Donald L. Bjerke , Jin Li , Yuan Gao , Ping Hu , Karl Lintner , Tomohiro Hakozaki
{"title":"A framework for the safety evaluation of peptides in cosmetics","authors":"Donald L. Bjerke , Jin Li , Yuan Gao , Ping Hu , Karl Lintner , Tomohiro Hakozaki","doi":"10.1016/j.crtox.2026.100291","DOIUrl":"10.1016/j.crtox.2026.100291","url":null,"abstract":"<div><div>As the cosmetic industry replaces traditional animal safety studies with next generation risk assessment approaches, the approach to safety substantiation for peptides used in cosmetic products must also evolve. While the need to provide assurances of safety for local and systemic toxicity endpoints remains the same, adoption of bioinformatic tools developed in the food, agricultural biotechnology, and drug development industries may add to the weight of evidence for the safety substantiation of peptides in cosmetics. Here we review the historical development and safety evaluation of peptides utilized in the cosmetic industry and provide a new safety evaluation framework that incorporates six bioinformatic tools. To test the framework, a variety of peptides (palmitoyl hexapeptide-12, caffeoyl hexapeptide-9, palmitoyl pentapeptide-4, amanitin alpha, conotoxin ArlB, bradykinin, and enkephaline) are evaluated with NCBI BLASTp, ToxinPred3.0, Peptipedia, BIOPEP-UWM, AllerCatPro 2.0, and IEDB bioinformatic tools. The results correctly identified safety concerns (toxins) for amanitin and conotoxin peptides and the biological actions of bradykinin and enkephaline, while palmitoyl hexapeptide-12, caffeoyl hexapeptide-9, and palmitoyl pentapeptide-4 demonstrated sequence homology with extracellular matrix proteins in the skin (collagen, elastin, fibronectin) without the safety concerns of the other peptides. The incorporation of bioinformatic tools into the safety framework provides an additional means to screen for toxins and allergens as well as insights into potential biological activities when sequence homology with existing proteins and peptides occurs. Further testing of the framework by the cosmetic industry is needed to lend support and reveal opportunities for refinements that advance the safety substantiation of peptides.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100291"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147600269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eriton E.L. Valente , David L. Harmon , John May , Huihua Ji , Ronald J. Trotta , James L. Klotz
{"title":"Association of serotonin and ergot alkaloids on tissue partitioning and contractile response of bovine blood vessels","authors":"Eriton E.L. Valente , David L. Harmon , John May , Huihua Ji , Ronald J. Trotta , James L. Klotz","doi":"10.1016/j.crtox.2025.100272","DOIUrl":"10.1016/j.crtox.2025.100272","url":null,"abstract":"<div><div>Ergot alkaloids can bind serotonin (5-HT) receptors interfering with many physiological functions. However, the mechanism has not been completely established. The objective was to evaluate whether the association of 5-HT and the ergot alkaloid, ergovaline, in a 24-h pre-incubation can affect vascular tissue partitioning and contractile responses. Cross-sections of saphenous veins from five steers were used. In the tissue partitioning experiment, the treatments were the combination of three levels of ergovaline (2.01 × 10<sup>−8</sup> M, 2.01 × 10<sup>−7</sup> M and 2.01 × 10<sup>−6</sup> M) with three levels of 5-HT and a control (5 × 10<sup>−8</sup> M, 5 × 10<sup>−7</sup> M, 5 × 10<sup>−6</sup> M and 0 M). After 24-h exposure to the treatments, the blood vessels were washed. Afterward, the tissues were analyzed for ergovaline and 5-HT concentrations. For the contractility experiment, a parallel set of blood vessels was evaluated in the myograph after 24-h pre-incubation with the respective treatments: 1) no additional compound; 2) tall fescue seed extract (2.01 × 10<sup>−7</sup> M of ergovaline); 3) serotonin (5 × 10<sup>−7</sup> M)<em>;</em> or 4) ERV plus 5-HT. The tissue ergovaline increased (P < 0.001) about 27.5-fold when the concentration in the media increased 100-fold (2.01 × 10<sup>−8</sup> M to 2.01 × 10<sup>−6</sup> M). However, the presence of 5-HT did not affect (P = 0.368) tissue ergovaline partitioning. When 5-HT was not added, ergovaline reduced (P < 0.05) the 5-HT concentration in the blood vessel. Pre-incubation with ergovaline reduced contractile response by about 95 % (P < 0.05) and 5-HT did not change its effect. Ergot alkaloid partitioning is associated with reduced tissue 5-HT levels and blood vessel contractility.