Pub Date : 2025-02-01DOI: 10.1016/j.fct.2025.115286
A.M. Api , A. Bartlett , D. Belsito , D. Botelho , M. Bruze , A. Bryant-Friedrich , G.A. Burton Jr. , M.A. Cancellieri , H. Chon , M. Cronin , S. Crotty , M.L. Dagli , W. Dekant , C. Deodhar , K. Farrell , A.D. Fryer , L. Jones , K. Joshi , A. Lapczynski , D.L. Laskin , Y. Thakkar
{"title":"RIFM fragrance ingredient safety assessment, 9-undecenal, CAS Registry Number 143-14-6","authors":"A.M. Api , A. Bartlett , D. Belsito , D. Botelho , M. Bruze , A. Bryant-Friedrich , G.A. Burton Jr. , M.A. Cancellieri , H. Chon , M. Cronin , S. Crotty , M.L. Dagli , W. Dekant , C. Deodhar , K. Farrell , A.D. Fryer , L. Jones , K. Joshi , A. Lapczynski , D.L. Laskin , Y. Thakkar","doi":"10.1016/j.fct.2025.115286","DOIUrl":"10.1016/j.fct.2025.115286","url":null,"abstract":"","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"197 ","pages":"Article 115286"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.fct.2024.115168
Xin Gao , Huan He , Qi Zheng , Siju Chen , Yu Wei , Taifa Zhang , Yi Wang , Bo Wang , Dake Huang , Shengquan Zhang , Sumei Zhang , Jinxia Zhai
BDE-209 exposure induced male reproductive toxicity with sperm quality decline. However, the role of autophagy in this was unclear. The purpose was to evaluate the protective effect and its potential mechanism of trehalose (Tre, autophagy inducer) on reproductive damage during spermiogenesis induced by BDE-209. We used 2% w/v Tre and 75 mg/kg/d BDE-209 cotreated mice for 42 days. GC-2 spd cells were cotreated with Tre, chloroquine (CQ, inhibition of autophagic flux), compound C (CC, AMPK inhibitor), and BDE-209. Tre intake significantly recovered decrease in sexual organ ratio and poor sperm quality in BDE-209-exposed mice. Supplementation with Tre rescued sperm head malformation by improving aberrant histone-protamine exchange in BDE-209-exposed mice. However, Tre intake couldn't restore the acrosome biogenesis. In addition, Tre supplementation improved testicular damage induced by BDE-209. BDE-209 blocked autophagic flux with increased P62 and LC3BⅡ/Ⅰ levels. Mechanistically, CQ treatment aggravated elevation of P62 and LC3BⅡ/Ⅰ levels induced by BDE-209, otherwise, CC and Tre treatments inhibited the rise in p-AMPK, p-ULK1, P62 and LC3BⅡ/Ⅰ levels induced by BDE-209. Tre supplementation improved reproductive injury in BDE-209-exposed mice by regulating autophagic flow via AMPK-ULK1 signaling pathways, which providing a new theoretical basis and possible therapeutic targets for male reproductive toxicity.
