Subchronic GenX Exposure Induces Hepatic Alterations Accompanied by Changes in PPAR-Related Lipid Metabolism and Autophagy-Related Proteins in Adult Male C57BL/6J Mice: Partial Attenuation by Chlorogenic Acid

2-Ethylhexyl Diphenyl Phosphate (EHDPP) Induces Hepatic Expression of Cytochrome P450s, Liver Damage, and Genotoxicity in Mice

As a commonly present organophosphorus flame retardant and persistent organic pollutant, 2-ethylhexyl diphenyl phosphate (EHDPP) has been observed to be genotoxic in cultured human hepatoma (HepG2) cells which depends on CYP activities. Yet, its impacts on hepatic Cyp expression, hepatotoxicity and genotoxicity in intact mammalians remain unidentified. In this study, adult male C57BL/6J mice received EHDPP by gastric gavage at doses of 50, 100, and 150 mg/kg (b.w.)/d for 7 d, then the hepatic expression of several Cyp proteins, aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) was analyzed by Western blotting; hepatoxicity was determined by serum ALT/AST activities and hepatic histological examination, while genotoxicity by comet assay, phosphorylated histone (γ-H2AX) protein, micronucleus test, and Pig-a assay. A micronucleus test in mouse hepatoma (Hepa1-6) cells in vitro was employed to observe the modulating effect of PCB 126 (100 nM)/BAY-218 (700 nM) (Ahr-Cyp1a1 activator/inhibitor). The results indicated that EHDPP induced hepatic Cyp1a1, 2e1, AhR, Cyp1a2, Cyp3a4 and PXR proteins and histologic liver damage at 50 mg/kg/d and/or higher doses, while at the highest dose (150 mg/kg/d) with hepatic DNA damage and micronucleus formation in bone marrow polychromatic erythrocytes. The result of Pig-a assay (at 14 and 28 d) was negative. In Hepa1-6 cells EHDPP induced micronucleus marginally; however, this effect was enhanced by PCB 126, while abolished by BAY-218. This study suggests that EHDPP may enhance protein expression of hepatic Cyp1a1, Cyp2e1, AhR and PXR and induce liver damage and DNA/chromosome damage in mice; Cyp1a1 might be a major activating enzyme.

Chronic BDE-47 Exposure Induces DNA Damage in Hepatocytes: Involvement of Oxidative Stress and CYP1A1/2 Upregulation

2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47) is a persistent food-chain pollutant targeting the liver, whose genotoxic potential remains poorly understood. Here we investigated BDE-47-triggered DNA damage using HepG2 cells and C3H/He mice. BDE-47 exposure markedly elevated DNA damage-related γ-H2AX foci in mouse liver. Cellular tests further validated BDE-47-induced DNA damage, manifested as elevated γ-H2AX foci, a higher comet tail DNA percentage, and a longer tail length. Mechanistically, BDE-47 activated the aryl hydrocarbon receptor (AHR) and raised hepatic reactive oxygen species (ROS) and malondialdehyde levels. In cellular assays, antioxidants alleviated DNA damage, whereas AHR inhibitors suppressed ROS overproduction. BDE-47 also upregulated hepatic CYP1A1/2, whose expression positively correlated with the severity of hepatic DNA injury in mice. In conclusion, BDE-47 exposure induces hepatocellular DNA damage, and its mechanism of action is closely associated with AHR-mediated oxidative stress and CYP1A1/2 upregulation, which offers new experimental evidence to clarify the hepatotoxic and genotoxic mechanisms of BDE-47.

Mangiferin mitigates mercuric chloride-induced hepatotoxicity: targeting Nrf2, NF-κB, NLRP3, and ER stress.

Oxidative Stress-Mediated DNA Damage and Macrophage Polarization Microenvironment: A Novel Mechanism of DCHP-Induced Male Reproductive System Impairment.

The global decline in male fertility has emerged as a major public health challenge, with mounting evidence pointing to a close association between endocrine-disrupting chemicals (EDCs) and reproductive dysfunction. As a representative member of this class, dicyclohexyl phthalate (DCHP) exhibits strong environmental persistence and bioaccumulation potential within the mammalian reproductive system. In the present study, male ICR mice were orally administered DCHP at 10, 100, or 300mg/kg/day for six consecutive weeks, and GC‑2 mouse spermatocyte cells were exposed to 5, 20, or 50μM DCHP for 24h. Long‑term, high‑dose DCHP exposure (300mg/kg/day) was associated with significant testicular histopathological alterations and impaired epididymal sperm parameters in mice. Both the in vivo and in vitro models revealed that DCHP treatment correlated with cell cycle disruption and proliferative arrest. Western blotting and TUNEL assays further indicated that DCHP could triggered apoptosis. As an exploratory acute ex vivo assessment, 35 human semen samples were exposed to DCHP (5, 20 and 50μM) for 12h, which revealed a dose-dependent reduction in sperm quality. At the mechanistic level, our data suggest a potential cascade wherein DCHP exposure is linked to oxidative stress, concomitant DNA damage, and mitochondrial dysfunction. RNA‑seq analysis further highlighted the enrichment of inflammatory responses and related signaling pathways. Subsequent validation experiments showed that DCHP exposure was accompanied by an increased testicular M1 macrophage population, elevated secretion of pro‑inflammatory cytokines (IL‑6, TNF‑α), and activation of the NF‑κB pathway-changes that may collectively contribute to an unfavorable testicular microenvironment and impaired sperm quality. Overall, our findings reveal close associations between DCHP exposure and testicular injury, proposing a working model involving oxidative stress and inflammation; however, further functional studies are required to establish definitive causal relationships.

