Although inhalation of nanoplastics (NPs) is widely recognized as a trigger of pulmonary injury, the mechanisms underlying lung damage induced by orally ingested NPs remain largely uncharacterized. Computational toxicology profiling predicted the involvement of efferocytosis in nanoplastic toxicity. Protein phosphatase 2A (PP2A) is an important regulator of macrophage function, and PP2A Aα deficiency impaired efferocytosis. To delineate the contribution of efferocytosis to nanoplastics-induced pulmonary toxicity, myeloid-specific PP2A Aα-deficient (HO) mice model (Ppp2r1a gene deletion) and matched wild-type (WT) littermates were administrated with polystyrene nanoplastics (PS-NPs) by gavage at dose of 10 mg/kg·bw for 4 successive weeks. PS-NPs treatment led to sex-dependent lung inflammation, oxidative damage, and apoptosis in WT mice, which were further aggravated in HO mice. Proteomics analysis revealed impaired efferocytosis in HO mice was associated with perturbations in protein kinase A, ERK/MAPK, Hedgehog signaling pathway etc. In vitro studies confirmed that PP2A Aα deficiency dysregulated Hedgehog signaling, thereby suppressing macrophage efferocytosis and exacerbating pulmonary injury following PS-NPs exposure. Notably, we identified biochanin A as a compound capable of attenuating PS-NPs-induced pulmonary inflammation by enhancing efferocytosis. Together, these findings uncover a novel PP2A-Hedgehog-efferocytosis axis in NPs-induced pulmonary injury and highlight biochanin A as a potential intervention candidate for particulate pollutants-associated respiratory diseases. • Myeloid-specific deletion of the PP2A Aα gene impairs macrophage efferocytosis. • Efferocytosis plays a role in PS-NPs-induced pulmonary injury and is mediated by the PP2A/Hedgehog signaling pathway. • Biochanin A alleviates PS-NPs-induced pulmonary inflammatory injury by activating macrophage efferocytosis.

The increasing frequency of heat waves, combined with elevating ozone levels, constitutes an increasingly significant threat to public health. In this study, 8-week-old male C57BL/6J mice were subjected to individual or combined exposure of ozone (1 ppm) and heat (34°C) for 4 weeks. Both ozone and heat exposure disrupted intestinal barrier integrity and intestinal stem cell (ISC) function, with the most severe effects observed under combined exposure. Notably, co-exposure to ozone and heat resulted in the largest increase in Alistipes finegoldii (A. finegoldii) abundance, accompanied by enhanced tryptophan metabolism activity. Gut microbiota depletion and vertical microbiota transfer, together with intestinal content gavage, demonstrated the critical role of gut microbiota and their metabolites in mediating intestinal disruption. Colonization by A. finegoldii impaired ISC proliferation and differentiation, with elevated levels of indole and its derivatives, including indole-3-acetic acid (IAA) and tryptamine. Moreover, inhibition of aryl hydrocarbon receptor (AhR) signaling alleviated co-exposure-induced of intestinal injury. Mechanistically, AhR activation contributed to mitochondrial dysfunction. Interaction analysis indicated that ozone and heat primarily acted in an additive manner on gut integrity and microbiota dysbiosis. This study reveals that the A. finegoldii-tryptophan catabolite-AhR axis mediates the disruption of intestinal homeostasis induced by combined ozone and heat exposure.