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100272"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Application to developmental toxicity testing of a novel method for whole-brain imaging of microglia in zebrafish","authors":"Mizuki Yuge , Junko Koiwa , Takashi Shiromizu , Eri Wakai , Akira Migoguchi , Yuhei Nishimura","doi":"10.1016/j.crtox.2025.100276","DOIUrl":"10.1016/j.crtox.2025.100276","url":null,"abstract":"<div><div>Microglia, parenchymal macrophages resident in the central nervous system, regulate brain development by dynamically changing their functional and morphological states in a spatiotemporal-dependent manner. Because the function of microglia may differ depending on their location, their status should ideally be assessed within discrete brain regions. In this study, we developed a novel whole-brain imaging method to visualize microglial morphology in the forebrain, midbrain, and hindbrain of live zebrafish larvae at 5–6days post-fertilization, and quantified various morphological parameters using MorphoLibJ, a publicly available tool for mathematical analysis of three-dimensional images. We applied this method to assess the developmental toxicity of ethanol and valproic acid on microglial morphology in the zebrafish larvae, and were able to detect marked differences in the spatiotemporal effects of each compound. The duration of exposure required to detect significant changes in microglial morphology was shorter for ethanol than for valproic acid, and microglia in the forebrain diencephalon region were more susceptible to toxicity induced by ethanol compared with valproic acid. These results suggest that our whole-brain microglial imaging and modeling method may be a versatile tool to assess the developmental toxicity of chemicals in zebrafish.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100276"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhuoxiao Han , Ying Han , Ranran Li , Kexin Fan , Xiao Zhang , Tengfei Sun , Yue Li , Hua Qiao
{"title":"The NLRP3 inhibitor, MCC950, attenuates environmental pollutant PM2.5-induced acute lung injury by inhibiting alveolar macrophage pyroptosis","authors":"Zhuoxiao Han , Ying Han , Ranran Li , Kexin Fan , Xiao Zhang , Tengfei Sun , Yue Li , Hua Qiao","doi":"10.1016/j.crtox.2026.100282","DOIUrl":"10.1016/j.crtox.2026.100282","url":null,"abstract":"<div><div>PM<sub>2.5</sub> is a key environmental pollutant that induces inflammatory lung injury.</div><div>Effective prevention and treatment for PM<sub>2</sub>.<sub>5</sub>-induced lung damage remain lacking.</div><div>This study investigated MCC950′s protective role in PM<sub>2</sub>.<sub>5</sub>-exposed mice and macrophages.</div><div>PM<sub>2</sub>.<sub>5</sub> triggers NLRP3/Caspase-1-mediated pyroptosis, amplifying pulmonary inflammation.</div><div>MCC950 attenuates injury by inhibiting pyroptosis, suggesting therapeutic potential.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100282"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147303424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ying Yang , Minfei Hou , Minghong Li , Mengyi Duan , Yuchao Hao , Yifan Zhao , Xiaotong Ji , Jianying Bai
{"title":"Effects of the combination of brefeldin A and tunicamycin on endoplasmic reticulum stress and apoptosis in human normal hepatocytes","authors":"Ying Yang , Minfei Hou , Minghong Li , Mengyi Duan , Yuchao Hao , Yifan Zhao , Xiaotong Ji , Jianying Bai","doi":"10.1016/j.crtox.2026.100297","DOIUrl":"10.1016/j.crtox.2026.100297","url":null,"abstract":"<div><h3>Background</h3><div>Due to its ability to inhibit the growth of hepatoma cells, brefeldin A (BFA) has been considered a promising drug candidate for liver cancer. However, there is limited research on its safety profile and potential impacts when administered alone or in combination with other anticancer drugs.</div></div><div><h3>Objective</h3><div>To evaluate the safety of BFA in combination with tunicamycin (TM, a candidate anticancer drug) in human normal liver cells (HL-7702) in terms of its ability to induce endoplasmic reticulum (ER) stress and apoptosis.</div></div><div><h3>Methods</h3><div>HL-7702 cells were exposed to BFA (0–2.5 mg/L) and TM (0–5 mg/L), either alone or in combination, for 24 h. Cell viability was measured using the CCK-8 assay, and apoptotic rates were determined using flow cytometry. The mRNA and protein levels of key factors related to cell proliferation, ER stress, and apoptosis were determined using quantitative RT-PCR and Western blot, respectively.