Jin-Long Li

Mycotoxins are common contaminants in agricultural products and feed, which pose a serious threat to public health. Zearalenone (ZEA) is a well-known environmental endocrine disruptor that causes reproductive disorders. Lycopene (LYC) is a possible therapeutic and preventive agent for male diseases. Here, we aim to explore the mechanism of ZEA-induced swine testicular (ST) cell injury and antagonism of lycopene. ST cells were treated with lycopene and/or ZEA for mechanistic validation. In this study, ZEA caused pronounced mitochondrial structural damage, whereas lycopene restored mitochondrial integrity. Lycopene also reduced ZEA-induced lipid peroxidation and ferrous ion levels, eventually inhibiting ferroptosis. Mechanistically, lycopene recovered PPARγ expression and regulated AMPK/mTOR signaling, thereby facilitating TFRC turnover. Of note, PPARγ knockdown weakened the effects of lycopene on ferroptosis, whereas TFRC overexpression diminished the protection afforded by autophagy activation. These findings indicate that lycopene mitigates ZEA-induced ferroptosis by regulating the PPARγ-AMPK-mTOR pathway and thus promoting autophagy-mediated TFRC degradation.

Di-2-ethylhexyl phthalate (DEHP) accumulates in the food chain, threatening human and animal health. However, how DEHP induces neurotoxicity by interfering with microglia has not been fully revealed. Our research aims to explore the effects of DEHP on microglia and identify relevant targets that cause neurotoxicity. The results indicated that DEHP damaged neurons, leading to swelling, demyelination, and abnormal autophagy. Inhibition of autophagy resulted in α-Syn misfolding, characterized by an increase in dimers with increasing additive concentrations (P = 0.0096). Dimer formation was promoted by the addition of additives, which increased the electrostatic force, along with interactions between Glu106, Gly51, and Val66. Transmitted from neurons to microglia (Pearson r2 = 0.889), pathological aggregates under DEHP exposure induced microglial M1 subtype switching. This study elucidated a novel mechanism by which DEHP damages the nerves of birds and provided a therapeutic target for the neurotoxic disease risk caused by the transmission of plastic additives through the food chain.

Di(2-ethylhexyl)phthalate (DEHP), a common environmental endocrine disruptor and agricultural organic pollutant, has drawn wide concern for its hepatotoxicity. However, the molecular mechanisms underlying DEHP-induced hepatic fibrosis remain unclear. Through network toxicology analysis, lipid metabolism and autophagy pathways are involved in DEHP-related hepatic fibrosis. Subchronic DEHP exposure (50–500 mg/kg) induced dose-dependent hepatic fibrosis in mice, while its metabolite MEHP synergized with TGF-β1 to promote LX2 cell activation in vitro. Crucially, MEHP activates lipophagy by targeting Beclin1, thereby mobilizing energy for the activation of hepatic stellate cells (HSCs). Attenuating autophagy with 3-Methyladenine (3-MA) or Chloroquine (CQ), or via Beclin1 knockdown, all rescued the activation phenotype induced by MEHP. These results suggest that DEHP acts as a trigger for fibrosis, promoting this process by inducing the activation of HSCs. This work identifies the lipophagy pathway as a crucial mechanistic link between environmental toxin exposure and HSC-mediated hepatic fibrosis progression.

Di(2-ethylhexyl) phthalate (DEHP) is widely acknowledged as a prevalent environmental pollutant, mainly due to its extensive use in plastics. This widespread application has resulted in its presence in air, soil, water, and various food items, as well as in agricultural products and tissues of both humans and animals. With the extensive use of plastic products in daily life, the teenage group is facing an increasing risk of DEHP exposure. However, the mechanism of DEHP-induced liver injury, especially during adolescence, remain unclear. This study utilized metabolomics analysis and molecular biology approaches to explore the effects of DEHP on liver function in adolescent mice. We found that DEHP exposure caused hepatic dysfunction, histopathological abnormalities, and lipid deposition. Metabolomics analysis identified the dysregulation of lipid metabolism, especially the fatty acid pathway. Mechanistically, DEHP and its main metabolite, mono(2-ethylhexyl) phthalate (MEHP) drived the ectopic formation of mitochondrial-associated endoplasmic reticulum membranes (MAMs) by up-regulating glucose-regulated protein 75 (GRP75). Such a process is characterized by a reduced interorganellar contact distance between the endoplasmic reticulum and mitochondria as well as elevated expression of MAM-resident proteins. Notably, overexpression of GRP75 alone recapitulated the lipid accumulation phenotype. Conversely, knockdown of GRP75 attenuated MEHP-induced lipid accumulation in AML12 cells. Moreover, a combination of molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays collectively corroborated the direct physical interaction between MEHP and GRP75. Collectively, our findings demonstrate that DEHP/MEHP disrupts the lipid metabolism regulated by MAM through a GRP75-dependent mechanism, thereby leading to liver steatosis. This study clarified the toxicological mechanisms underlying DEHP-induced hepatic dysfunction in adolescent mice, providing new insights into its health risk assessment and potential intervention strategies.

Per‐ and polyfluoroalkyl substances (PFAS) are ubiquitous persistent environmental pollutants with high bioaccumulation potential and widespread human exposure risks in contaminated water, soil, and biota. Although extensive studies have established the hepatotoxic potential of PFAS, much less is known regarding their cardiotoxicity and the underlying molecular mechanisms. Here, we investigated the cardiotoxic effects and molecular pathways of two representative PFAS, perfluorooctanoic acid (PFOA) and its alternative hexafluoropropylene oxide trimer acid (HFPO‐TA). Exposure to either PFOA or HFPO‑TA caused cardiac structural and functional damage, mitochondrial morphological abnormalities, and increased cardiac senescence, with HFPO‐TA eliciting greater cardiotoxicity. Mechanistically, PFOA and HFPO‐TA suppress CDK4 expression, destabilize mitochondria‐endoplasmic reticulum contacts (MERCs), and impair PINK1/Parkin‐mediated mitophagy. This defective mitophagy promotes mitochondrial DNA leakage and subsequent activation of the cGAS‐STING pathway, ultimately driving cardiac senescence. Notably, cycloastragenol (CAG) effectively reverses CDK4 downregulation, restores MERCs stability, and attenuates PFOA/HFPO‐TA‐induced cardiac senescence in vitro. Collectively, this study uncovers a CDK4/MERCs/PINK1 axis mediating PFOA/HFPO‐TA‐induced myocardial toxicity and identifies CAG as a promising natural product for mitigating environmental pollutant‐induced cardiac senescence, offering insights for PFAS health risk assessment and intervention strategies.