Ozone pollution is a growing global health threat, yet current evidence lacks cellular-level resolution to pinpoint its systemic damage. This randomized controlled crossover trial introduces plasma cell-free DNA (cfDNA) as a novel, sensitive biosensor for ozone-induced injury. In 29 healthy adults, acute ozone exposure (282.2 +/- 44 ppb) significantly altered cfDNA characteristics: it reduced the proportion of 150-165 bp fragments and increased cfDNA derived from megakaryocytes (21.35%), vascular endothelia (135.10%), and B/NK/T cells (174.69%), revealing these as key cellular targets. Epigenetic analysis revealed increased perplexity at transcription start sites, indicating enhanced entropy and potential transcriptional dysregulation. These cfDNA signatures correlated with systemic physiological changes, including elevated inflammatory markers (interleukin-6, tumor necrosis factor-alpha), oxidative stress (8-hydroxy-2 '-deoxyguanosine), endothelial dysfunction (endothelin-1), and lung epithelial injury (Clara cell secretory protein 16). Our findings demonstrate that cfDNA profiling can dynamically reflect ozone-induced cellular damage in the vascular, hematopoietic, and immune systems, moving beyond organ-level assessments. This approach provides a powerful and noninvasive tool for monitoring early systemic effects of air pollution, with implications for understanding mechanistic pathways and developing targeted interventions.

Background: Evidence concerning greenspace and ocular and adnexal diseases (OADs) is scarce. Methods: This prospective cohort study followed 241,576 UK participants from baseline (2006-2010, age range: 37 to 73 years old) until May to October 2022, identifying 9 OAD subtypes through electronic health records. Residential greenspace was evaluated using the percentage of greenspace (GS%) derived from the 2005 General Land Use Database. Cox proportional hazards models and mediation analyses were employed to assess the associations. Results: The associations between greenspace and OAD varied by subtype, exhibiting nearly inverse J-shaped or inverse U-shaped exposure-response curves. Comparing the highest with the lowest quartile of GS% within a 300-m buffer, beneficial associations were observed for (a) lens disorders [hazard ratio (HR): 0.931 [95% confidence interval (CI): 0.896 to 0.968]] and (b) choroid and retina disorders (HR: 0.935 [95% CI: 0.874 to 1.000]). These beneficial associations for lens disorders were partially mediated by physical activity and air pollution. In contrast, detrimental associations were found for (a) eyelid, lacrimal system, and orbit disorders (HR: 1.082 [95% CI: 1.018 to 1.150]) and (b) conjunctiva disorders (first quartile versus third quartile, HR: 1.129 [95% CI: 1.027 to 1.241]). Conclusions: Greenspace exposure may exert both beneficial and detrimental associations across various OAD subtypes. The findings may inform the development of area- or individual-level greenspace interventions to mitigate OAD burden.

Arsenic (As) is classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC). Exposure to As has been associated with an increased risk of various cancers, particularly lung cancer. However, the precise molecular mechanisms contributing to this carcinogenesis are not well understood. In our study, we analyzed transcriptomic data from the GEO database (GSE36684), identifying 764 differentially expressed genes (DEGs) in BEAS-2B cells treated with environmentally relevant doses of As for 8 weeks. A KEGG pathway enrichment analysis suggested that the FoxO pathway activation might be a novel key signaling event in As-induced carcinogenesis. We further analyzed the expression of 11 DEGs involved in the FoxO pathway using the TCGA-LUSC dataset. The findings revealed that four genes displayed expression patterns in tumor tissues consistent with those observed after As treatment in GEO dataset. Among them, USP7 was upregulated, while ATM, S1PR1, and PLK2 were downregulated in cancer tissues. High USP7 expression was specifically linked to a poor prognosis in lung squamous cell carcinoma (LUSC). To explore the role of USP7 in As-induced malignant transformation, BEAS-2B cells were exposed to NaAsO2 concentrations of 0.2 μM and 2 μM for up to 20 weeks. Experimental results confirmed that NaAsO2 treatment suppressed the FoxO transcriptional activity by upregulating USP7 expression, subsequently downregulating ATM and PLK2 expression, which led to abnormalities in cell cycle regulation and apoptosis. Notably, knocking down USP7 in As-transformed cells resulted in significant reductions in cell proliferation, colony formation, and tumor formation ability in nude mice, indicating the USP7-regulated FOXO3A pathway could be central to As-induced lung carcinogenesis. Moreover, our research demonstrated that USP7 inhibited FOXO3A's ability to translocate from the cytoplasm to the nucleus by affecting its monoubiquitination status. Additionally, we speculated that As-induced the elevation of USP7 expression due to the excessive inflammatory cytokines secretion and the activation of mTORC1/WTAP pathway. These findings offer novel insights into the molecular mechanisms underlying As-mediated lung cancer.