{"title":"Protective effect of trehalose on sperm chromatin condensation failure and semen quality decline in BDE-209-exposed mice","authors":"Xin Gao , Huan He , Qi Zheng , Siju Chen , Yu Wei , Taifa Zhang , Yi Wang , Bo Wang , Dake Huang , Shengquan Zhang , Sumei Zhang , Jinxia Zhai","doi":"10.1016/j.fct.2024.115168","DOIUrl":"10.1016/j.fct.2024.115168","url":null,"abstract":"<div><div>BDE-209 exposure induced male reproductive toxicity with sperm quality decline. However, the role of autophagy in this was unclear. The purpose was to evaluate the protective effect and its potential mechanism of trehalose (Tre, autophagy inducer) on reproductive damage during spermiogenesis induced by BDE-209. We used 2% w/v Tre and 75 mg/kg/d BDE-209 cotreated mice for 42 days. GC-2 spd cells were cotreated with Tre, chloroquine (CQ, inhibition of autophagic flux), compound C (CC, AMPK inhibitor), and BDE-209. Tre intake significantly recovered decrease in sexual organ ratio and poor sperm quality in BDE-209-exposed mice. Supplementation with Tre rescued sperm head malformation by improving aberrant histone-protamine exchange in BDE-209-exposed mice. However, Tre intake couldn't restore the acrosome biogenesis. In addition, Tre supplementation improved testicular damage induced by BDE-209. BDE-209 blocked autophagic flux with increased P62 and LC3BⅡ/Ⅰ levels. Mechanistically, CQ treatment aggravated elevation of P62 and LC3BⅡ/Ⅰ levels induced by BDE-209, otherwise, CC and Tre treatments inhibited the rise in p-AMPK, p-ULK1, P62 and LC3BⅡ/Ⅰ levels induced by BDE-209. Tre supplementation improved reproductive injury in BDE-209-exposed mice by regulating autophagic flow via AMPK-ULK1 signaling pathways, which providing a new theoretical basis and possible therapeutic targets for male reproductive toxicity.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"196 ","pages":"Article 115168"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.fct.2024.115231
Adio J. Akamo , Adetutu O. Ojelabi , Naomi M. Akamo , Ibiyemi O. Opowoye , Boluwatife A. Olagunju , Oluwatobi T. Somade , Ofem E. Eteng , Adedayo A. Adebisi , Taiwo S. Oguntona , Mushafau A. Akinsanya , Abiola F. Adenowo , Tolani E. Oladele , Adewale M. Taiwo , Iyabode A. Kehinde , Jacob K. Akintunde , Regina N. Ugbaja
Dichlorvos (DDVP) is an organophosphate insecticide that enhances food production and repels disease vectors. However, it provokes cytotoxicity. 2S-hesperidin (2S-HES) is a potent antioxidant, anti-inflammatory, and anti-lipidemic flavanone. Regardless, the 2S-HES impact on DDVP-occupied hepatic injury remains fuzzy. We evaluated the therapeutic potential of 2S-HES in a rat model of DDVP-elicited hepatic intoxication. Forty-two rats were randomly allotted to seven groups (n = 6/condition): control, DDVP (8 mg kg⁻1day⁻1), DDVP with 2S-HES (50 and 100 mg kg⁻1day⁻1), DDVP with atropine, and 2S-HES alone (50 and 100 mg kg⁻1day⁻1). DDVP was administered orally for 7 days, followed by 14 days of 2S-HES chemotherapy. 2S-HES intervention partially mitigated DDVP-triggered alterations in leakage enzymes (ALT, AST, ALP, LDH-5), total protein, albumin, globulin, bilirubin, electrolytes, ion-transporters, lipid profiles, and HMG-CoA reductase. Furthermore, 2S-HES partially reversed DDVP-provoked increases in hepatic H₂O₂, NO, and malondialdehyde; transposed DDVP-mediated decreased liver GSH amount and activities of GST, SOD, catalase, and GPx; attenuated DDVP-triggered upregulated NF-κB-p65 and caspase-3; and abated DDVP-engendered repressed interleukin-10 mRNA expression. Cytoarchitectural analyses authenticated the 2-HES reduction in DDVP-evoked hepatocellular vacuolation. Altogether, 2S-HES elicited promising alternative or adjunctive therapy for partially mitigating DDVP-incited hepatic injury by attenuating leakage enzymes, ionoregulatory disruptions, ion pump inhibition, dyslipidemias, oxidative stress, inflammation, and apoptosis.