</div></div><div><h3>Results</h3><div>BFA and TM, either alone or in combination, significantly reduced the viability of HL-7702 cells. BFA alone and BFA + TM combination could weakly induce apoptosis, increase the expression of caspase 12, and reduce the protein level of proliferating cell nuclear antigen (PCNA). BFA alone and BFA + TM combination could significantly increase the mRNA and protein levels of binding immunoglobulin protein (<em>BiP</em>) and activating transcription factor 4 (<em>ATF4</em>), but did not affect the mRNA and protein levels of C/EBP homologous protein (<em>CHOP</em>) and poly (ADP-ribose) polymerase-1 (PARP-1).</div></div><div><h3>Conclusion</h3><div>This study demonstrates that BFA, alone and in combination with TM, exerts mild pro-apoptotic effects on HL-7702 cells, independent of the CHOP and caspase-3 pathways. These findings underscore the necessity of evaluating the potential hepatotoxicity of BFA-based therapies, particularly in combination treatments, to ensure their safe clinical application.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100297"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147951275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chunjing Qiu , Chenxu Guo , Xia Xue , Pengya Feng , Qiang Zhang , Ya Li , Simeng Liu , Yingying Li , Ihtisham Bukhari , Feifei Ren , Yuexiao Zhang , Pengyuan Zheng , Yang Mi
{"title":"Exposure to calcium stearyl lactylate induces hepatointestinal toxicity and gut microbiota dysbiosis in mice","authors":"Chunjing Qiu , Chenxu Guo , Xia Xue , Pengya Feng , Qiang Zhang , Ya Li , Simeng Liu , Yingying Li , Ihtisham Bukhari , Feifei Ren , Yuexiao Zhang , Pengyuan Zheng , Yang Mi","doi":"10.1016/j.crtox.2026.100301","DOIUrl":"10.1016/j.crtox.2026.100301","url":null,"abstract":"<div><div>Calcium stearyl lactylate (CSL) is a widely used food emulsifier, particularly in pasta products. In this study, we investigated the potential toxicological effects of CSL exposure on organ health and gut microbiota in mice. Over a 12-week period, mice were administered CSL at 50, 500, and 5000 mg/kg·bw. Our study found that CSL exposure induced liver and colon inflammation, significantly elevating hepatic injury markers (ALT and AST). In parallel, key intestinal functional markers (CXCL-1, CXCL-2, IL-1β, TNF-α, ZO-1, and Occludin) were markedly altered, indicating compromised gut barrier integrity. 16S rRNA sequencing revealed that CSL administration disrupted gut microbial diversity, characterized by decreased beneficial bacteria (e.g., <em>Bifidobacterium</em> and <em>Lactobacillus</em>) and increased potentially harmful genera, including <em>Anaerotruncus</em>, <em>Desulfovibrio</em>, and <em>Helicobacter</em>. These findings indicate that long-term CSL intake can induce hepatointestinal damage and provoke significant dysbiosis of the gut microbiome.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100301"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148231061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Do the habits and preferences of heated-tobacco-product users affect the emission characteristics of nicotine, PG, and VG?","authors":"Dong-Han Kim, Dae-Hyeon Kim, Youn-Suk Son","doi":"10.1016/j.crtox.2026.100303","DOIUrl":"10.1016/j.crtox.2026.100303","url":null,"abstract":"<div><div>In this study, the delivery of three substances (nicotine, propylene glycol (PG), and vegetable glycerin (VG)) in vapor generated by HTPs was evaluated based on the habits and preferences of users. To achieve this, the following five key characteristics were considered: operation method, device temperature, impact of the cartridge, flavor, and capsule break. These key features, influenced by the habits and preferences of users, were shown to affect emission profiles. This study was conducted in compliance with Health Canada Intense and used a smoking machine to capture vapor from HTPs. Each device has different operation methods that can be chosen by users. The cartridge had the most significant impact on substance delivery depending on the operation mechanism. Additionally, device temperature was correlated with concentrations of emitted substances. Tobacco sticks also showed significant impact on substance delivery. Notably, capsule break increased relative standard deviation (RSD) of PG from 2.17% to 10.22% and RSD of VG from 3.57% to 28.07% in Glo Hyper X2 fruit-flavored tobacco sticks. These findings suggest that delivery of substances is influenced by conditions of HTPs and the conditions are influenced by the habits, behaviors, and preferences of users.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100303"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148167722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mengqin Tao, Shu Ai, Xiaozhen Gu, Mengmeng Wang, Mingli Sun, Hui-Li Wang