BACKGROUND:Nasopharyngeal carcinoma is an aggressive malignancy originating from the nasopharyngeal mucosa and associated with genetic factors. Many nasopharyngeal carcinoma susceptibility loci have been identified by genome-wide association studies (GWASs), but their underlying functional insights are largely unexplained. RESULTS:A meta-GWAS including 5073 nasopharyngeal carcinoma patients and 5860 controls from nasopharyngeal carcinoma endemic areas identifies a total of 863 significant SNPs, including SNPs at a novel locus 3p24.1 (rs56365817; nearby genes: CMC1/EOMES). By integrating the GWAS signals with single-cell and bulk profiles, we find nasopharyngeal carcinoma susceptibility robustly associated with T cells in different methods and datasets. In nasopharyngeal carcinoma-associated cell type, we identify 234 putative susceptibility genes (81.62% of them novel), mainly enriched in immune-related biological processes. Five putative causal genes are prioritized. We perform in-depth bioinformatic analysis and functional experiments for EOMES, finding that the nasopharyngeal carcinoma-risk alleles of four functional SNPs upregulate EOMES expression by promoting the activity of regulatory elements in T cells, and EOMES participates in nasopharyngeal carcinoma tumorigenesis via regulation of CD8+ T cell exhaustion in the tumor microenvironment. CONCLUSIONS:This study uncovers novel nasopharyngeal carcinoma susceptibility genes and their functional cell types, which improves the understanding of nasopharyngeal carcinoma genetic etiology.

Epidemiological studies have demonstrated associations between heat waves, ozone (O3) pollution, and cardiovascular morbidity and mortality. High temperature (HT) and higher levels of O3 usually co-exist in the atmosphere. However, few studies have investigated the adverse effects of HT and O3 co-exposure on cardiovascular system. Therefore, this study aimed to examine the effects of HT and O3 co-exposure on biomarkers of cardiovascular damage and potential mechanisms. Sixty-four healthy SPF male C57BL/6N mice, aged 8 weeks, were randomly allocated into four groups: control, O3, HT, and co-exposure (HT+O3). Mice inhaled filtered air or 1 ppm O3 at 24 °C or 36 °C, respectively, 4 h/day, for 5 consecutive days. Following the exposure, the biological samples of mice were collected for examination of biomarkers of cardiovascular disorders. Exposure to HT+O3 exacerbated cardiovascular pathological damage induced by HT or O3 alone. Compared to the control, the co-exposure group caused significant alterations of cardiovascular biomarkers. Moreover, co-exposure enhanced reduction of Lactobacillus and Ruminococcus and increases in Prevotella and Alistipe abundances induced by either HT or O3. Moreover, co-exposure also promoted O3-induced plasma metabolic disorder and these metabolites were enriched in multiple metabolic pathways typified by steroid hormone biosynthesis, biosynthesis of unsaturated fatty acids, and phenylalanine metabolism, among others. Spearman correlation analysis indicated that alterations of gut microbiota were significantly correlated with biomarkers of cardiovascular damage as well as plasma metabolic disorder. Exposure to HT and O3 leads to cardiovascular damage, which possibly implicates gut microbial dysbiosis and plasma metabolic disorder.