{"title":"Therapeutic potential of 2S-hesperidin against the hepatotoxic effects of dichlorvos in rats","authors":"Adio J. Akamo , Adetutu O. Ojelabi , Naomi M. Akamo , Ibiyemi O. Opowoye , Boluwatife A. Olagunju , Oluwatobi T. Somade , Ofem E. Eteng , Adedayo A. Adebisi , Taiwo S. Oguntona , Mushafau A. Akinsanya , Abiola F. Adenowo , Tolani E. Oladele , Adewale M. Taiwo , Iyabode A. Kehinde , Jacob K. Akintunde , Regina N. Ugbaja","doi":"10.1016/j.fct.2024.115231","DOIUrl":"10.1016/j.fct.2024.115231","url":null,"abstract":"<div><div>Dichlorvos (DDVP) is an organophosphate insecticide that enhances food production and repels disease vectors. However, it provokes cytotoxicity. 2S-hesperidin (2S-HES) is a potent antioxidant, anti-inflammatory, and anti-lipidemic flavanone. Regardless, the 2S-HES impact on DDVP-occupied hepatic injury remains fuzzy. We evaluated the therapeutic potential of 2S-HES in a rat model of DDVP-elicited hepatic intoxication. Forty-two rats were randomly allotted to seven groups (n = 6/condition): control, DDVP (8 mg kg⁻<sup>1</sup>day⁻<sup>1</sup>), DDVP with 2S-HES (50 and 100 mg kg⁻<sup>1</sup>day⁻<sup>1</sup>), DDVP with atropine, and 2S-HES alone (50 and 100 mg kg⁻<sup>1</sup>day⁻<sup>1</sup>). DDVP was administered orally for 7 days, followed by 14 days of 2S-HES chemotherapy. 2S-HES intervention partially mitigated DDVP-triggered alterations in leakage enzymes (ALT, AST, ALP, LDH-5), total protein, albumin, globulin, bilirubin, electrolytes, ion-transporters, lipid profiles, and HMG-CoA reductase. Furthermore, 2S-HES partially reversed DDVP-provoked increases in hepatic H₂O₂, NO, and malondialdehyde; transposed DDVP-mediated decreased liver GSH amount and activities of GST, SOD, catalase, and GPx; attenuated DDVP-triggered upregulated NF-κB-p65 and caspase-3; and abated DDVP-engendered repressed interleukin-10 mRNA expression. Cytoarchitectural analyses authenticated the 2-HES reduction in DDVP-evoked hepatocellular vacuolation. Altogether, 2S-HES elicited promising alternative or adjunctive therapy for partially mitigating DDVP-incited hepatic injury by attenuating leakage enzymes, ionoregulatory disruptions, ion pump inhibition, dyslipidemias, oxidative stress, inflammation, and apoptosis.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"196 ","pages":"Article 115231"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.fct.2024.115140
Ruiqi Zhang, Bingxin Huangfu, Tongxiao Xu, Victor Olusola Opatola, Qiushi Ban, Kunlun Huang, Xiaoyun He
Zearalenone (ZEA), a mycotoxin prevalent in food crops, poses significant health risks, particularly through its impact on the gut-uterus axis. This study assessed the effects of a 5 mg/kg body weight ZEA dosage in female SD rats, focusing on gut microbiota alterations, inflammatory responses, and uterine changes. Our findings revealed substantial shifts in microbial composition, including significant reductions in beneficial genera such as Akkermansia and Ruminococcaceae and marked increases in pathogenic staphylococci, which correlated with elevated levels of toxic shock syndrome toxin-1 (TSST-1) in serum and uterine tissue. RNA sequencing of uterine samples indicated activation of the extracellular matrix (ECM) pathway, along with significant upregulation of MMP-2 and TIMP-2, enzymes associated with ECM remodelling. Correlation analysis showed a strong link between staphylococcal proliferation and ECM pathway activation, suggesting that ZEA-induced gut dysbiosis contributes to uterine inflammation and structural alterations. These results reveal how ZEA disrupts gut and uterine health, highlighting critical pathways that could serve as targets for future preventive and therapeutic strategies against mycotoxin exposure.
