure to low dose of Bisphenol A (BPA) intensifies kidney oxidative stress, inflammatory factors expression and modulates Angiotensin II signaling under hypertensive milieu.

Humans are constantly exposed to low concentrations of ubiquitous environmental pollutant, Bisphenol A (BPA). Due to the prevalence of hypertension (one of the major risk factors of cardiovascular disease [CVD]) in the population, it is necessary to explore the adverse effect of BPA under hypertension associated pathogenic milieu. The current study exposed the Nω-nitro-l-arginine methyl ester (L-NAME) induced hypertensive Wistar rats to low dose BPA (50 µg/kg) for 30 days period. In tissue samples immunohistochemistry, real-time quantitative polymerase chain reaction and enzymatic assays were conducted. Moreover, studies on primary kidney cell culture were employed to explore the impact of low dose of BPA exposure at nanomolar level (20-80 nM range) on renal cells through various fluorescence assays. The observed results illustrate that BPA exposure potentiates/aggravates hypertension induced tissue abnormalities (renal fibrosis), oxidative stress (ROS generation), elevated angiotensin-converting enzyme activity, malfunction of the antioxidant and tricarboxylic acid cycle enzymes, tissue lipid abnormalities and inflammatory factor expression (both messenger RNA and protein level of TNF-α and IL-6). Further, in vitro exposure of nM levels of BPA to primary kidney cells modulates oxidative stress (both superoxide and total ROS), mitochondrial physiology (reduced mitochondrial transmembrane potential-∆ψm) and lipid peroxidation in a dose dependent manner. In addition, angiotensin II induced ROS generation was aggravated further by BPA during coexposure in kidney cells. Therefore, during risk assessment, a precise investigation on BPA exposure in hypertensive (CVD vulnerable) populations is highly suggested.

System-wide health risk prediction for 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene(MBP), a major active metabolite of environmental pollutant and food contaminant - Bisphenol A.

Human exposure to plastic contaminated foods and environmental micro/nano plastic derived chemicals necessitates system-wide health risk assessment. Hence, current study intend to explore the mode of action (MoA) based adverse outcome pathways of 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the major active metabolite of bisphenol A (BPA). The computational study employed broad range of target prediction, systems biology tools and molecular docking protocols. Further, validation of MBP targets was done using protein-ligand fluorescence quenching assay, endothelial cell culture and chicken embryo vascular angiogenesis models. Interestingly, the current results illustrate that various physiological signaling pathways (MAPK and VEGF related angiogenesis signaling) and disease progression pathways (hypertension, cancer and endocrine disorders) were enriched as potential targets of MBP. Further, docking studies highlights the possible binding mechanism of MBP with important targets including endothelial nitric oxide synthase (eNOS) and serum albumin (BSA). In addition, the validation studies on MBP-BSA interaction (fluorescence quenching), eNOS derived nitric oxide (NOx) generation in endothelial cells and chicken embryo angiogenesis support the system-wide impacts of MBP with highlights on cardiovascular pathogenesis. Thus, the current observation provides novel insights into the system wide impacts of MBP for the futuristic health risk assessment of plastic derived chemicals.

Al2O3 nanoparticles trigger the embryonic hepatotoxic response and potentiate TNF-α-induced apoptosis-modulatory effect of p38 MAPK and JNK inhibitors.

Recent evidences illustrated that the release of aluminum oxide nanoparticles (Al2O3-NPs) into the biosphere may pose risk to the environment and cause adverse effects on living organisms including humans. The current study assessed the hepatotoxic effects of Al2O3-NPs on developing chicken embryo and cell culture models. Results demonstrated that Al2O3-NPs exposure causes histological abnormalities and increased the level of tissue damage markers (ALP, AST, and ALT) in the embryonic liver. Furthermore, increased oxidative stress (TBARS) and impaired function of antioxidant enzymes (SOD, CAT, and GPx) were also observed. Moreover, it adversely affects red blood cells (RBC) morphology, liver metabolism, and stress response gene expression (HO-1 and NQO-1). Dose-dependent ROS generation and cytotoxic response in addition to potentiating effect on tumor necrosis factor alpha (TNF-α)-induced apoptosis (caspase-3 activity) were also observed. Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) pathways modulates Al2O3-NPs-induced apoptosis in HepG2 cells. Novel mechanisms behind embryonic hepatotoxicity, cytotoxic potentiating effects, and possible prevention strategies have been explored.

