Single-cell RNA sequencing reveals the heterogeneity of hepatic non-parenchymal cell responses to chronic PFO5DoDA exposure in male mice.

Perfluoroalkyl ether carboxylic acids (PFECA) have emerged as novel alternatives to legacy per- and polyfluoroalkyl substances (PFAS). Existing research has revealed hepatoxicity induced by various PFAS, including PFECA. However, these studies have primarily focused on overall changes in whole liver tissue, particularly in hepatocytes, with the impact of PFAS on diverse liver non-parenchymal cells (NPCs) still inadequately understood. In the present study, we examined the heterogeneous responses of hepatic NPCs following exposure to perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoDA), a type of PFECA, by administering PFO5DoDA (5 µg/L)-contaminated water to male mice for one year. Single-cell RNA sequencing (scRNA-seq) of 15 008 cells from the liver identified 10 distinct NPC populations. Notably, although relative liver weight remained largely unchanged following exposure to 5 µg/L PFO5DoDA, there was an observed increase in proliferating cells, indicating that proliferating NPCs may contribute to the hepatomegaly frequently noted in PFAS-exposed livers. There was also a considerable alteration in the composition of hepatic NPCs. Specifically, the total number of B cells decreased substantially, while many other cells, such as monocytes and macrophages, increased after PFO5DoDA exposure. In addition, interactions among the hepatic NPC populations changed variously after PFO5DoDA exposure. The findings emphasize the heterogeneity in the responses of hepatic NPCs to PFO5DoDA exposure. Taken together, the changes in immune cell populations and their intercellular interactions suggest that PFO5DoDA disrupts immune homeostasis in the liver. These findings offer new insights into the cellular mechanisms of PFAS-induced liver damage.

[Advances in the applications of exposomics in the identification of environmental pollutants and their health hazards].

Environmental pollution has become a prominent global problem, and the potential health hazards of pollutants have caused widespread concern. However, revealing the relationship between complex-pollutant exposure and disease development remains an immense challenge. The core of environmental-health research and risk assessment is the identification of contaminants and their effects. Exposomics provides a new approach in the study of the relationship between environmental factors and human health. Both "top-down" and "bottom-up" strategies are employed in exposomics research. The development of new technologies for chemical detection and "multi-omics" has greatly facilitated the implementation of these strategies. Exposomics focuses on the measurement of an individual's lifelong exposure and aims to identify the health effects of such exposure. It involves the dynamic monitoring of external and internal exposure levels at different stages of life through traditional biomonitoring and exposomic methods. It also includes the identification of biomarkers, which indicate specific environmental exposures and the adverse effects of these exposures on health. Compared with traditional environmental-health studies, exposomics can more accurately reflect the diversity of exposure factors such as pollutants, natural factors, and lifestyles in the real environment, as well as the complexity of their in vivo processes and the responses they trigger in an organism. Powerful chemical analytical tools such as high-resolution mass spectrometry (HRMS) are widely used in studies related to the field of exposomics. Liquid chromatography-mass spectrometry (LC-MS) has been applied in the detection and analysis of environmental pollutants. Proteomics and metabolomics, as two important tools for biomarker identification and effects analysis, are widely used to explore the relationship between environmental factors and diseases. Pollutants can lead to pathological changes and even toxic effects by interacting with proteins. In the case of mixed exposure, some contaminants may present joint toxicity. The interaction between contaminants may change their environmental behavior or the amount of each contaminant that enters the human body, which, in turn, affects their health effects.

Environmentally relevant concentrations of fipronil selectively disrupt venous vessel development in zebrafish embryos/larvae.

The pesticide fipronil is widely dispersed in aquatic environments and frequently detected in the general population. Although the adverse effects on embryonic growth by fipronil exposure have been extensively documented, the early responses for its developmental toxicity are largely unknown. In the present study, we explored the sensitive targets of fipronil, focusing on vascular injury using zebrafish embryos/larvae and cultured human endothelial cells. Exposure to 5-500 µg/L fipronil at the early stage impeded the growth of sub-intestinal venous plexus (SIVP), caudal vein plexus (CVP), and common cardinal veins (CCV). The damages on venous vessels occurred at exposure to the environmentally relevant concentration as low as 5 µg/L fipronil, whereas no significant change was observed in general toxicity indexes. In contrast, vascular development of the dorsal aorta (DA) or intersegmental artery (ISA) was not affected. In addition, the mRNA levels of vascular markers and vessel type-specific function genes exhibited significant decreases in venous genes, including nr2f2, ephb4a, and flt4, but no appreciable change in arterial genes. Likewise, the more pronounced changes in cell death and cytoskeleton disruption were shown in human umbilical vein endothelial cells as compared with human aortic endothelial cells. Furthermore, molecular docking supported a stronger affinity of fipronil and its metabolites to the proteins correlated with venous development, such as BMPR2 and SMARCA4. These results reveal the heterogeneity in developing vasculature responsive to fipronil's exposure. The preferential impacts on the veins confer higher sensitivity, allowing them to be appropriate targets for monitoring fipronil's developmental toxicity.