{"title":"Zearalenone enhances TSST-1 production by intestinal Staphylococcus and increases uterine immune stress in rats","authors":"Ruiqi Zhang, Bingxin Huangfu, Tongxiao Xu, Victor Olusola Opatola, Qiushi Ban, Kunlun Huang, Xiaoyun He","doi":"10.1016/j.fct.2024.115140","DOIUrl":"10.1016/j.fct.2024.115140","url":null,"abstract":"<div><div>Zearalenone (ZEA), a mycotoxin prevalent in food crops, poses significant health risks, particularly through its impact on the gut-uterus axis. This study assessed the effects of a 5 mg/kg body weight ZEA dosage in female SD rats, focusing on gut microbiota alterations, inflammatory responses, and uterine changes. Our findings revealed substantial shifts in microbial composition, including significant reductions in beneficial genera such as <em>Akkermansia</em> and <em>Ruminococcaceae</em> and marked increases in pathogenic <em>staphylococci</em>, which correlated with elevated levels of toxic shock syndrome toxin-1 (TSST-1) in serum and uterine tissue. RNA sequencing of uterine samples indicated activation of the extracellular matrix (ECM) pathway, along with significant upregulation of <em>MMP-2</em> and <em>TIMP-2</em>, enzymes associated with ECM remodelling. Correlation analysis showed a strong link between staphylococcal proliferation and ECM pathway activation, suggesting that ZEA-induced gut dysbiosis contributes to uterine inflammation and structural alterations. These results reveal how ZEA disrupts gut and uterine health, highlighting critical pathways that could serve as targets for future preventive and therapeutic strategies against mycotoxin exposure.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"196 ","pages":"Article 115140"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fluoride consumption through food and drinking water above permissible levels poses serious health risks. Managing fluoride intake from community water sources is a considerable challenge. This study aimed to understand the synergistic effect of vitamin C supplementation in a mouse model exposed to sodium fluoride (NaF) and ovalbumin (OVA) allergen. In brief, Balb/c mice received 100 ppm NaF daily in drinking water and intragastrical administration of 5 mg OVA as a food allergen. Further, OVA-specific IgE and IgG1 humoral immune responses, leukocytes infiltration, and histopathological alterations in tissues of the liver, kidney, thymus and spleen were analysed by ELISA and microscopic examination. Results showed that NaF and OVA administration developed clinical symptoms of food allergy, followed by dental fluorosis in the lower incisors, evidenced by Thylstrup-Fejerskov index in mice. Besides, Vitamin C supplementation, as a potential antioxidant and anti-allergic molecule effectively reduced the symptoms of food allergy, dental fluorosis, eosinophils infiltration, and histological alterations in mice which exposed to sodium fluoride and OVA allergen. In conclusion, the study provides compelling evidence that vitamin C might be a potential therapeutic drug for mitigating both dental fluorosis and food allergy induced by excessive fluoride intake through food and water.
{"title":"Synergistic effects of vitamin C mitigates sodium fluoride-induced dental fluorosis and allergic immune responses in mice","authors":"Harshitha Kurbur Parashivamurthy , Shiva Siddappa , Pavan Kumar Subbanakodige Venkatakrishna , U.K. Ambikathanaya , Radhakrishna Shetty , Kiran Kumar Mudnakudu-Nagaraju","doi":"10.1016/j.fct.2024.115164","DOIUrl":"10.1016/j.fct.2024.115164","url":null,"abstract":"<div><div>Fluoride consumption through food and drinking water above permissible levels poses serious health risks. Managing fluoride intake from community water sources is a considerable challenge. This study aimed to understand the synergistic effect of vitamin C supplementation in a mouse model exposed to sodium fluoride (NaF) and ovalbumin (OVA) allergen. In brief, Balb/c mice received 100 ppm NaF daily in drinking water and intragastrical administration of 5 mg OVA as a food allergen. Further, OVA-specific IgE and IgG1 humoral immune responses, leukocytes infiltration, and histopathological alterations in tissues of the liver, kidney, thymus and spleen were analysed by ELISA and microscopic examination. Results showed that NaF and OVA administration developed clinical symptoms of food allergy, followed by dental fluorosis in the lower incisors, evidenced by Thylstrup-Fejerskov index in mice. Besides, Vitamin C supplementation, as a potential antioxidant and anti-allergic molecule effectively reduced the symptoms of food allergy, dental fluorosis, eosinophils infiltration, and histological alterations in mice which exposed to sodium fluoride and OVA allergen. In conclusion, the study provides compelling evidence that vitamin C might be a potential therapeutic drug for mitigating both dental fluorosis and food allergy induced by excessive fluoride intake through food and water.