Toxicological Sciences最新文献

Understanding the mechanisms by which environmental chemicals cause toxicity is necessary for effective human health risk assessment. High-Throughput Transcriptomics (HTTr) can be used to inform risk assessment on toxicological mechanisms, hazards, and potencies. We applied HTTr to elucidate the molecular mechanisms by which Per- and Polyfluoroalkyl Substances (PFAS) cause liver perturbations. We contrasted transcriptomic profiles of PFOA, PFBS, PFOS, and PFDS against transcriptomic profiles from established liver-toxic and non-toxic reference compounds, alongside peroxisome proliferator-activated receptors (PPARs) agonists. Our analysis was conducted on metabolically competent 3-D human liver spheroids produced from primary cells from 10 donors. Pathway analysis showed that PFOS and PFDS perturb many of the same pathways as the known liver-toxic compounds in the spheroids, and that the cholesterol biosynthesis pathways are significantly affected by exposure to these compounds. PFOA alters lipid metabolism-related pathways but its expression profile does not closely match reference compounds. PFBS upregulates many degradation-related pathways and targets many of the same pathways as the PPAR agonists and acetaminophen. Our transcriptional analysis does not support that these PFAS are DNA damaging in this model. A multidimensional scaling analysis revealed that PFOS, PFOA, and PFDS cluster together in the same multidimensional space as liver-damaging compounds; whereas, PFBS clusters more closely with the non-liver-damaging compounds. Benchmark concentration-response modeling predicts that all the PFAS are bioactive in the liver. Overall, our results show that these PFAS produce unique transcriptional changes but also alter pathways associated with established liver-toxic chemicals in this liver spheroid model.

In utero exposure to polybrominated diphenyl ethers (PBDEs) is linked to adverse pregnancy and fetal health outcomes, including altered thyroid hormone (TH) levels. Despite their phase-out, PBDEs are still commonly detected in newborn cord blood. While PBDEs can cross the placenta, few studies have separately assessed PBDEs or THs in the maternal and fetal placental tissues. Additionally, no studies have separately assessed THs in these tissues across mid- and late gestation, during the onset of fetal TH synthesis. To address these gaps, we conducted a study with Wistar rats and examined PBDE accumulation in the maternal and fetal placenta. Pregnant dams were exposed daily to sesame oil vehicle, a low dose, or high dose PBDE mixture. At GD15 and 20, dams were sacrificed and placental tissues were collected. Tissues were analyzed for PBDEs, T3, rT3, and T4 using mass spectrometry. BDE-47, -99, -100, and -209 were frequently detected in both the fetal and maternal placenta. At GD15, higher concentrations of BDE-99, -100, and -209 were measured in the fetal placenta; however, this trend reversed by GD20, with higher maternal placental concentrations. Placental T3 and T4 were significantly impacted by exposure, tissue, and exposure × tissue at GD15, with significant reductions in both THs following low-dose exposure in the maternal placenta. By GD20, maternal placental T3 was only significantly reduced in the high exposure groups and there was no effect on placental T4. Overall, these results highlight the rapid developmental changes that occur throughout gestation between the maternal and fetal placenta, and the differential impacts of gestational PBDE exposure on placental T3 and T4 across mid- and late gestation.

Obesity, a significant global health issue, heightens the risk of non-alcoholic fatty liver disease (NAFLD). Its interaction with environmental pollutants might exacerbate NAFLD's severity. Haloacetamides (HAcAms), a group of emerging nitrogenous disinfection byproducts (DBPs) and potent oxidative stressors, are found in chlorinated drinking water. Since oxidative stress is associated with HAcAms-DBP cytotoxicity and a key factor in NAFLD pathogenesis, we hypothesize that HAcAms-DBPs could exacerbate liver injury and NAFLD, particularly with high-fat diets. This study examined HAcAms-DBPs' impact on liver lipid metabolism in mice treated with 1 to 100 times the background drinking water level (13.05 µg/L) for up to 16 weeks of oral administration. Compared to a high-fat-only group, mice co-exposed to a high-fat diet and HAcAms-DBPs for 16 weeks had elevated serum alanine transaminase, aspartate transaminase, triglyceride, hepatic lipid aggregation, and inflammation response. Under high-fat conditions, background drinking water levels of HAcAms significantly upregulated liver Acetyl-CoA carboxylase 1, fatty acid synthase, peroxisome proliferator-activated receptor gamma (PPARγ), PPARγ coactivator-1α, glucose transporter 1 and 4 protein expression in C57BL/6J mice; 10 times background significantly increased expression of inflammatory marker tumor necrosis factor and liver fibrosis marker protein alpha-smooth muscle actin; 100 times further increased both liver damage and markers of early non-alcoholic steatohepatitis phenotypes like steatosis and lobular inflammation. HAcAms-DBPs plus high-fat conditions worsened liver damage. The possible health risks of NAFLD induced by HAcAms in obese individuals deserve further study.

