Toxics
·
2024
·Vol. 12
·期 11
·810
·
IF 3.9
Xiangsheng Tian,Yiquan Ou,Shengyuan Shi,Qiuhua Zhou,Sihong Long,Yao Xiang,Weichao Zhao,Dingxin Long
This study explores the neuroprotective effects of resveratrol (Resv) against tri-o-cresyl phosphate (TOCP)-induced neurotoxicity in the spinal cord of adult hens. It is well documented that TOCP exposure causes significant neurodegeneration via mechanisms that involve endoplasmic reticulum (ER) stress and impaired autophagy. In this experiment, adult hens were assigned to one of four groups: Control, Resv, TOCP, and TOCP + Resv. The spinal cord tissues were examined through transmission electron microscopy, hematoxylin and eosin (HE) staining, Nissl staining, and Western blotting to evaluate key proteins associated with ER stress and autophagy. Additionally, RT-qPCR and immunofluorescence were employed to measure sirtuin1 (SIRT1) expression. The findings revealed that TOCP induced severe ultrastructural damage, including disrupted myelin sheaths, dilated ER, and extensive neurodegeneration, as confirmed by histological evaluations. The expression levels of GRP78, p-PERK, p-eIF2α, ATF4, CHOP, Beclin-1, P62, and LC3-II were also significantly elevated by TOCP. However, Resv treatment markedly attenuated these pathological changes by reducing ER stress, restoring autophagic flux, and upregulating SIRT1 expression, preserving spinal cord integrity. These results indicate that Resv can effectively counteract TOCP-induced neurotoxicity by modulating ER stress and autophagy, underscoring its potential as a therapeutic agent for neuroprotection.
研究领域:
神经科学
·
毒理学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENT INTERNATIONAL
·
2024
·
IF 10.3
Bilin Zhao,Shuang Zheng,Gaoxiang Yang,Zhijun He,Jiewei Deng,Lijuan Luo,Xinyan Li,Tiangang Luan
Aryl organophosphorus flame retardants (aryl-OPFRs), commonly used product additives with close ties to daily life, have been regrettably characterized by multiple well-defined toxicity risks. Triphenyl phosphate (TPHP) and tri-o-cresyl phosphate (TOCP), two structurally similar aryl-OPFRs, were observed in our previous study to exhibit contrasting immunotoxic effects on THP-1 macrophages, yet the underlying mechanisms remain unclear. This study sought to address the knowledge gap by integrating transcriptomic and metabolomic analyses to elucidate the intricate mechanisms. During individual omics analyses, we unfortunately only obtained highly similar results for both TPHP and TOCP, failing to identify the key reasons for their differences. These results revealed comparable disturbances induced by both compounds, including disruptions in nucleic acid synthesis and energy metabolism, blocking ADP to ATP conversion by reducing TCA cycle intermediates, consequently leading to ATP depletion. However, through integrative analysis, specific pathways affected by each compound were successfully identified, shedding light on their unique effects. TPHP reduced GTP levels necessary for Rap1 activation, thereby inhibiting phagocytosis and adhesion of THP-1 macrophages. Conversely, TOCP stimulated the mTOR signaling pathway, enhancing phosphorylation of downstream proteins S6K, RHOA, and PKC, consequently promoting immune responses. This study not only clarified the distinct immunotoxic mechanisms of TPHP and TOCP but also provided critical insights into how structural variations in aryl-OPFRs can lead to markedly different immune responses, thereby informing future risk assessments and regulatory strategies for these compounds.
研究领域:
毒理学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
REPRODUCTIVE TOXICOLOGY
·
2018
·
IF 2.58
Liaoliao Hu,Tingting Peng,Jian Huang,Tie Su,Ruichen Luo,Yuehui Zheng,Zhisheng Zhong,Peiling Yu,Kun Nie,Liping Zheng
As a plasticizer widely used in society, tri-ortho-cresyl phosphate (TOCP) is reported to inhibit spermatogenesis and growth of spermatogonial stem cells. However, its effects on female reproductive system are virtually unknown. The present study investigated the effects of TOCP on ovarian follicle development by using mouse model of chronic TOCP exposure, and examined the expression of the core components of the Hippo pathway, which had been proven to be crucial for ovarian follicle development. Furthermore, through up-regulation of Hippo-yes-associated protein 1 ( Yap1 ) in ovaries, the potential protective effects of Yap1 over-expression on TOCP-induced ovarian dysfunction were observed. The results showed that TOCP impaired ovarian function in a dose-dependent manner, and the expression of the Hippo pathway changed significantly in TOCP-exposed ovaries. Further, YAP1 over-expression partially reversed the TOCP-induced ovarian impairment. Collectively, these data indicate that the Hippo pathway is involved in the mechanism by which TOCP elicits ovarian function impairment.