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"196 ","pages":"Article 115164"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Favipiravir, a broad-spectrum RNA-dependent RNA polymerase inhibitor widely used during the COVID-19 pandemic, effectively reduces viral load but has been linked to inflammatory changes in tissues such as the liver and kidneys. High-dose and prolonged use of favipiravir for COVID-19 raises concerns about its potential toxic effects on the lungs, particularly in patients with pre-existing pulmonary conditions. This study investigated favipiravir's effects on lung tissue in healthy rats. Experimental groups included a Control (saline) and three favipiravir doses: Low (200 mg/kg/day loading, 100 mg/kg/day maintenance), Medium (400 mg/kg/day loading, 200 mg/kg/day maintenance), and High (600 mg/kg/day loading, 300 mg/kg/day maintenance), all administered via gavage for 10 days. Histopathological analysis showed normal lung structure in the Control group, while favipiravir-treated groups exhibited Bronchus-Associated Lymphoid Tissue (BALT) enlargement, inflammation, fibrosis, and hemorrhage. Immunohistochemical analysis revealed dose-dependent increases in TNF-α, TGF-β, IL-6, IFN-γ, IL1-β, α-SMA, and collagen-1, especially in the High-dose group (p < 0.05). These findings suggest favipiravir may induce lung inflammation and fibrosis, emphasizing the need for careful evaluation of its safety in clinical settings, particularly for COVID-19 treatment. Future research should investigate the underlying mechanisms of these effects with clinical studies to assess their relevance to humans, high-risk pulmonary patients.
{"title":"Evaluation of the effects of favipiravir (T-705) on the lung tissue of healty rats: An experimental study","authors":"Menekşe Ülger , Birkan Ülger , Işıl Tuğçe Turan , Şahin Temel , Arzu Yay , Betül Yalçın , Birkan Yakan","doi":"10.1016/j.fct.2025.115235","DOIUrl":"10.1016/j.fct.2025.115235","url":null,"abstract":"<div><div>Favipiravir, a broad-spectrum RNA-dependent RNA polymerase inhibitor widely used during the COVID-19 pandemic, effectively reduces viral load but has been linked to inflammatory changes in tissues such as the liver and kidneys. High-dose and prolonged use of favipiravir for COVID-19 raises concerns about its potential toxic effects on the lungs, particularly in patients with pre-existing pulmonary conditions. This study investigated favipiravir's effects on lung tissue in healthy rats. Experimental groups included a Control (saline) and three favipiravir doses: Low (200 mg/kg/day loading, 100 mg/kg/day maintenance), Medium (400 mg/kg/day loading, 200 mg/kg/day maintenance), and High (600 mg/kg/day loading, 300 mg/kg/day maintenance), all administered via gavage for 10 days. Histopathological analysis showed normal lung structure in the Control group, while favipiravir-treated groups exhibited Bronchus-Associated Lymphoid Tissue (BALT) enlargement, inflammation, fibrosis, and hemorrhage. Immunohistochemical analysis revealed dose-dependent increases in TNF-α, TGF-β, IL-6, IFN-γ, IL1-β, α-SMA, and collagen-1, especially in the High-dose group (p < 0.05). These findings suggest favipiravir may induce lung inflammation and fibrosis, emphasizing the need for careful evaluation of its safety in clinical settings, particularly for COVID-19 treatment. Future research should investigate the underlying mechanisms of these effects with clinical studies to assess their relevance to humans, high-risk pulmonary patients.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"196 ","pages":"Article 115235"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.fct.2025.115247
Maja Stevanoska , Karsten Beekmann , Ans Punt , Shana J. Sturla , Georg Aichinger
Hop extracts containing prenylated polyphenols such as 8-prenylnaringenin (8-PN) and its precursor isoxanthohumol (iXN) are popular among women seeking natural alternatives to hormone therapy for postmenopausal symptoms. Due to structural similarities with estrogens, these compounds act as estrogen receptor agonists. Especially 8-PN, described as the most potent phytoestrogen known to date, poses a potential risk for endocrine disruption. Therefore, its use as a hormone replacement raises concerns for human health. However, a significant challenge in assessing the potential endocrine-disruptive effects of hop polyphenols is the lack of data on their toxicokinetics. Particularly, information on in vivo concentrations in target tissues is lacking. To address this gap, we developed a physiologically based kinetic (PBK) model tailored to female physiology. The model was used to predict the levels of hop polyphenols in human blood and target tissues under realistic exposure scenarios. The predictions suggest that iXN and 8-PN concentrations in target tissues reach the low nanomolar range after dietary supplementation. This study enhances our understanding of internal concentrations of iXN and 8-PN after dietary consumption and is of direct applicability for respective risk assessment.
