Toxicological Sciences最新文献

The toxicologic impacts on the normative function of the chemosensory system and the loss of its contribution to organism protection and homeostasis remain an underrepresented area of interest in the published literature. The impact of chemical constituents in electronic nicotine delivery system e-liquids or aerosols on the chemosensory system is even less known, as are the effects on product selection and use behavior-and this may be an overlooked impact on the public health. This review is a snapshot of the current state of the science and opportunities for improving and increasing the volume of publications in chemosensory toxicology on the potential impacts of tobacco products. The proposed solutions rely on the determination of the scientific community to take advantage of an unexplored field of opportunity. Active research engagement and use of an integrative, risk-driven planning framework to address harmonization and data gaps in neurosensory research programs would support harmonization, improve scientific visibility in the published literature, and recruit additional investigators to this research community.

Chemosensory systems detect and discriminate a wide variety of molecules to monitor internal and external chemical environments. They initiate olfactory, gustatory, and chemesthetic sensations; influence human brain cognition and emotion; and guide a wide variety of behaviors essential for survival, including protective reactions, such as avoidance of contaminated foods and potential toxicants. Electronic nicotine delivery systems (ENDS) aerosolize e-liquids for inhaled consumption that typically contain flavorants, propylene glycol, vegetable glycerin, and nicotine. E-liquid aerosols also contain toxicants, such as formaldehyde, acetaldehyde, acrolein, and heavy metals. Chemosensory evaluation of ENDS aerosol plays an essential role in the assessment of whether a product will attract new users of all ages, as well as determining their likely use patterns, perceptions of product harm, satisfaction, and product selection. Nicotine and individual flavorant constituents stimulate multiple sensory receptor systems in complex patterns, initiating distinctive sensory perceptions depending on the chemical properties and quantity in the aerosol. There are limited data on chemosensory evaluation of ENDS aerosols and their influence on ENDS use and protective biologic mechanisms. This two-part manuscript provides an overview of (i) the physiology of the olfactory, gustatory, and chemesthetic chemosensory systems, their detection mechanisms, and their role in protective defenses; and (ii) the in vitro, in vivo, and in silico computer-based methodology available to evaluate ENDS irritants and toxicants, their impact on chemosensory pathways, the current state of the science related to e-liquid and ENDS aerosols, and challenges for future studies and scientific innovation.

Microphysiological systems (MPS) contain multiple cell types in three dimensions and often incorporate fluidic shear forces. There is interest in MPS for disease and efficacy modeling, safety and disposition studies. Animal cell-based MPS are needed to provide confidence in the translation of data from human cell-based MPS. We developed rat and dog quad-culture liver MPS incorporating primary hepatocytes, sinusoidal endothelial, Kupffer, and stellate cells. Using cryopreserved primary cells, we established a protocol for co-culturing cells under physiological flow conditions. Cells were evaluated for viability, morphology, and function (e.g. albumin production, cytochrome P450, and flavin-containing monooxygenase [FMO] activity). Optimized culture conditions maintained high-quality rat and dog liver chips for up to 7 days. Model performance was evaluated with ABT-288, a histamine-3 receptor antagonist that caused elevated serum transaminases in dogs but not rats. This finding was partially attributed to the high levels of FMO-mediated N-oxide metabolites produced in the dog. Key findings in our study were (i) dog chips showed much higher FMO-mediated N-oxidation compared with rat, and (2) dog chips exhibited modestly higher sensitivity to ABT-288 toxicity endpoints (albumin, alanine transaminase, and lactate dehydrogenase) compared with rat. Species differences in N-oxidation were not observed in rat and dog liver microsomes or 2D hepatocyte monocultures, suggesting that properties of the quad-culture MPS were necessary to model higher FMO activity observed in dogs in vivo. The data suggest that this preclinical species liver chip model provides novel understanding of in vitro to in vivo translation of ABT-288 dog liver toxicity.