Systems toxicology approach explores target-pathway relationship and adverse health impacts of ubiquitous environmental pollutant bisphenol A.

The effects of environmental chemicals on health outcomes may be underestimated due to deficiency of knowledge regarding the actions of compounds on toxico-pathogenic mechanisms underlying biological systems outcomes. In this regard, the current study aimed to explore the potential target-pathway-disease relationship attributed to bisphenol A (BPA) responses in target tissues. Computational methods including reverse pharmacophore mapping approach, structural similarity based search and kinome wide interaction profiling were employed with molecular docking validation. Gene ontology (GO) enrichment analysis and protein-protein interaction (PPI) network based illustrations were utilized to prioritize target-pathway and disease relationships. Data illustrated that BPA possessed multi-target nature since this chemical potentially interacted with various protein targets where many of these were validated through docking. Potential BPA targets were significantly enriched to various cellular signaling pathways including steroid biosynthesis, peroxisome proliferator-activated receptor gamma (PPARℽ) and cancer. Further, hypertension was prioritized as disease target. In addition, BPA targeted 17 cell signaling kinases encompassed in the human kinome. In addition, inflammatory (5-LO) and apoptosis regulators (Bcl-X and Bcl-2) were also explored as novel targets. Evidence indicates that the multi-target nature and plausible mechanisms underlying BPA actions in a system wide manner aids toward understanding of adverse effects. This observation may lead us to more precise method to elucidate the toxico-pathogenic mechanisms of BPA with an environmental health perspective.

Exposure to zinc oxide nanoparticles (ZnO-NPs) induces cardiovascular toxicity and exacerbates pathogenesis - Role of oxidative stress and MAPK signaling.

The precise toxico-pathogenic effects of zinc oxide nanoparticles (ZnO-NPs) on the cardiovascular system under normal and cardiovascular disease (CVD) risk factor milieu are unclear. In this study, we have investigated the dose-dependent effects of ZnO-NPs on developing chicken embryo and cell culture (H9c2 cardiomyoblast, HUVEC and aortic VSMC) models. In addition, the potentiation effect of ZnO-NPs on simulated risk factor conditions was evaluated using; 1. Reactive oxygen species (ROS) induced cardiac remodeling, 2. Angiotensin-II induced cardiac hypertrophy, 3. TNF-α induced HUVEC cell death and 4. Inorganic phosphate (Pi) induced aortic VSMC calcification models. The observed results illustrates that ZnO-NPs exposure down regulates vascular development and elevates oxidative stress in heart tissue. At the cellular level, ZnO-NPs exposure reduced the cell viability and increased the intracellular ROS generation, lipid peroxidation and caspase-3 activity in a dose-dependent manner in all three cell types. In addition, ZnO-NPs exposure significantly suppressed the endothelial nitric oxide (NO) generation, cardiac Ca2+ - ATPase activity and enhanced the cardiac mitochondrial swelling. Moreover, inhibition of p38 MAPK and JNK signaling pathways influence the cytotoxicity. Overall, ZnO-NPs exposure affects the cardiovascular system under normal conditions and it exacerbates the cardiovascular pathogenesis under selected risk factor milieu.

Exposure to a "safe" dose of environmental pollutant bisphenol A elevates oxidative stress and modulates vasoactive system in hypertensive rats.

Due to the prevalence of hypertension (one of the major risk factors of CVD) in the population, it is necessary to explore the adverse effects of daily tolerable and "safe" dose of bisphenol A (BPA) under hypertensive conditions. The current study exposed the Nω-nitro-l-arginine methyl ester (L-NAME, 40 mg/kg b.w/day) induced hypertensive Wistar rats to BPA (50 µg/kg b.w/day) by oral administration along with appropriate controls for 30 days period. The results illustrate that a 'safe' dose of BPA does not influence the systolic blood pressure (SBP) and levels of circulatory biomarkers of tissue damage. On the other hand, BPA exposure significantly (p < 0.05) elevates the thiobarbituric acid reactive substances (TBARS) content in plasma and tissues (heart, aorta, liver and kidney) in hypertensive rats when compared with respective control (BPA alone exposed) rats. Similarly, a significant modulation of ROS generation in RBC, plasma nitric oxide (NO) level and angiotensin-converting enzyme (ACE) activity was observed only under hypertensive milieu. In conclusion, the observed adverse effects during 'safe' dose of BPA exposure are specific to the hypertensive condition. Therefore, a precise investigation to explore the effects of BPA exposure in vulnerable hypertensive populations is highly suggested.