Fipronil (FIP), a widely used agricultural insecticide, has raised significant concerns due to its harmful environmental residues and neurotoxic effects. Although FIP's toxicological impact has been studied in some neuronal cell models, its specific effects on human glial cells remain poorly understood. This study sought to investigate the mechanisms of FIP-induced toxicity and evaluate the protective potential of vitamin E (VE), a known antioxidant. Using human astrocyte (GHA) cells, we treated cells with FIP (5–25 μM), VE (20 μM), or both and compared their responses to untreated controls. Our findings revealed that FIP significantly reduced cell viability and caused morphological changes in astrocytes, including cellular shrinkage and detachment. FIP also increased the production of reactive oxygen species (ROS) and depleted intracellular glutathione (GSH) levels, indicating a disruption of cellular redox balance and the onset of oxidative stress. Furthermore, FIP triggered the activation of apoptotic pathways through upregulation of Bax, caspase-9, and caspase-3, coupled with downregulation of the antiapoptotic protein Bcl-2. Concurrently, FIP disrupted antioxidant defense mechanisms by modulating the Nrf2/HO-1/NQO1 signaling pathway. Interestingly, pretreatment with VE effectively reversed these effects. VE reduced ROS levels, replenished GSH, mitigated apoptosis, and restored antioxidant protein expression, protecting astrocytes against FIP-induced cytotoxicity and oxidative damage. These findings highlight oxidative stress as a critical factor in FIP-induced astrocyte toxicity and position VE as a promising protective agent. Further research is essential to explore VE's therapeutic potential in mitigating oxidative stress-related neurotoxicity caused by environmental toxins like FIP.
Lung and multi-organ injuries are caused by the herbicide paraquat (PQ). Safranal (Saf), the principal compound found in Crocus sativus , exhibits a diverse array of pharmacological properties, encompassing anti-inflammatory, anti-oxidative, and immunoregulatory activities. The potential preventive impacts of Saf and pioglitazone (Pio), in comparison to dexamethasone (Dexa), were investigated in rats to assess their efficacy in mitigating lung injury induced by PQ aerosol. Saline aerosol was given to the control (Ctrl) group of rats, whereas PQ aerosol was given to the other six groups (PQ), eight times every other day. PQ groups were given either saline (PQ), two doses of Saf (Saf (L), 0.8 mg/kg/day and Saf (H), 3.2 mg/kg/day), pioglitazone (Pio, 5 mg/kg/day), the combination of Saf (L) + Pio, or Dexa (0.03 mg/kg/day) during PQ exposure for 16 days. Superoxide dismutase (SOD), catalase (CAT), and thiol levels decreased, while malondialdehyde (MDA) in the bronchoalveolar lavage fluid (BALF), lung tissue levels of tumor necrosis factor (TNF-α) and interleukin 10 (IL-10), tracheal responsiveness (TR) to methacholine, and lung pathological changes were increased in the PQ group. Significant improvements were seen in all treated groups, with the exception of a few variables in Saf (L). The combination of Saf (L) + Pio had a greater effect than Saf (L) or Pio alone. All comparisons had p values < 0.05 to < 0.001. The Saf and Pio show promising combined preventative abilities, suggesting that the PPARγ receptor plays a role in Saf impact.
Butylparaben (BuP) recurrently contaminates soils worldwide, mainly by incorporating sewage sludge into cultivated areas, using wastewater in irrigation, and leaching contaminated soils. However, there are few studies on the ecotoxicological effects of this paraben on edaphic organisms. The ecotoxicity of BuP was evaluated in seeds of Daucus carota , Allium cepa , and Cucumis sativus , in the roots of A. cepa bulbs, and in Eisenia fetida earthworms, at concentrations of 10, 50, 100, and 500 ng/L. In root meristems, the four concentrations of BuP induced lipid peroxidation and raised the levels of superoxide radicals, which triggered inhibition of cell division and mitotic spindle alteration, significantly reducing the growth of roots in seeds and bulbs. In animals, BuP at 10, 50, 100, and 500 ng/L caused 80%, 80%, 70%, and 90% evasion of earthworms from artificial soil, respectively. In addition, this paraben did not cause mortality in earthworms after 14 days of exposure. However, all concentrations increased the production of superoxide and hydroxyl radicals in cells and caused lipid peroxidation. Thus, increased exposure to this compound can affect the ecological functions negatively and/or cause the death of these animals. Therefore, recurrent contamination with BuP can negatively impact soil quality, posing a risk to agricultural productivity and the environment. This study is a pioneer in the ecotoxicological evaluation of BuP in plants at environmentally relevant concentrations and in the behavioral and oxidative stress study in earthworms.