Global warming has increased the frequency of simultaneous ozone and heat exposure, raising significant public health concerns. This study investigates the impacts of gestational exposure to ozone (1 ppm) and heat (34°C) under real-world conditions on fetal and placental development in C57BL/6 J mice, with a particular focus on the role of maternal hepatic lipid metabolism. Pregnant mice were exposed from gestational day (GD) 0 to GD17. Co-exposure to ozone and heat significantly reduced fetal birth weight and crown-rump length, and exacerbated adverse pregnancy outcomes, while exposure to ozone or heat alone did not significantly reduce fetal birth weight or crown-rump length. Placental development was impaired in the co-exposure group, particularly in the trophoblast zone. Ex vivo cell experiments revealed that plasma from co-exposed pregnant mice induced functional impairment in HTR-8/SVneo trophoblast cells. Maternal plasma analysis revealed a strong association between impaired placental and fetal development and abnormal lipid levels, which play a key role in causing developmental toxicity. Transcriptomic analysis of maternal liver tissue revealed that ozone exposure suppressed LDL and VLDL absorption, while heat promoted triglyceride synthesis. Co-exposure further exacerbated disruptions in hepatic lipid homeostasis. These findings highlight the detrimental effects of ozone and heat co-exposure on maternal and fetal health, suggesting that fetal impairments may be mediated by maternal hepatic lipid metabolism dysregulation.

The ability of organisms to recover from microplastic (MP) exposure is critical for forming global strategies for MP regulation, risk mitigation, and health protection. However, the recovery dynamics following chronic exposure to environmentally relevant concentrations (ERCs) of MPs remains poorly understood. Here, we present a comprehensive investigation into postexposure recovery following long-term ingestion of polystyrene MPs (40-100 μm) in mice. Animals were fed MPs at either an ERC (approximately 512-2060 particles/day) or a high-dose level (ten times ERC) for 21 weeks, followed by a 4 week recovery period without exposure. Despite cessation of exposure, disruptions in lipid metabolism and gut microbiota persisted in dose- and size-dependent manners, with high-dose groups showing markedly limited recovery. Mechanistic in vitro studies using Caco-2 cells further revealed that MPs impair lipid metabolic homeostasis via sustained suppression of the AMP-activated protein kinase (AMPK) signaling pathway. Together, our findings provide crucial in vivo evidence via a mammalian model that chronic exposure to ERCs of MPs can lead to long-lasting metabolic and microbiome disturbances postexposure. These results underscore the urgency of reassessing the long-term health risks of MPs and developing strategies that address both exposure and postexposure recovery.

Di(2-ethylhexyl) phthalate (DEHP) is a widespread ubiquitous phthalate environmental contaminant. The male reproductive toxicity (MRT) from exposure to DEHP and its main metabolite, mono(2-ethylhexyl) phthalate (MEHP), has been well documented. Fully elucidating its toxic mechanism and discovering effective antagonists are desirable means to reduce the health risks of DEHP. In this study, 552 genes related to MRT induced by DEHP/MEHP were screened out from the Comparative Toxicogenomics Database (CTD) and DisGeNET database. Next, we developed a global adverse outcome pathway (AOP) network based on the existed AOP-wiki. After functional enrichment analyses and mapping to the global AOP network, we found that the increased ROS level, cell cycle arrest, and increased apoptosis are key events (KEs) involved in DEHP-mediated MRT, which was validated in TM3 Leydig cell model. Among them, cellular apoptosis is the core KE in DEHP-induced MRT via network topological analysis. Eventually, we developed a novel in silico antagonist screening platform (http://43.136.69.224:3838/wlab/) based on drug-target gene set enrichment analysis (dtGSEA version 2.0). Several potential candidates that mitigate DEHP-mediated cellular apoptosis have been screened out, including quercetin, taurine, methionine, and phloridzin. Further experimental results demonstrated that phloridzin provided the most effective protection against MEHP-induced apoptosis in TM3 cells probably through the p53 and MAPK signaling pathways. Molecular docking and molecular dynamics simulations suggest that STAT3 and RUNX1 may be important targets for phloridzin to antagonize MEHP-induced MRT. Our study provides a new approach to discover the antagonists for the toxicity of environmental contaminants based on AOP network and dtGSEA methods.