Acute exposure to ozone (O3) causes pulmonary inflammation and injury in humans and animal models. In rodents, acute O3-induced inflammation and injury can be mitigated by pre-exposure to relatively low concentrations of O3, a phenomenon referred to as tolerance. Although tolerance was first described long ago, the underlying mechanisms are not known. We hypothesized that alveolar macrophages (AMs) play a key role in tolerance to O3 based on prior studies with other exposures. To enable our studies, we first generated a mouse model in which female C57BL6/NJ mice were pre-exposed to filtered air or 0.8 ppm O3 for 4 days (4 h/day), then challenged with 2 ppm O3 (3 h) 2 days later, and phenotyped for airway inflammation and injury 6 or 24 h thereafter. As expected, pre-exposure to O3 resulted in significantly reduced airway inflammation and injury 24 h following O3 challenge. Tolerance was associated with regenerative hyperplasia in the terminal bronchioles and changes in the frequency of proliferating alveolar type 2 cells. O3 pre-exposure altered the expression of ∼1,500 genes in AMs, most notably downregulation of Toll-like receptor and proinflammatory cytokine signaling pathways, suggesting AMs had become hypo-responsive. Depletion of tolerized AMs prior to acute O3 challenge did not, however, alter inflammation and injury. Additionally, adoptive transfer of tolerized AM to naïve recipient mice failed to alter responses to acute O3 challenge. In total, our results argue against an important role for AMs in tolerance to ozone and suggest that other cell types are involved.

C12 alkyl benzoate is present in the commercial emollient cosmetic ingredient C12-15 alkyl benzoate (Finsolv TN). Finsolv TN is a mixture of linear and branched esters of benzoic acid and aliphatic alcohols where linear C12 alkyl benzoate is a representative homolog with the shortest alkyl C-chain and lowest molecular weight. A preliminary non-GLP in vitro skin penetration study which monitored dermal bioavailability of all C12-15 alkyl benzoate constituents using GC-MS was carried out which demonstrated C12 alkyl benzoate could be considered a worst-case representative constituent to determine dermal absorption of the overall substance. Subsequently, [14C]-C12 alkyl benzoate was mixed into Finsolv TN, and applied, neat (10 µl/cm2), to dermatomed human skin mounted in a flow-through diffusion cell system. Receptor fluid was collected up to 24 h postdose and the skin was decontaminated at 8 h postdose. The absorbed dose, dermal delivery, potentially absorbable dose and dermally absorbed value of [14C]-C12 alkyl benzoate were 0.41%, 0.97%, 2.20%, and 2.97%, respectively. Metabolism during absorption was assessed in skin from the same donors, with no C12 alkyl benzoate detected in the receptor fluid, although the primary metabolite, [14C]-benzoic acid (>93%), was detected. A phenyl acetate esterase assay confirmed the presence of esterase activity in the donor skins used. Therefore, this study confirmed that dermal exposure of C12-15 alkyl benzoate (Finsolv TN) results in an absorbed dose of 2.97% completely metabolized to benzoic acid and aliphatic alcohol(s) in human skin. These findings indicate that a more in-depth investigation and assessment of toxicokinetic behavior (specifically for occupational exposures via the skin) provide opportunities to develop exposure-led strategies to avoid unnecessary animal testing allowing registrants to fulfill obligations to adhere to the "last resort" principle under REACH.

Human health reference values (HHRVs) developed by US governmental agencies and professional organizations are derived for specific purposes related to their organizational or statutory mandates, and for individual chemicals or substance groups (e.g. manganese compounds). Choosing an appropriate chemical-specific value should be based on the risk assessment need and the specific exposure context, along with a basic understanding of the various types and the intended purposes of each available HHRV. In this overview, HHRVs have been broadly organized into 3 main categories: values for the general public, occupational exposure limits, and emergency response values. The goal of this overview is to equip the reader with a greater understanding of HHRVs, how they are meant to be applied, and key aspects to consider in selecting the most appropriate value. These key aspects include target population (e.g. general public of all ages vs. working-age adults), duration and frequency of exposure, health effect severity, confidence in the data set, use of well-documented and contemporary derivation methods, transparency and documentation of the value derivation, and the thoroughness of the review process. Chemical- and exposure scenario-specific needs should determine which HHRV is most appropriate; however, a most appropriate HHRV may not be available for every chemical and situation. Therefore, we present both considerations and limitations to guide the selection of an alternate HHRV based on suitability for the assessment scenario from among the available chemical-specific values.