{"title":"Predicting in vivo concentrations of dietary hop phytoestrogens by physiologically based kinetic modeling","authors":"Maja Stevanoska , Karsten Beekmann , Ans Punt , Shana J. Sturla , Georg Aichinger","doi":"10.1016/j.fct.2025.115247","DOIUrl":"10.1016/j.fct.2025.115247","url":null,"abstract":"<div><div>Hop extracts containing prenylated polyphenols such as 8-prenylnaringenin (8-PN) and its precursor isoxanthohumol (iXN) are popular among women seeking natural alternatives to hormone therapy for postmenopausal symptoms. Due to structural similarities with estrogens, these compounds act as estrogen receptor agonists. Especially 8-PN, described as the most potent phytoestrogen known to date, poses a potential risk for endocrine disruption. Therefore, its use as a hormone replacement raises concerns for human health. However, a significant challenge in assessing the potential endocrine-disruptive effects of hop polyphenols is the lack of data on their toxicokinetics. Particularly, information on <em>in vivo</em> concentrations in target tissues is lacking. To address this gap, we developed a physiologically based kinetic (PBK) model tailored to female physiology. The model was used to predict the levels of hop polyphenols in human blood and target tissues under realistic exposure scenarios. The predictions suggest that iXN and 8-PN concentrations in target tissues reach the low nanomolar range after dietary supplementation. This study enhances our understanding of internal concentrations of iXN and 8-PN after dietary consumption and is of direct applicability for respective risk assessment.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"196 ","pages":"Article 115247"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.fct.2024.115195
Shaik Abdullah Nawabjan , Kailash Singh , Muthu Iswarya G S , Rex K.H. Au-Yeung , Fengwei Zhang , Li Zhang , Hani El-Nezami , Billy K.C. Chow
The Secretin receptor (SCTR) presents a promising path for hypertension management, with KSD179019 as identified as a Positive Allosteric Modulator (PAM) of SCTR, demonstrating anti-hypertensive effects in animal models. Our objective was to comprehensively evaluate the potential toxicity of KSD179019 through in vitro and in vivo investigations. Initial in vitro studies showed minimal toxicity in liver and kidney cells and non-mutagenicity in bacterial assays. A 14-day acute toxicity test indicated an LD50 over 5000 mg/kg body weight, suggesting a safe profile, yet necessitating further in vivo analysis before progressing to human trials. Following OECD protocols, we conducted sub-chronic (90 days) and chronic (180 days) toxicity studies in male and female C57 mice at various dosages. These included comprehensive hematological, biochemical, macroscopic, urinalysis, and histopathological examinations. The sub-chronic study reported minimal toxicity except at the highest doses (700 and 1000 mg/kg), while the chronic study suggested a no-observed-adverse-effect-level (NOAEL) at 250 mg/kg with limitations. QSAR analysis supported the non-mutagenic nature of KSD179019. KSD179019 demonstrated a favorable general toxicity profile at a dose of 250 mg/kg in a 180-day chronic testing study. However, further preclinical investigations, including assessments of in vivo mutagenicity, reproductive and developmental toxicity, and carcinogenicity, are required to comprehensively establish its safety profile.