研究领域:
毒理学
·
生殖生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2026
·
IF 7.2
Xinyan Li,Dongmei Lai,Yao Yao,Jiewei Deng,Lijuan Luo,Xiaoping Liang,Tiangang Luan
Aryl organophosphate flame retardants (aryl-OPFRs), such as triphenyl phosphate (TPHP) and tris(2-methylphenyl) phosphate (TOCP), have been identified as ubiquitous environmental contaminants, but their immunotoxicity and underlying mechanisms in aquatic organisms remain largely unclear. This study investigated the immunomodulatory effects of two structurally analogous aryl-OPFRs using zebrafish larvae during the window of exclusively innate immunity, prior to the maturation of the adaptive immune system. Strikingly, they induced opposite immune responses: TOCP increased macrophage numbers and provoked inflammation, whereas TPHP decreased neutrophil and macrophage counts and suppressed inflammation. This divergence challenges the conventional structure-activity relationship paradigm. Both compounds ultimately compromised antibacterial capacity. To elucidate the mechanism, integrated transcriptomic and metabolomic analyses were performed, revealing that the opposing phenotypes were linked to differential regulation of energy-related pathways, including glycolysis and purine metabolism. Molecular docking predicted AMPK as a potential common target, while subsequent molecular dynamics simulations provided a critical dynamic perspective: TPHP rapidly dissociated from AMPK, whereas TOCP maintained a more persistent interaction. This differential binding stability offers a plausible mechanistic basis for their distinct immunometabolic reprogramming. Overall, these findings demonstrate that the structural analogs TOCP and TPHP induce divergent immunotoxicity in zebrafish, potentially mediated through a differential disruption of host energy metabolism during the early innate immune phase.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2026
·
IF 5.2
Shujuan Hu,Shule Tan,Sangping Li,Dingxin Long
Tri-ortho-cresyl phosphate (TOCP) is a widely used organophosphate ester with established multiple organ toxicity, yet its neurotoxic mechanisms remain incompletely elucidated. This study integrated network toxicology, molecular docking, and animal experiments to investigate the molecular mechanisms underlying TOCP-induced sciatic nerve toxicity. A total of 173 potential targets were identified through public databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that these targets are significantly involved in autophagy, apoptosis, glycerolipid metabolism, and multiple neurodegenerative pathways. Focusing on four core targets (BECN1, SQSTM1/p62, SLC7A11, GLUL), molecular docking demonstrated strong binding affinities between TOCP and these proteins (binding energies < −5 kcal/mol). In a hen model, TOCP exposure (750 mg/kg, single oral gavage) induced marked sciatic nerve damage, characterized by myelin disruption and axonal degeneration. Western blot analysis further validated protein expression changes: compared with the control group, TOCP exposure upregulated Beclin-1, SQSTM1/p62, LC3II/Ⅰ, NCOA4, ACSL4, and Fe 2+ levels by 1.919-, 2.443-, 1.497-, 1.506-, 1.243-, and 1.669-fold, respectively ( P < 0.05), while downregulating SLC7A11, GLUL, FTH1, and GPX4 expression to 0.458-, 0.893-, 0.813-, and 0.573-fold of the control levels ( P < 0.05). Collectively, these findings demonstrate that TOCP exerts neurotoxicity primarily by disrupting autophagic balance and impairing the oxidative defense system. This study provides novel insights into the molecular mechanisms of TOCP-induced sciatic neurotoxicity and offers a theoretical foundation for its prevention and treatment.
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Sangping Li,Shule Tan,Xiangsheng Tian,Yiquan Ou,Shujuan Hu,Weichao Zhao,Dingxin Long
This study investigated the protective effects of resveratrol (Res) against tri-o-cresyl phosphate (TOCP)-induced spinal cord neurotoxicity in adult hens, focusing on its modulation of ferroptosis via the p62/Keap1/Nrf2 pathway. Resveratrol is a classical neuroprotective compound with antioxidant properties and the ability to activate Nrf2. Adult hens were assigned to six groups: Control, TOCP, Ferrostatin-1 (Fer-1), Ferrostatin-1 + TOCP, Resveratrol, and Resveratrol + TOCP. Spinal cord tissues were analyzed using behavioral OPIDN scoring, histology (hematoxylin–eosin and Nissl staining), biochemical assays, and Western blotting for ferroptosis- and p62/Keap1/Nrf2-related proteins. TOCP exposure induced severe ultrastructural damage, including myelin sheath disruption and neuronal degeneration, along with increased malondialdehyde (MDA) and Fe 2+ levels and decreased glutathione (GSH) and superoxide dismutase (SOD) activity. Western blot analysis demonstrated upregulation of NCOA4, ACSL4, Nrf2, P62, and LC3 II, with downregulation of GPX4, SLC7A11, FTH1, and Keap1. Resveratrol treatment significantly attenuated these molecular, biochemical, and histopathological alterations, mitigating oxidative stress and ferroptotic changes.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）