7,12-Dimethylbenz[a]anthracene (DMBA) is a polycyclic aromatic hydrocarbon that causes female infertility via DNA damage, and the ovary has the capacity to mitigate DMBA exposure via the action of proteins including the glutathione S-transferase (GST) family. Due to previous findings of DNA damage and a reduced ovarian chemical biotransformation response to DMBA exposure in hyperphagia-induced obese mice, this study investigated the hypothesis that diet-induced obesity would hamper the ovarian biotransformative response to DMBA exposure. Six-week-old C57BL6/J mice were fed either a normal rodent diet (L) or a high fat high sucrose diet (O) until the O group was ∼30% heavier than the L. Both L and O mice were exposed to either corn oil (C) or DMBA (1 mg/kg) for 7 d. Liver weight was increased (P < 0.05) in obese mice exposed to DMBA but no effect on spleen weight, uterine weight, ovary weight, estrous cyclicity, or circulating 17β-estradiol and progesterone were observed. Primordial and preantral follicle numbers were higher (P < 0.05) in the obese mice and there was a tendency (P = 0.055) for higher antral follicles in DMBA-exposed obese mice. The ovarian proteome was identified by LC-MS/MS analysis to be altered both by diet-induced obesity and by DMBA exposure with changes observed in levels of proteins involved in oocyte development and chemical biotransformation, including GST isoform pi. Fewer proteins were affected by the combined exposure of diet and DMBA than by a single treatment, indicating that physiological status impacts the response to DMBA exposure.

For many years, a method that allowed systemic toxicity safety assessments to be conducted without generating new animal test data, seemed out of reach. However, several different research groups and regulatory authorities are beginning to use a variety of in silico, in chemico, and in vitro techniques to inform safety decisions. To manage this transition to animal-free safety assessments responsibly, it is important to ensure that the level of protection offered by a safety assessment based on new approach methodologies (NAMs), is at least as high as that provided by a safety assessment based on traditional animal studies. To this end, we have developed an evaluation strategy to assess both the level of protection and the utility offered by a NAM-based systemic safety "toolbox." The toolbox comprises physiologically based kinetic models to predict internal exposures, and bioactivity NAMs designed to give broad coverage across many different toxicity modes of action. The output of the toolbox is the calculation of a bioactivity:exposure ratio (analogous to a margin of internal exposure), which can be used to inform decision-making. In this work, we have expanded upon an initial pilot study of 10 chemicals with an additional 38 chemicals and 70 consumer exposure scenarios. We found that, for the majority of these (>90%), the NAM-based workflow is protective of human health, enabling us to make animal-free safety decisions for systemic toxicity and preventing unnecessary animal use. We have also identified critical areas for improvement to further increase our confidence in the robustness of the approach.

Inhalation of smoke from burn pits during military deployment is associated with several adverse pulmonary outcomes. We exposed human airway epithelial cells to smoke condensates from burn pit waste materials. Single and repeated exposure to condensates triggered unique and common responses in terms of gene expression that were sustained through the recovery phase. Source material and combustion condition influenced the outcome. Intensified response in female donor cells indicated a determining role of biological sex. The observations indicate a lasting impact of burn pit smoke exposure on epithelial gene expression, potentially contributing to disease pathogenesis.

Traditional approaches for quantitatively characterizing uncertainty in risk assessment require adaptation to accommodate increased reliance on observational (vs experimental) studies in developing toxicity values. Herein, a case study with perfluorooctanoic acid (PFOA) and PFOS and vaccine response explores approaches for qualitative and-where possible-quantitative assessments of uncertainty at each step in the toxicity value development process when using observational data, including review and appraisal of individual studies, candidate study selection, dose-response modeling, and application of uncertainty factors. Each of the 15 studies identified had uncertainties due to risk of bias in confounding, outcome, and exposure ascertainment, likely contributing to the observed inconsistencies within and across studies, and resulting in lack of candidacy for dose-response assessment. Nonetheless, 2 representative studies were selected to demonstrate possible methods to quantify uncertainty in the remaining steps. Data simulations indicated lack of a clear dose-response relationship; dose-response models fit to representative simulations indicated high uncertainty in both the magnitude and direction of effect with simulated benchmark dose and its lower limit values varying at least 66- and 86-fold for PFOA and PFOS. Uncertainty factor application added minimal uncertainty. Combined, a high level of uncertainty was observed, precluding the ability to confidently assess causal dose-response relationships with the observational data, alone. This case study highlights the need for quantitative uncertainty analysis when developing toxicity values with observational data and, importantly, emphasizes the need for application of additional techniques to directly assess causality and the specificity of dose-response when relying on studies of association in quantitative risk assessment.