{"title":"Preclinical toxicity evaluation of the novel anti-hypertensive compound KSD179019","authors":"Shaik Abdullah Nawabjan , Kailash Singh , Muthu Iswarya G S , Rex K.H. Au-Yeung , Fengwei Zhang , Li Zhang , Hani El-Nezami , Billy K.C. Chow","doi":"10.1016/j.fct.2024.115195","DOIUrl":"10.1016/j.fct.2024.115195","url":null,"abstract":"<div><div>The Secretin receptor (SCTR) presents a promising path for hypertension management, with KSD179019 as identified as a Positive Allosteric Modulator (PAM) of SCTR, demonstrating anti-hypertensive effects in animal models. Our objective was to comprehensively evaluate the potential toxicity of KSD179019 through in vitro and in vivo investigations. Initial in vitro studies showed minimal toxicity in liver and kidney cells and non-mutagenicity in bacterial assays. A 14-day acute toxicity test indicated an LD50 over 5000 mg/kg body weight, suggesting a safe profile, yet necessitating further in vivo analysis before progressing to human trials. Following OECD protocols, we conducted sub-chronic (90 days) and chronic (180 days) toxicity studies in male and female C57 mice at various dosages. These included comprehensive hematological, biochemical, macroscopic, urinalysis, and histopathological examinations. The sub-chronic study reported minimal toxicity except at the highest doses (700 and 1000 mg/kg), while the chronic study suggested a no-observed-adverse-effect-level (NOAEL) at 250 mg/kg with limitations. QSAR analysis supported the non-mutagenic nature of KSD179019. KSD179019 demonstrated a favorable general toxicity profile at a dose of 250 mg/kg in a 180-day chronic testing study. However, further preclinical investigations, including assessments of in vivo mutagenicity, reproductive and developmental toxicity, and carcinogenicity, are required to comprehensively establish its safety profile.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"196 ","pages":"Article 115195"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.fct.2024.115198
Cynthia Recoules , Mathilde Touvier , Fabrice Pierre , Marc Audebert
Food additives are present in more than 50% of food products. Several studies have suggested a link between the consumption of certain food additives and an increased risk of developing cancer. This study aimed to evaluate the genotoxicity of 32 additives and six mixtures identified by the NutriNet-Santé cohort as the most widely consumed. Genotoxicity screening was conducted using the γH2AX (for clastogenic compounds) and pH3 (for aneugenic compounds) biomarkers in four human cell models (colon, liver, kidney, and neurons) representing the target organs of food contaminants. The 32 compounds were categorized into five groups based on their toxicological profiles. Eight additives were cytotoxic, four promoted cell proliferation, two were genotoxic with a clastogenic mode of action, and the remaining 19 were neither cytotoxic nor genotoxic at the concentration tested. Among the six mixtures tested, three were neither cytotoxic nor genotoxic, one was cytotoxic, and two were genotoxic at the highest tested concentrations. The observed genotoxicity of the mixtures could not be attributed to the relative concentrations of the individual additives. These findings suggest the possibility of toxic synergies in mixtures and highlight the challenges of studying the combined effects of multiple substances.
