Toxicological Sciences最新文献

Carbamazepine (CBZ) has been identified in the aquatic environment as an emerging contaminant. Its immune effect across generations at environmentally relevant concentrations is little known. We aim to elucidate the effects of CBZ on the immune system in zebrafish (Danio rerio), hypothesizing the effects caused by CBZ exposure in the parental generation can be passed on to its offspring, leading to impairment of innate immune function and defense against pathogen weakened. A suite of bioassays (including a test with added lipopolysaccharide) was used to measure the effects of environmentally relevant levels of CBZ (1, 10, and 100 μg/l) on zebrafish at multiple biological levels, and across 2 successive generations (21 days exposure for F0; 5 and 21 days exposure or nonexposure for F1). The results showed that CBZ affected homeostasis in the immune system, caused liver vacuolization, increased the inflammation-related microbiota proportion in gut, and decreased reproduction, by induction of oxidative stress and modulation of Toll-like receptors (TLR) signaling pathway on gut-liver axis. The effects of exposure to CBZ over 21 days in F0 could be passed to the next generation. Intergenerational effects on TLR and antioxidant defense system were also observed in nonexposed F1 at 5 days post-fertilization (5 dpf), but diminished at 21 dpf. The finding provided evidence to unravel immune response by gut-liver axis mediated and oxidative stress under 4 test conditions. The study has raised a potential concern about the multigenerational immune effects of environmental pollutants and calls for a focus on the risk of synergetic pathogen infection.

The success and sustainability of U.S. EPA efforts to reduce, refine, and replace in vivo animal testing depends on the ability to translate toxicokinetic and toxicodynamic data from in vitro and in silico new approach methods (NAMs) to human-relevant exposures and health outcomes. Organotypic culture models employing primary human cells enable consideration of human health effects and inter-individual variability but present significant challenges for test method standardization, transferability, and validation. Increasing confidence in the information provided by these in vitro NAMs requires setting appropriate performance standards and benchmarks, defined by the context of use, to consider human biology and mechanistic relevance without animal data. The human thyroid microtissue (hTMT) assay utilizes primary human thyrocytes to reproduce structural and functional features of the thyroid gland that enable testing for potential thyroid-disrupting chemicals. As a variable-donor assay platform, conventional principles for assay performance standardization need to be balanced with the ability to predict a range of human responses. The objectives of this study were to (1) define the technical parameters for optimal donor procurement, primary thyrocyte qualification, and performance in the hTMT assay, and (2) set benchmark ranges for reference chemical responses. Thyrocytes derived from a cohort of 32 demographically diverse euthyroid donors were characterized across a battery of endpoints to evaluate morphological and functional variability. Reference chemical responses were profiled to evaluate the range and chemical-specific variability of donor-dependent effects within the cohort. The data-informed minimum acceptance criteria for donor qualification and set benchmark parameters for method transfer proficiency testing and validation of assay performance.

Intestinal failure-associated liver disease (IFALD) is a relatively common complication in individuals receiving parenteral nutrition (PN). IFALD can be manifested as different types of liver injury, including steatosis, cholestasis, and fibrosis, and could result in liver failure in some cases. The onset and progression of IFALD are highly dependent on various patient and PN-related risk factors. Despite still being under investigation, several mechanisms have been proposed. Liver injury can originate due to caloric overload, nutrient deficiency, and toxicity, as well as phytosterol content, and omega-6 to omega-3 fatty acids ratio contained in lipid emulsions. Additional mechanisms include immature or defective bile acid metabolism, acute heart failure, infections, and sepsis exerting negative effects via Toll-like receptor 4 and nuclear factor κB inflammatory signaling. Furthermore, lack of enteral feeding, gut dysbiosis, and altered enterohepatic circulation that affect the farnesoid x receptor-fibroblast growth factor 19 axis can also contribute to IFALD. Various best practices can be adopted to minimize the risk of developing IFALD, such as prevention and management of central line infections and sepsis, preservation of intestine's length, a switch to oral and enteral feeding, cyclic PN, avoidance of overfeeding and soybean oil-based lipid formulations, and avoiding hepatotoxic substances. The present review thus provides a comprehensive overview of all relevant aspects inherent to IFALD. Further research focused on clinical observations, translational models, and advanced toxicological knowledge frameworks is needed to gain more insight into the molecular pathogenesis of hepatotoxicity, reduce IFALD incidence, and encourage the safe use of PN.

Large-scale production and waste of plastic materials have resulted in widespread environmental contamination by the breakdown product of bulk plastic materials to micro- and nanoplastics (MNPs). The small size of these particles enables their suspension in the air, making pulmonary exposure inevitable. Previous work has demonstrated that xenobiotic pulmonary exposure to nanoparticles during gestation leads to maternal vascular impairments, as well as cardiovascular dysfunction within the fetus. Few studies have assessed the toxicological consequences of maternal nanoplastic (NP) exposure; therefore, the objective of this study was to assess maternal and fetal health after a single maternal pulmonary exposure to polystyrene NP in late gestation. We hypothesized that this acute exposure would impair maternal and fetal cardiovascular function. Pregnant rats were exposed to nanopolystyrene on gestational day 19 via intratracheal instillation. 24 h later, maternal and fetal health outcomes were evaluated. Cardiovascular function was assessed in dams using vascular myography ex vivo and in fetuses in vivo function was measured via ultrasound. Both fetal and placental weight were reduced after maternal exposure to nanopolystyrene. Increased heart weight and vascular dysfunction in the aorta were evident in exposed dams. Maternal exposure led to vascular dysfunction in the radial artery of the uterus, a resistance vessel that controls blood flow to the fetoplacental compartment. Function of the fetal heart, fetal aorta, and umbilical artery after gestational exposure was dysregulated. Taken together, these data suggest that exposure to NPs negatively impacts maternal and fetal health, highlighting the concern of MNPs exposure on pregnancy and fetal development.

Per- and polyfluoroalkyl substances (PFAS) are a class of over 8000 chemicals, many of which are persistent, bioaccumulative, and toxic to humans, livestock, and wildlife. Serum protein binding affinity is instrumental in understanding PFAS toxicity, yet experimental binding data is limited to only a few PFAS congeners. Previously, we demonstrated the usefulness of a high-throughput, in vitro differential scanning fluorimetry assay for determination of relative binding affinities of human serum albumin for 24 PFAS congeners from 6 chemical classes. In the current study, we used this assay to comparatively examine differences in human, bovine, porcine, and rat serum albumin binding of 8 structurally informative PFAS congeners from 5 chemical classes. With the exception of the fluorotelomer alcohol 1H, 1H, 2H, 2H-perfluorooctanol (6:2 FTOH), each PFAS congener bound by human serum albumin was also bound by bovine, porcine, and rat serum albumin. The critical role of the charged functional headgroup in albumin binding was supported by the inability of albumin of each species tested to bind 6:2 FTOH. Significant interspecies differences in serum albumin binding affinities were identified for each of the bound PFAS congeners. Relative to human albumin, perfluoroalkyl carboxylic and sulfonic acids were bound with greater affinity by porcine and rat serum albumin, and the perfluoroalkyl ether acid congener bound with lower affinity to porcine and bovine serum albumin. These comparative affinity data for PFAS binding by serum albumin from human, experimental model, and livestock species reduce critical interspecies uncertainty and improve accuracy of predictive bioaccumulation and toxicity assessments for PFAS.