Environmental ozone pollution may adversely impact human health, while dysbiosis is implicated in various health outcomes. However, the effects of ozone exposure on the human microbiome remain unclear. This study conducted a controlled, randomized, crossover ozone exposure trial with 29 participants exposed to filtered air and ozone. Oral microbiome samples were collected for 16S rRNA sequencing. A mixed-effects model was used to analyze the impact of ozone exposure on the diversity and composition of the oral microbiome, as well as their association with lung functions. The results showed that the ozone concentration remained stable at 5 ± 5.1 parts per billion (ppb) under filtered air and 282.2 ± 44 ppb during ozone exposure. Acute ozone exposure significantly impaired lung function and reduced oral microbiome diversity, with forced vital capacity (FVC) decreasing by 0.41 L, expiratory volume in one second (FEV1) by 0.36 L, and peak expiratory flow (PEF) by 0.81 L, while observed species richness (Sobs), abundance-based coverage estimator (Ace), and chao indices (Chao) decreased by 21.83, 22.24, and 21.87%, respectively. Males exhibited greater sensitivity to ozone exposure than females, reflected in both reduced lung function and alterations in the oral microbiome. The altered microbiome was mainly enriched in metabolic pathways. Among the microbiome, Treponema medium exhibited a significant correlation and mediating effect on ozone-induced lung function impairment, which may serve as a sensitive indicator of changes in lung function. These findings provide new insights into the health effects caused by ozone exposure.

Although the effects of ozone and heat on health have been studied independently, the impact of combined exposure remains poorly understood. In this study, C57BL/6 J male mice were individually exposed to ozone (1 ppm), heat (34 degrees C), or both in combination for 4 weeks (5 days/week, 3 h/day). In the Co-exposure group, stress hormones were increased, intensifying the activation of both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) axis. Co-exposure to ozone and heat disrupted lipid homeostasis, as evidenced by elevated low-density lipoprotein cholesterol (LDL-C) and free fatty acids (FFA). Additionally, the combined exposure promoted hepatic lipid accumulation and oxidative stress. Co-exposure also induced the whitening of brown adipose tissue, reducing its capacity for thermogenesis and potentially worsening lipid dysregulation in the liver and systemic circulation. Transcriptomic analysis of the liver identified perturbations in key pathways related to cellular stress response and lipid metabolism. Notably, key enzymes responsible for cholesterol clearance, such as cholesterol 7 alpha-hydroxylase (Cyp7a1), and ATP-binding cassette transporters G5 (Abcg5) and G8 (Abcg8) were suppressed in the Co-exposure group. These findings underscore the additive effects of simultaneous ozone and heat exposure in lipid metabolism, highlighting the increased risk of metabolic disorders under environmental stress.

Ozone, a prevalent environmental pollutant, poses significant risks to human health. This study systematically evaluates the impact of subchronic ozone exposure on multiple organs using three-month-old male C57BL/6 J mice exposed to 0.5 or 2.0 ppm ozone for 12 weeks, followed by 4-week recovery period. Subchronic ozone exposure caused systemic damage, including weight loss, inflammation, oxidative stress, and dyslipidemia, with varying degrees of reversibility. Comprehensive histopathological and functional analyses revealed dose-dependent injuries, organ-specific response patterns, and varying recovery capacities within a 4-week cessation of exposure. The lung demonstrated the highest susceptibility with dose-dependent damage and high reversibility. In contrast, the liver, kidneys, and brain, exhibited milder yet largely irreversible damage, particularly at 2.0 ppm. Transcriptomic analyses identified high reversibility in lung inflammation pathways, persistent metabolic dysregulation in the liver and kidneys, neurodegeneration-related perturbations in the brain with minimal recovery capacity. Furthermore, common molecular drivers, such as oxidative stress and inflammation, were identified across all organs, revealing both unique and shared mechanisms of injury and recovery. These findings underscore the systemic nature of ozone toxicity and the need for targeted interventions. Persistent dyslipidemia and metabolic dysregulation in the liver and kidneys emphasize the necessity for ongoing monitoring and potential interventions for individuals exposed to elevated ozone levels.

