Cadmium (Cd) is a toxic pollutant that is associated with several severe human diseases. Cd can be easily absorbed in significant quantities from air contamination/industrial pollution, cigarette smoke, food, and water and primarily affects the liver, kidney, and lungs. Toxic effects of Cd include hepatotoxicity, nephrotoxicity, pulmonary toxicity, and the development of various human cancers. Cd is also involved in the development and progression of fatty liver diseases and hepatocellular carcinoma. Cd affects liver function via modulation of cell survival/proliferation, differentiation, and apoptosis. Moreover, Cd dysregulates hepatic autophagy, an endogenous catabolic process that detoxifies damaged cell organelles or dysfunctional cytosolic proteins through vacuole-mediated sequestration and lysosomal degradation. In this article, we review recent developments and findings regarding the role of Cd in the modulation of hepatotoxicity, autophagic function, and liver diseases at the molecular level.

Freshwater prokaryotic cyanobacteria within harmful algal blooms produce cyanotoxins which are considered major pollutants in the aquatic system. Direct exposure to cyanotoxins through inhalation, skin contact, or ingestion of contaminated drinking water can target the liver and may cause hepatotoxicity. In the current study, we investigated the effect of low concentrations of cyanotoxins on cytotoxicity, inflammation, modulation of unfolded protein response (UPR), steatosis, and fibrosis signaling in human hepatocytes and liver cell models. Exposure to low concentrations of microcystin-LR (MC-LR), microcystin-RR (MC-RR), nodularin (NOD), and cylindrospermopsin (CYN) in human bipotent progenitor cell line HepaRG and hepatocellular carcinoma (HCC) cell lines HepG2 and SK-Hep1 resulted in increased cell toxicity. MC-LR, NOD, and CYN differentially regulated inflammatory signaling, activated UPR signaling and lipogenic gene expression, and induced cellular steatosis and fibrotic signaling in HCC cells. MC-LR, NOD, and CYN also regulated AKT/mTOR signaling and inhibited autophagy. Chronic exposure to MC-LR, NOD, and CYN upregulated the expression of lipogenic and fibrosis biomarkers. Moreover, RNA sequencing (RNA seq) data suggested that exposure of human hepatocytes, HepaRG, and HCC HepG2 cells to MC-LR and CYN modulated expression levels of several genes that regulate non-alcoholic fatty liver disease (NAFLD). Our data suggest that low concentrations of cyanotoxins can cause hepatotoxicity and cell steatosis and promote NAFLD progression.

α-Pinene caused a concentration-responsive increase in bladder hyperplasia and decrease in sperm counts in rodents following inhalation exposure. Additionally, it formed a prospective reactive meta...

Human exposure to vanadium (V) is anticipated because it is a drinking water contaminant. Due to limited data on soluble V salts, the National Toxicology Program is investigating the toxicity in rodents following drinking water exposure. Measurement of internal V dose allows for interpretation of toxicology data. The objective of this study was to develop and validate an inductively coupled plasma-mass spectrometric method to quantitate total V in rat plasma. The method was linear (r ≥ 0.99) from 5.00 − 1,000 ng V/mL. Intra- and inter-day relative error (% RE) and relative standard deviation (% RSD) of spiked plasma samples were 8.5% to 15.6% RE and ≤ 1.8% RSD and 7.3% to 11.7% RE and ≤ 3.1% RSD, respectively. The limit of detection was 0.268 ng V/mL plasma and absolute percent recovery was 113%. Standards up to 7,500 ng V/mL plasma were diluted into the validated range (5.6% RE, 0.9% RSD). V in extracted plasma samples over 15 days at ambient and refrigerated conditions was from 97.7 to 126% of day 0. Determined plasma V concentrations after three freeze-thaw cycles and after frozen storage for up to 63 days ranged from 100 to 106% and 100 to 122% of day 0, respectively. The method was extended to rat urine (accuracy and precision −2.0 to 0.3% RE and <0.6% RSD, respectively for same linear range). These data demonstrate that the method is suitable to quantitate V in rat plasma and urine.

Thallium (Tl) can be released as a byproduct of smelting, mining, and other industries, causing human exposure. There are knowledge gaps on the toxicity of thallium compounds, so the National Toxicology Program is investigating the toxicity of thallium (I) sulfate in rodents. We developed and validated a method to quantitate Tl in rodent plasma and secondary matrices. Primary matrix standards and validation samples were digested with nitric acid and analyzed for Tl by inductively-coupled plasma – mass spectrometry (ICP-MS). Method performance was validated for linearity, accuracy, precision, and other criteria. Calibration was linear from 1.25 to 500 ng Tl/mL plasma; accuracy (RE) was −5.9 to 2.6% for all calibration standards. The lower limit of quantitation (LLOQ) was 1.25 ng Tl/mL plasma, and the limit of detection was 0.0370 ng Tl/mL plasma. Intra- and interday RE and precision (RSD) were −5.6 to −1.7% and ≤0.8% (intraday) and −4.8 to −1.3% and ≤4.3% (interday), respectively, at three sample concentration levels. Standards up to 10.0 x 10³ ng/mL could be analyzed by dilution with digested blank matrix, with −6.4% RE and 5.4% RSD. Method was also evaluated in post-natal day 4 (PND4) Hsd:Sprague Dawley SD (HSD) dam and pup plasma, gestation day 18 (GD 18) HSD rat fetal homogenate, HSD rat urine, female HSD rat brain homogenate, female B6C3F1 mouse plasma. Background Tl was detected in control fetal and brain homogenates and urine at < 30% of LLOQ response. Results demonstrate that the method is suitable for determination of Tl in rodent matrices for toxicology studies.