{"title":"Developmental lead (pb) exposure induces anxiety and depression-like behaviors via inhibiting the AMPK/ACSS2 pathway","authors":"Mengqin Tao, Shu Ai, Xiaozhen Gu, Mengmeng Wang, Mingli Sun, Hui-Li Wang","doi":"10.1016/j.crtox.2026.100312","DOIUrl":"10.1016/j.crtox.2026.100312","url":null,"abstract":"<div><div>Environmental lead (Pb) exposure is a risk factor for anxiety and depression. Our previous study showed Pb-induced neurotoxicity involves dysregulated epigenetic modifiers, yet the role of acyl-CoA synthetase short-chain family member 2 (ACSS2)—a key regulator of histone acetylation—in these behaviors remains unclear. Beginning at gestational day 0 (GD 0, plug day) and continuing through weaning (PND 21), C57BL/6 J dams received 100 ppm Pb in drinking water, exposing offspring indirectly <em>via</em> placenta and milk; after weaning, offspring received the same Pb solution directly from drinking water until PND 60. Behavioral tests revealed developmental Pb exposure induced anxiety and depression-like behaviors, accompanied by neuronal morphological damage in the medial prefrontal cortex (mPFC). Mechanistically, Pb inhibited AMP-activated protein kinase (AMPK) activity, suppressing ACSS2 expression and its nuclear translocation, which reduced nuclear acetyl-CoA and histone H3 lysine 9 acetylation (H3K9ac). The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) restored ACSS2 expression and phosphorylation, confirming AMPK as its upstream regulator. These epigenetic changes accompanied downregulated synaptic molecules (GluN2A, VGLUT1, PSD-95). ACSS2 restoration <em>via</em> D-mannose supplementation rescued synaptic protein loss, reversed neuronal structural impairments, and alleviated Pb-induced emotional deficits. Our findings identify the AMPK/ACSS2 pathway as a core regulator of Pb-induced affective disorders, whereby its inhibition epigenetically silences synaptic molecular expression, and nominates ACSS2 augmentation as a viable therapeutic strategy.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"11 ","pages":"Article 100312"},"PeriodicalIF":4.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Multigenerational effects of uranium exposure reveal stronger testicular dysregulation in the second generation","authors":"Audrey Legendre , Céline Gloaguen , Dimitri Kereselidze , Nawel Saci , Sophia Murat El Houdigui , Pascal Froment , Christelle Elie , Catherine Defoort , Philippe Lestaevel , Mohamed Amine Benadjaoud , Maâmar Souidi , Stéphane Grison","doi":"10.1016/j.crtox.2025.100279","DOIUrl":"10.1016/j.crtox.2025.100279","url":null,"abstract":"<div><h3>Background</h3><div>Infertility is a significant public health issue that can be influenced by environmental pollutants. As a radioactive heavy metal and environmental contaminant, uranium has the potential to impact fertility.</div></div><div><h3>Objective</h3><div>This study assesses the multigenerational reproductive effects of chronic, non-nephrotoxic uranium exposure across three generations of male rats.</div></div><div><h3>Methods</h3><div>In this study, a non-nephrotoxic uranium solution (40 mg/L) was chronically administered <em>via</em> drinking water to male and female F0 rats (n = 20 per group) throughout their lifespan. The objective was to evaluate the potential reprotoxic effects of uranium on males across three generations (F0, F1, F2), with a focus on spermatogenesis, steroidogenesis, and testicular homeostasis, including oxidative stress, inflammation, apoptosis, and vitamin D metabolism.</div></div><div><h3>Results</h3><div>Steroidogenesis was modulated in all generation, with dysregulation of sex and pituitary hormones (testosterone, estradiol, gonadotropins, Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH). Morphological and histological changes in the testes were observed in both the F1 and F2 generations. Spermatogenesis was dysregulated by an increased proportion of seminiferous tubules at stage I-VI and reduced expression of <em>TH2B</em> and <em>eppin</em> mRNA. Interestingly, gene expression analysis of several markers involved in the regulation and protection of testicular homeostasis revealed significant effects only on the F2 generation. In this generation, uranium exposure also disrupted vitamin D metabolism in the testes.</div></div><div><h3>Conclusion</h3><div>Uranium may impair testicular function, with more pronounced effects observed in the F2 generation. These findings highlight its potential for multigenerational toxicity and underscore the need for further research into its impact on human reproductive health.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"10 ","pages":"Article 100279"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}