Histone modifications maintain genomic stability and orchestrate gene expression at the chromatin level. Benzo [a]pyrene (BaP) is the ubiquitous carcinogen widely spread in the environment, but the role and regulatory mechanism of histone modification in its toxic effects remain largely undefined. In this study, we found a dose-dependent reduction of histone H3 methylations at lysine4, lysine9, lysine27, lysine36 in HBE cells treated with BaP. We observed that inhibiting H3K27 and H3K36 methylation impaired cell proliferation, whereas the loss of H3K4, H3K9, H3K27, and H3K36 methylation led to increased genomic instability and delayed DNA repair. H3K36 mutation at both H3.1 and H3.3 exhibited the most significant impacts. In addition, we found that the expression of SET domain containing 2 (SETD2), the unique methyltransferase catalyzed H3K36me3, was downregulated by BaP dose-dependently in vitro and in vivo. Knockdown of SETD2 aggravated DNA damage of BaP exposure, which was consistent with the effects of H3K36 mutation. With the aid of chromatin immunoprecipitation (ChIP) -seq and RNA-seq, we found that H3K36me3 was responsible for transcriptional regulation of genes involved in pathways related to cell survival, lung cancer, metabolism and inflammation. The enhanced enrichment of H3K36me3 in genes (CYP1A1, ALDH1A3, ACOXL, WNT5A, WNT7A, RUNX2, IL1R2) was positively correlated with their expression levels, while the reduction of H3K36me3 distribution in genes (PPARGC1A, PDE4D, GAS1, RNF19A, KSR1) were in accordance with the downregulation of gene expression. Taken together, our findings emphasize the critical roles and mechanisms of histone lysine methylation in mediating cellular homeostasis during BaP exposure.

The high incidence of colorectal cancer (CRC) is closely associated with environmental pollutant exposure. To identify potential intestinal carcinogens, we developed a cell transformation assay (CTA) using mouse adult stem cell-derived intestinal organoids (mASC-IOs) and assessed the transformation potential on 14 representative chemicals, including Cd, iPb, Cr-VI, iAs-III, Zn, Cu, PFOS, BPA, MEHP, AOM, DMH, MNNG, aspirin, and metformin. We optimized the experimental protocol based on cytotoxicity, amplification, and colony formation of chemical-treated mASC-IOs. In addition, we assessed the accuracy of in vitro study and the human tumor relevance through characterizing interdependence between cell-cell and cell-matrix adhesions, tumorigenicity, pathological feature of subcutaneous tumors, and CRC-related molecular signatures. Remarkably, the results of cell transformation in 14 chemicals showed a strong concordance with epidemiological findings (8/10) and in vivo mouse studies (12/14). In addition, we found that the increase in anchorage-independent growth was positively correlated with the tumorigenicity of tested chemicals. Through analyzing the dose-response relationship of anchorage-independent growth by benchmark dose (BMD) modeling, the potent intestinal carcinogens were identified, with their carcinogenic potency ranked from high to low as AOM, Cd, MEHP, Cr-VI, iAs-III, and DMH. Importantly, the activity of chemical-transformed mASC-IOs was associated with the degree of cellular differentiation of subcutaneous tumors, altered transcription of oncogenic genes, and activated pathways related to CRC development, including Apc, Trp53, Kras, Pik3ca, Smad4 genes, as well as WNT and BMP signaling pathways. Taken together, we successfully developed a mASC-IO-based CTA, which might serve as a potential alternative for intestinal carcinogenicity screening of chemicals.