Exposures to per- and polyfluoroalkyl substances (PFAS) are associated with various adverse health outcomes, and a wide range of PFAS compounds have been detected in human serum, the environment, and food. Toxicokinetic models, however, have been developed for only a subset of the compounds of interest. To facilitate reverse dosimetry and risk assessment for the less studied PFAS compounds in food, we developed and evaluated an approach to adapt existing toxicokinetic models for nonhuman primates to predict human serum levels. The approach was validated with perfluorooctanoic acid and perfluorooctanesulfonic acid data and applied to perfluorohexanesulfonate. Results indicate that the approach yields similar dosimetry estimates to those of other models, particularly those used for regulatory purposes, suggesting the methodology can be leveraged to inform decision-making in data-sparse spaces. Applying and adapting the framework will improve our ability to connect dietary PFAS exposures to endpoints of concern for a wide range of PFAS compounds.

Congenital heart defects (CHDs) are common birth defects attributed to genetic and environmental factors, such as pharmaceuticals and chemicals. Identifying modifiable environmental factors and understanding their impact on heart development is crucial for mitigating chemical-induced CHDs. Given the increasing number of chemical agents, efficient high-throughput systems are essential to evaluate their teratogenic potential during cardiovascular development, which is a major concern for chemical safety. In this study, we developed 3 transgenic zebrafish reporter lines, myl7:EGFP, kdrl:mRFP, and gata1:mKate2, which enable real-time visualization of myocardial and endocardial development and cardiac function based on blood flow. These transgenic embryos were used to investigate the teratogenic effects of chemicals well known to induce heart defects in mammals, including humans. Our real-time imaging revealed that the teratogens induced significant malformations in cardiac morphogenesis, including abnormal heart tube formation, incomplete cardiac looping, and reduced heart chamber size. These teratogens also disrupted the expression of cardiac progenitor markers, suggesting impaired cardiac progenitor development. These defects were detected at the early stages (4-48 h post-fertilization), suggesting that the stages of progenitor development to heart looping were most susceptible to teratogen exposure, i.e. the critical period for teratogen-induced heart defects. Functional defects, such as impaired blood flow, were observed using real-time imaging of the gata1-reporter line. This study demonstrates the utilization of transgenic zebrafish embryo models for high-throughput teratogenicity testing, which also allows us to analyze the mechanisms underlying chemical-induced heart defects. Therefore, our zebrafish models would contribute to the identification and reduction of risks associated with CHDs.

Astrocytes, the most abundant glial cells in the central nervous system (CNS), play essential roles in maintaining neuronal homeostasis, synaptic regulation, and blood-brain barrier integrity. However, these cells can undergo senescence-a cellular state characterized by irreversible growth arrest and the secretion of proinflammatory factors-in response to aging and pathological stressors, contributing to synaptic dysfunction and neurodegenerative diseases. This review examines the molecular mechanisms driving astrocytic senescence, including oxidative stress, DNA damage, and inflammatory signaling pathways such as NF-κB and the senescence-associated secretory phenotype. A particular focus is placed on the diverse array of known chemical inducers of astrocyte senescence, such as pesticides and heavy metals, which provide critical insights into the processes governing cellular aging in the brain. By analyzing the effects of these inducers, we highlight their implications for neurodegenerative disease progression and brain aging. Understanding astrocytic senescence offers new insights into age-related neuropathology and presents promising avenues for targeted therapies in neurodegenerative disorders induced by environmental toxicants.

Exposure to the ambient air pollutant ozone induces acute and chronic respiratory health effects in part by causing inflammation of the airways. Several aspects of the inflammatory response to ozone can be modeled in vitro using primary human bronchial epithelial cells (HBECs) cultured at an air-liquid interface. We tested two commonly used HBEC culture media systems, one proprietary and one non-proprietary, to identify which system yielded the most in vivo-like pro-inflammatory response to acute ozone exposure as reflected by gene expression. Cells from 6 donors were grown in each culture system in parallel, followed by examination of epithelial morphology and cell type proportions prior to ozone exposure. Cultures grown in the proprietary system were notably thicker and contained more ciliated and secretory cells, as well as internal cyst-like structures. The transcriptomic response to acute ozone exposure (0.5 parts per million ozone × 2 h) was strongly affected by media type. HBECs grown in the proprietary system exhibited minimal changes after ozone, with only 7 differentially expressed genes (DEGs). In contrast, HBECs grown in the non-proprietary system exhibited a more dynamic response with 128 DEGs, including hallmark response genes indicative of inflammation (CXCL8) and oxidative stress (HMOX1). Gene set enrichment analysis using the 128 DEGs further corroborated upregulation of oxidative stress and inflammation pathways. In total, our results indicate that the choice of HBEC culture media should be carefully considered to best model the in vivo response to ozone.