{"title":"Evaluation of the toxic effects of food additives, alone or in mixture, in four human cell models","authors":"Cynthia Recoules , Mathilde Touvier , Fabrice Pierre , Marc Audebert","doi":"10.1016/j.fct.2024.115198","DOIUrl":"10.1016/j.fct.2024.115198","url":null,"abstract":"<div><div>Food additives are present in more than 50% of food products. Several studies have suggested a link between the consumption of certain food additives and an increased risk of developing cancer. This study aimed to evaluate the genotoxicity of 32 additives and six mixtures identified by the NutriNet-Santé cohort as the most widely consumed. Genotoxicity screening was conducted using the γH2AX (for clastogenic compounds) and pH3 (for aneugenic compounds) biomarkers in four human cell models (colon, liver, kidney, and neurons) representing the target organs of food contaminants. The 32 compounds were categorized into five groups based on their toxicological profiles. Eight additives were cytotoxic, four promoted cell proliferation, two were genotoxic with a clastogenic mode of action, and the remaining 19 were neither cytotoxic nor genotoxic at the concentration tested. Among the six mixtures tested, three were neither cytotoxic nor genotoxic, one was cytotoxic, and two were genotoxic at the highest tested concentrations. The observed genotoxicity of the mixtures could not be attributed to the relative concentrations of the individual additives. These findings suggest the possibility of toxic synergies in mixtures and highlight the challenges of studying the combined effects of multiple substances.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"196 ","pages":"Article 115198"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Methyl donors regulate the one-carbon metabolism and have significant potential to reduce oxidative stress and inflammation. Therefore, this study aims to investigate the protective effect of methyl donors against CCl4-induced liver fibrosis. Liver fibrosis was induced in male Sprague Dawley rats using CCl4 at a dose of 1 ml/kg (twice a week for a 4-week, via intraperitoneal route). Subsequently, methyl donor treatments were given orally for the next six weeks while continuing CCl4 administration. After 10 weeks, biochemical, histopathology, immunohistochemistry, western blotting, and qRT-PCR were performed. Methyl donor treatment significantly ameliorated ALT, AST, ALP levels, and oxidative stress associated with CCl4-induced liver injury. The histopathological investigation also demonstrated the hepatoprotective effect of methyl donors against CCl4-induced liver fibrosis, showing reduced tissue damage, collagen deposition, and attenuating the expression of the COL1A1 gene. Further, methyl donors inhibited the CCl4-induced increase in DNMT-1 and NF-κB p65 expression with an upregulation of AMPK. Methyl donor downregulated the CCl4-induced increase in inflammatory and fibrosis related gene expression and inhibited the apoptosis with a downregulation of EGFR expression. Here, we provide the first evidence that methyl donor combinations prevent liver fibrosis by attenuating oxidative stress, inflammation, and fibrosis through DNMT-1 and EGFR downregulation.
{"title":"Methyl donor ameliorates CCl4-induced liver fibrosis by inhibiting inflammation, and fibrosis through the downregulation of EGFR and DNMT-1 expression","authors":"Manish Bishnolia , Poonam Yadav , Sumeet Kumar Singh , Nirmal Manhar , Sonu Rajput , Amit Khurana , Jasvinder Singh Bhatti , Umashanker Navik","doi":"10.1016/j.fct.2024.115230","DOIUrl":"10.1016/j.fct.2024.115230","url":null,"abstract":"<div><div>Methyl donors regulate the one-carbon metabolism and have significant potential to reduce oxidative stress and inflammation. Therefore, this study aims to investigate the protective effect of methyl donors against CCl<sub>4</sub>-induced liver fibrosis. Liver fibrosis was induced in male Sprague Dawley rats using CCl<sub>4</sub> at a dose of 1 ml/kg (twice a week for a 4-week, <em>via</em> intraperitoneal route). Subsequently, methyl donor treatments were given orally for the next six weeks while continuing CCl<sub>4</sub> administration. After 10 weeks, biochemical, histopathology, immunohistochemistry, western blotting, and qRT-PCR were performed. Methyl donor treatment significantly ameliorated ALT, AST, ALP levels, and oxidative stress associated with CCl<sub>4</sub>-induced liver injury. The histopathological investigation also demonstrated the hepatoprotective effect of methyl donors against CCl<sub>4</sub>-induced liver fibrosis, showing reduced tissue damage, collagen deposition, and attenuating the expression of the COL1A1 gene. Further, methyl donors inhibited the CCl<sub>4</sub>-induced increase in DNMT-1 and NF-κB p65 expression with an upregulation of AMPK. Methyl donor downregulated the CCl<sub>4</sub>-induced increase in inflammatory and fibrosis related gene expression and inhibited the apoptosis with a downregulation of EGFR expression. Here, we provide the first evidence that methyl donor combinations prevent liver fibrosis by attenuating oxidative stress, inflammation, and fibrosis through DNMT-1 and EGFR downregulation.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"196 ","pages":"Article 115230"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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