Atmospheric particulate matter (PM) exposure-induced neuroinflammation is critical in mediating nervous system impairment. However, effective intervention is yet to be developed. In this study, we examine the effect of β-nicotinamide mononucleotide (NMN) supplementation on nervous system damage upon PM exposure and the mechanism of spatial regulation of lipid metabolism. 120 C57BL/6 male mice were exposed to real ambient PM for 11 days (subacute) or 16 weeks (sub-chronic). NMN supplementation boosted the level of nicotinamide adenine dinucleotide (NAD+) in the mouse brain by 2.04 times. This augmentation effectively reduced neuroinflammation, as evidenced by a marked decrease in activated microglia levels across various brain regions, ranging from 29.29 to 85.96

The mode of action (MOA) framework is proposed to inform a biological link between chemical exposures and adverse health effects. Despite a significant increase in knowledge and awareness, the application of MOA in human health risk assessment (RA) remains limited. This study aims to discuss the adoption of MOA for health RA within a regulatory context, taking our previously proposed but not yet validated MOA for lead neurotoxicity as an example. We first conducted a quantitative weight of evidence (qWOE) assessment, which revealed that the MOA has a moderate confidence. Then, targeted bioassays were performed within an in vitro blood-brain barrier (BBB) model to quantitatively validate the scientific validity of key events (KEs) in terms of essentiality and concordance of empirical support (dose/temporal concordance), which increases confidence in utilizing the MOA for RA. Building upon the quantitative validation data, we further conducted benchmark dose (BMD) analysis to map dose-response relationships for the critical toxicity pathways, and the lower limit of BMD at a 5% response (BMDL5) was identified as the point of departure (POD) value for adverse health effects. Notably, perturbation of the Aryl Hydrocarbon Receptor (AHR) signaling pathway exhibited the lowest POD value, measured at 0.0062 μM. Considering bioavailability, we further calculated a provisional health-based guidance value (HBGV) for children's lead intake, determining it to be 2.56 μg/day. Finally, the health risk associated with the HBGV was assessed using the hazard quotient (HQ) approach, which indicated that the HBGV established in this study is a relative safe reference value for lead intake. In summary, our study described the procedure for utilizing MOA in health RA and set an example for MOA-based human health risk regulation.

Hexavalent chromium (Cr(VI)) exposure has been linked with gastrointestinal toxicity, whereas the molecular pathways and key targets remain elusive. Computational toxicology analysis predicted the correlation between protein phosphatase 2A (PP2A) and genes regarding Cr(VI)-induced intestinal injury. Here, we generated a mouse model with intestinal epithelium-specific knock-out of Ppp2r1a (encoding PP2A Aα subunit) to investigate the mechanisms underlying Cr(VI)-induced small intestinal toxicity. Heterozygous mice (HE) and matched wild-type (WT) littermates were administrated with Cr(VI) at 0, 5, 20, 80 mg/L for 28 successive days. Cr(VI) treatment led to crypt hyperplasia, epithelial cell apoptosis, and intestinal barrier dysfunction, accompanied by the decline of goblet cell counts and Occludin expression in WT mice. Notably, these effects were aggravated in HE mice, indicating that PP2A Aα deficiency conferred mice with susceptibility to Cr(VI)-induced intestinal injury. Integrated data analysis and biological experiments revealed Cr(VI) exposure could decrease YAP1 phosphorylation at Ser127 but increase protein expression and activity, together with elevated TAZ protein driving epithelial crypt cells proliferation following damage, suggesting the involvement of Hippo/YAP1 signaling pathway in Cr(VI)-induced intestinal toxicity. Nevertheless, the enhanced phosphorylation of YAP1 in HE mice resulted in proliferation/repair defects in intestinal epithelium, thereby exacerbating Cr(VI)-induced gut barrier dysfunction. Notably, by molecular docking and further studies, we identified Urolithin A, a microbial metabolite, attenuated Cr(VI)-induced disruption of intestinal barrier function, partly by modulating YAP1 expression and activity. Our findings reveal the novel molecular pathways participated in Cr(VI)-caused small intestinal injury and urolithin A could potentially protect against environmental hazards-induced intestinal diseases.