Dexpanthenol Attenuates High-Fructose Corn Syrup-Induced Hepatic Injury in Young Adult Rats by Modulating Oxidative Stress, Apoptosis, and Inflammasome-Associated Pyroptotic Signaling

Excessive intake of high-fructose corn syrup (HFCS) contributes to pediatric metabolic dysfunction-associated steatotic liver disease, but the mechanisms linking fructose exposure to inflammatory cell death remain incompletely defined. This study investigated whether dexpanthenol (DEX) attenuates HFCS-induced liver injury by modulating oxidative stress, apoptosis, and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome-associated pyroptotic signaling. Thirty-two young adult male Wistar rats were assigned to control, HFCS, HFCS+DEX, and DEX groups (n = 8 each). HFCS-induced liver injury was established with 20% HFCS-55 in drinking water for 8 weeks. DEX (500 mg/kg/day, intraperitoneally) was administered from the end of week 4 to week 8. Liver tissues were assessed by histopathology; immunohistochemistry for caspase-3, malondialdehyde, and proliferating cell nuclear antigen; biochemical measurement of total antioxidant and oxidant status; and RT-qPCR analysis of Nlrp3, caspase-1, gasdermin D, and interleukin-1β. HFCS exposure caused steatosis, inflammation, and necrosis; increased histopathological scores; enhanced caspase-3, malondialdehyde, and proliferating cell nuclear antigen expression; elevated total oxidant status; and markedly upregulated inflammasome-related genes. Total antioxidant status did not differ among groups. DEX significantly improved hepatic architecture; reduced immunohistochemical markers of oxidative stress, apoptosis, and injury-associated proliferation; and downregulated NLRP3, caspase-1, gasdermin D, and interleukin-1β expression. These findings suggest that DEX attenuates HFCS-induced liver injury through a multi-target mechanism involving suppression of oxidative damage, apoptosis, and inflammasome-associated pyroptotic signaling in young adult rats.

Juglone Attenuates CCl₄‐Induced Hepatic Injury in Mice With Associated Modulation of Oxidative Stress and Inflammasome‐Related mRNA Expression

Carbon tetrachloride–induced liver injury is a well‐established model of toxic hepatitis, characterized by marked oxidative and inflammatory damage. It remains a relevant experimental system because broadly effective therapeutic options are still limited. Juglone, a natural naphthoquinone derived from Reynoutria japonica, has demonstrated antioxidant and anti‐inflammatory potential. However, mouse evidence combining standard liver injury measures with stress‐ and cell‐death gene profiling remains limited. Building on juglone studies in injury and fibrosis, we tested juglone in a CCl4 model. Male C57BL/6 mice were assigned to normal, vehicle, CCl₄, silymarin (200 mg/kg), and juglone (8 mg/kg) groups, and CCl₄ (in corn oil) was administered intraperitoneally. Endpoints included body weight, serum liver enzymes and lipid profile, H&E histology, and RT‐qPCR panels for inflammatory, pyroptosis‐associated, ER stress and autophagy‐linked, apoptotic, oxidative‐stress, and profibrotic transcripts. CCl₄ exposure was associated with weight loss, enzyme elevation, dyslipidemia, and architectural disruption, whereas juglone treatment was associated with improved biochemical indices and histology alongside coordinated downregulation of inflammatory/pyroptosis‐related transcripts (including Il-1β, Il-6, Nlrp3, and Gsdmd) and moderation of ER stress/autophagy and apoptosis‐linked transcripts, with downregulation of profibrotic transcripts (Acta2, Mmp2, and Tgfβ1). In this mouse CCl₄ model, juglone treatment was associated with reduced serum and tissue injury signatures together with changes in stress and inflammation‐linked transcriptional programs. Because the molecular findings are primarily based on RT‐qPCR, these results are best interpreted as gene‐level associations compatible with modulation of oxidative stress, inflammasome‐ and pyroptosis‐related mRNA expression, ER stress responses, apoptosis‐linked transcripts, and remodeling‐associated transcripts, rather than as confirmed pathway inhibition or established antifibrotic activity. These data support juglone as a hepatoprotective candidate and identify protein‐level and functional validation as important next steps.