Background Liver aging–induced failure and dysfunction in other organs constitute a critical aging phenotype that is distinct from chronological aging. Unlike intrinsic aging, hepatic senescence is predominantly driven by environmental factors. Tributyl phosphate (TBP) was identified as a potential key environmental trigger of liver aging; however, the underlying mechanisms remain largely elusive. Methods Rats and BRL-3A cells were treated with TBP. Serum metabolomics, liver proteomics, hepatocyte ultrastructure, β-galactosidase (β-GAL) activity, cell cycle progression, ROS and senescence-associated secretory phenotype (SASP) levels, as well as protein related to chromatin remodeling and DNA damage were used to evaluate liver aging. WRW4, ethidium bromide (EB), Lv-FH and monomethyl fumarate were utilized respectively to establish models of FPR2 inhibition, cytoplasmic mitochondrial DNA (mtDNA) depletion. fumarate clearance and supplied supplementation. Results TBP induced cell cycle arrest, increased β-GAL activity, and elevated ROS and MMP-1 levels while upregulating p53, lys9, and γ-H2A.X protein expression. Additionally, TBP inhibited HP1 protein expression in rat livers and cells(P < 0.05). Significant changes in metabolites and proteins following TBP exposure were enriched in aging-related pathways. After treating with, WRW4, EB, Lv/sh-FH and monomethyl fumarate respectively, these changes were all reversed in BRL-3A cells (P < 0.05). Conclusion This study elucidat the effect of fumarate-mediated mtDNA escape in liver aging induced by TBP. We found that exposure to TBP induces the levels of fumarate, which directly drives mtDNA escape and activates the FPR2, finally triggers liver aging of rats.
Arsenic is a naturally occurring metalloid, and its pollution poses a global threat to humanity. Studies have shown that arsenic exposure accelerates aging, but the effects and mechanisms of sodium arsenite exposure on aging across both parental and offspring remain unclear. In this study, we investigated the effects of sodium arsenite on lifespan, locomotion, heat tolerance, antioxidant defense systems, autophagy, and the insulin/IGF-1 signaling (IIS) pathway in Caenorhabditis elegans (C. elegans). Initially, exposure from the L1 to L4 larval stage to 100 μM or 200 μM sodium arsenite significantly shortened the lifespan of C. elegans. Sodium arsenite also reduced body length, body width, head-swing frequency, and heat-stress resistance. It also reduced superoxide dismutase (SOD) activity while increasing reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation in C. elegans parents and offspring. qRT-PCR analysis showed that sodium arsenite exposure activated the IIS pathway in C. elegans parents and offspring by upregulating the upstream genes age-1 and daf-2 and downregulating the downstream transcription factor daf-16. Concurrently, it reduced the mRNA levels of bec-1, lgg-1, and sod-3, indicating impaired autophagy and reduced DAF-16 activity. Furthermore, sodium arsenite exposure diminished the fluorescence intensity of LGG-1::GFP in the DA2123 strain and SOD-3::GFP in the CF1553 strain across both generations, consistent with the qRT-PCR results. To further investigate the role of autophagy, we treated worms with rapamycin, which alleviated the pro-aging effects of arsenite in both generations. Therefore, our results show that sodium arsenite exposure accelerates aging in both parental and offspring C. elegans, a process linked to the IIS pathway, oxidative stress, and autophagy.
Congenital anomalies of the kidney and urinary tract are the leading cause of chronic kidney disease in children. Cadmium (Cd is a developmental toxicant that acts primarily by impairing placental function. However, the underlying placenta-origin injury mechanisms of gestational Cd-induced fetal renal dysplasia have not been fully elucidated. Here, we established a mouse model by administering pregnant CD-1 mice a single intraperitoneal injection of cadmium chloride solution (0, 2.25, and 4.50 mg/kg) on gestational day 8. We demonstrated that gestational Cd treatment induced placental senescence and inhibited fetal renal proliferation. Based on the integration of mouse placental transcriptomic data with a senescence-associated secretory phenotype (SASP) database of human-mouse orthologous secretory proteins, we identified CXCL1 as a key SASP factor mediating Cd-induced fetal renal dysplasia. Additionally, mouse intervention experiments demonstrated that resveratrol supplementation effectively reversed both placental senescence and renal dysplasia. In cellular experiments, treatment with CXCL1 inhibited the proliferation of human embryonic kidney (HEK293T) cells. Furthermore, in human studies, CXCL1 expression was also increased in senescent placentae, and elevated neonatal serum CXCL1 levels were negatively correlated with renal function. Overall, these findings suggest that placenta-derived CXCL1 is associated with fetal renal dysplasia upon gestational Cd treatment, which provides a central mechanism for fetal-derived diseases.
Both preventing cadmium (Cd) from entering the food system and maximizing the utility of Cd-contaminated soils are of paramount importance. This study investigated the mitigation of Cd²⁺ toxicity in clove basil seedlings, an aromatic plant producing essential oil, by molybdenum (Mo) supplementation. The results revealed a distinct, Mo-mediated defense mechanism. First, phenotypic assessments showed that exogenous Mo application (0.08 μM) restored Cd-inhibited seedling growth, increasing whole-plant fresh weight by 37.62%. Concurrently, Mo application reduced Cd²⁺ levels by at least 8.31% and suppressed net Cd²⁺ translocation from roots to shoots. Second, transcriptomic analysis integrating WGCNA and GSEA revealed that Cd + Mo combination treatment induced lipid biosynthesis pathways while retarding detrimental lipid metabolism. These results were corroborated by metabolomics analysis, which showed that the most altered metabolites by Cd + Mo were lipids. Third, physiological measurements demonstrated that Cd + Mo enhanced the antioxidant activity. Specifically, glutathione reductase activity and glutathione content increased by 112.07% and 17.79%, respectively, while glutathione peroxidase activity was reduced by 92.18%. Mechanistically, multi-omics and physiological analyses highlighted that Mo mitigated Cd²⁺ toxicity primarily by reducing Cd²⁺ uptake, enhancing antioxidant activity, and modulating lipid metabolism. Therefore, this study provides critical mechanistic insights into Mo-mediated Cd tolerance, offering a significant contribution to the field by establishing a highly practical paradigm for both phytoremediation and safe land utilization. Cultivating non-food economic crops, such as clove basil, potentially represents an effective strategy for safely utilizing heavy metal-contaminated land.