Organophosphate flame retardants (OPFRs) are extensively used in the electronics industry, plastics, textiles, and other sectors to reduce flammability and enhance fire safety. However, excessive OPFR use has led to significant environmental accumulation, increasing ecological stress and potential human health risks. This study investigates the effects of 2-ethylhexyldiphenyl phosphate (EHDPP) on HepG2 cells, demonstrating that EHDPP exposure impairs normal cellular function through excessive autophagy, ultimately reducing cell viability. Our findings reveal a concentration-dependent decline in cell survival, with an LC50 of 120 μM. While lower concentrations (0, 1, 5, 10, and 50 μM) exerted minimal effects, 50 μM EHDPP significantly reduced cell viability. Further analysis confirmed that EHDPP exposure upregulates autophagy-related genes (ATG5, ATG12, VPS34, Beclin1, FIP200, ATG13, and ATG3), leading to an increased LC3-II/I ratio and a decrease in p62 levels, indicative of enhanced autophagic activity. Transmission electron microscopy (TEM) imaging confirmed a substantial increase in autophagosome formation at 50 μM EHDPP. These results provide new insights into the cytotoxic mechanisms of EHDPP, emphasizing its role in triggering excessive autophagy in hepatic cells.
Despite widespread human exposure to tin, its health effects remain poorly understood. This study examined the role of tin in neural tube defects (NTDs) through a case–control study and animal experiments. Tin levels in maternal serum and placentas were analyzed in 200 NTD cases and 400 controls to explore potential associations. Elevated tin concentrations in maternal serum were associated with an increased risk of NTDs, with an odds ratio of 2.31 (95% CI, 1.13–4.75), with similar associations found for placental tin and tributyltin (TBT) exposure. In animal experiments, pregnant mice exposed to 10–40 mg/kg TBT exhibited a 25.5%–27.6% incidence of fetal NTDs. Maternal TBT exposure increased oxidative stress and apoptosis in embryonic neural tissues. Antibody microarray analysis prioritized MAPK signaling as the dominant perturbed pathway. Subsequent western blot and RT-qPCR analysis convergently validated TBT-induced MAPK hyperactivation. Vitamin E supplementation had antagonistic effects, reducing these harmful outcomes. These findings suggest that prenatal tin exposure is a significant risk factor for NTDs. The teratogenic effect of TBT appears to be mediated by enhanced oxidative stress, activation of MAPK signaling, and apoptosis in the developing neural tube, processes that can be mitigated by Vitamin E supplementation. Thus, tin exposure during pregnancy is associated with an increased risk of fetal NTDs, and animal models demonstrate that TBT can induce these defects through specific biological pathways. This research highlights the need for further investigation into tin exposure and its potential health impacts on fetal development.
Glyphosate has been widely used in agricultural production as a highly effective, low-toxic, broad-spectrum organophosphorus herbicide. However, there has been controversy about whether it is toxic to the nervous system. In order to explore this issue in depth, the present study analyzed the molecular mechanism of action of glyphosate from four perspectives, namely, gene regulation, protein expression, morphological changes, and behavioral changes, and assessed the potential effects of glyphosate on the development of the nervous system of zebrafish through the establishment of a zebrafish model. The results showed that zebrafish embryos at 6 hpf after fertilization were exposed to glyphosate until 72 and 120 hpf. After exposure, it was found that the central nervous development-related gene Elavl3 was down-regulated, and GAP-43, Neurog1, and GFAP were up-regulated. The expression of HuC protein, which is used to maintain neuronal axonal homeostasis, was significantly reduced, and the expression of GFAP protein, which is used to repair neurological damage and inflammation, was significantly increased. Under the regulation of related genes and proteins, zebrafish larvae show abnormal changes during the development of a series of nervous systems such as heart rate slowing, somite shortening, spinal and brain malformations. At the same time, the zebrafish's action behavior also changed, with a significant decrease in its total time share in the low-speed shift and high-speed shift states, and a delayed response to dark-light environmental stimuli. In summary, studies have shown that glyphosate exposure may induce damage and inflammation of the zebrafish nervous system, resulting in developmental malformations, abnormal motor behavior, and potential neurotoxicity. Therefore, the possible neurotoxicity and environmental risks of glyphosate to aquatic animals should not be ignored and should be of great concern.
Titanium dioxide nanoparticles (TiO2-NPs) have been ever increasingly exposed to people through all possible routes, while studies focusing on their potential cardiovascular risks are relatively lacking, especially the underlying biological mechanisms that are not yet elucidated. In this study, the ferroptotic effect of TiO2-NPs (30 nm) at environmentally relevant concentrations (0, 3, 12, and 48 μg/mL) on human umbilical vein endothelial cells (HUVECs) and the potential molecular mechanism were studied with the corresponding biochemical and molecular biology assays. The results showed that TiO2-NPs at the tested concentrations could reduce HUVEC viability, but ferrostatin-1 might rescue this reduction in cell viability. Also, TiO2-NPs exposure increased Fe2+, reactive oxygen species, and malondialdehyde, but decreased glutathione, mitochondrial membrane potential, and activities of anti-oxidative enzymes (catalase, superoxide dismutase, and glutathione peroxidase) in HUVECs through an integrated signaling pathway. Meanwhile, enhanced p38 protein phosphorylation and keap1 protein and decreased Nrf2 protein phosphorylation with reductions in mRNA expressions of downstream anti-oxidative enzyme genes (catalase, superoxide dismutase, glutathione peroxidase, and phospholipid hydroperoxidase) were identified in the TiO2-NPs-exposed HUVECs. These indicated that TiO2-NPs exposure induced ferroptosis in HUVECs via the p38/keap1 inhibiting Nrf2 pathway. EC ferroptosis will be a promising biomarker for assessing the cardiovascular health risks of environmental contaminants.
Although chlorpyrifos poses considerable risks to the environment and human health, it is still used in many countries. This pesticide has various toxic effects on humans, including neurotoxicity, reproductive toxicity, genotoxicity, and organ damage caused by oxidative stress and DNA damage. However, its specific toxicity to the immune system remains unclear. In this study, we explored the intrinsic and extrinsic apoptotic pathways through which chlorpyrifos induces apoptosis in macrophages. RAW 264.7 macrophages were treated with chlorpyrifos at concentrations of 0, 2, 4, 10, and 20 ppm for 3 h. Cytotoxicity was assessed using a lactate dehydrogenase assay, whereas apoptosis was evaluated through flow cytometry. The levels of cysteinyl aspartate-specific proteinase (caspase)-3, caspase-8, and caspase-9 were measured. The disruption of mitochondrial function and the expression of the death receptors Fas receptor and tumor necrosis factor-alpha receptor were assessed through JC-1 stain reagent. The release of mitochondrial cytochrome c, expression of Bcl2 family proteins, and level of cleaved caspases were analyzed through Western blotting. Chlorpyrifos induced cytotoxicity and apoptosis in a concentration-dependent manner. It activated caspase-3, caspase-8, and caspase-9, as well as disrupted mitochondrial function and Bcl2 family protein balance. Furthermore, chlorpyrifos induced the release of cytochrome c from the mitochondria and upregulated the expression of Fas receptor and tumor necrosis factor-alpha receptor. These findings suggest that chlorpyrifos induces cytotoxicity through caspase-3-dependent apoptosis via the intrinsic pathway (caspase-8 activation, mitochondrial dysfunction, Bcl2 protein imbalance, and cytochrome c release) and the extrinsic pathway (caspase-9 activation and death receptor expression).
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