Current Research in Toxicology最新文献

{"title":"Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO","authors":"Umme Sabrina Haque ,&nbsp;Melissa Kohut ,&nbsp;Toshifumi Yokota","doi":"10.1016/j.crtox.2024.100182","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100182","url":null,"abstract":"<div><p>Duchenne Muscular Dystrophy (DMD) is a devastating X-linked genetic disorder characterized by progressive muscle degeneration due to mutations in the dystrophin gene. This results in the absence or dysfunction of the dystrophin protein, leading to muscle weakness, loss of ambulation, respiratory issues, and cardiac complications, often leading to premature death. Recently, antisense oligonucleotide (ASO)-mediated exon skipping has emerged as a promising therapeutic strategy for DMD. Notably, the FDA has conditionally approved four ASO therapies for DMD, with numerous others in various stages of clinical development, indicating the growing interest and potential in this field. To enhance ASO-based therapies, researchers have explored the novel concept of conjugating peptides to the phosphorodiamidate morpholino backbone (PMO) of ASOs, leading to the development of peptide-conjugated PMOs (PPMOs). These PPMOs have demonstrated significantly improved pharmacokinetic profiles, potentially augmenting their therapeutic effectiveness. Despite the optimism surrounding ASOs and PPMOs, concerns persist regarding their efficacy and safety. To comprehensively evaluate these therapies, it is imperative to expand patient populations in clinical trials and conduct thorough investigations into the associated risks. This article provides a comprehensive review and discussion of the available data pertaining to adverse reactions and toxicology associated with FDA-approved ASO drugs for DMD. Furthermore, it offers insights into the emerging category of peptide-conjugated ASO drugs those are clinical and preclinical trials, shedding light on their potential benefits and challenges.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100182"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000355/pdfft?md5=0ee155e7dc6de2577482f5fe36a61d0b&pid=1-s2.0-S2666027X24000355-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141435070","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":"Sublethal effects of early-life exposure to common and emerging contaminants in birds","authors":"Jacquelyn Grace ,&nbsp;Elena Duran ,&nbsp;Mary Ann Ottinger ,&nbsp;Terri Maness","doi":"10.1016/j.crtox.2024.100190","DOIUrl":"10.1016/j.crtox.2024.100190","url":null,"abstract":"<div><p>The plight of wild birds is becoming critical due to exposure to environmental contaminants. Although laboratory studies have provided insights into the developmental effects of chemical exposures, less is known about the adverse effects of environmental chemicals in developing wild birds. Early life stages are critical windows during which long-term organization of physiological, behavioral, and neurological systems can occur. Thus, contaminant exposure at early life stages can directly influence survival and reproductive success, with consequences for population stability and resilience in wild species. This review synthesizes existing knowledge regarding both short- and long-term effects of early-life exposure to widespread contaminants in birds. We focus especially on wild birds and on contaminants of concern within the Gulf of Mexico as an example of a habitat under anthropogenic stress from exposure to a complex mixture of chemicals and changing land uses that exacerbate existing vulnerabilities of wildlife in this region. Chemical contaminants for discussion in this review are based on avian mortality records from the Wildlife Health Information Sharing Partnership (WHISPers) database and on additional review of the literature regarding avian contaminants of concern for the northern Gulf of Mexico, and include oil and associated polycyclic aromatic hydrocarbons, dioxin and dioxin-like compounds, flame retardants, pesticides, heavy metals, and plastics. We provide an overview of effects in bird species at both the pre-hatching and post-hatching early life stages, discuss differences in sensitivities by route of exposure, life stage, and life history, and provide recommendations for future research. We find that additional research is needed on altricial species, post-hatching early-life exposure, long-term effects, and on ecologically relevant contaminant concentrations and routes of exposure. Given the increasing frequency and intensity of anthropogenic stressors encountered by wild animals, understanding both lethal and sublethal impacts of contaminants on the health of individuals and populations will be critical to inform restoration, management, and mitigation efforts.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100190"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000434/pdfft?md5=87270839d476de9548652c2bdce46fa7&pid=1-s2.0-S2666027X24000434-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141963231","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":"Toxicology study profile of Nicotinamide mononucleotide after acute and 90-day sub chronic dosing in Wistar rats and mutagenicity tests","authors":"Jianjun Yu,&nbsp;Qiang Shen,&nbsp;Jiayan Li","doi":"10.1016/j.crtox.2024.100171","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100171","url":null,"abstract":"<div><p>Nicotinamide mononucleotide (NMN) is an intermediate in biosynthesis pathway of Nicotinamide adenine dinucleotide (NAD+), an essential cofactor in all living cells involved in fundamental biological processes. Evidence stemming from recent studies have unveiled numerous roles of NAD+ metabolism on aging, longevity, delaying the progression of age-related diseases. A three-study genetic toxicity (genetox) battery (bacterial mutagenesis, in vitro cytogenetics, and in vivo mammalian test) is usually required to confirm safety of a new dietary ingredient and this study showed the data from in vivo mutagenicity test for the first time.</p><p>The acute oral LD50 of NMN was greater than 2000 mg/kg body weight with 5000 mg/kg body weight as LD50 cut-off value and was classified under “Category 5 or Unclassified” as per Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Based on 90 days repeated dose toxicity test the NOAEL was considered to be NLT 800 mg NMN/kg body weight in Wistar rats. The bacterial reverse mutation test, the in vitro and in vivo chromosomal aberration test, found NMN to be non-mutagenic. In the mammalian bone marrow chromosomal aberration test, it was concluded that NMN is non clastogenic at and up to 2,000 mg/kg body weight in all the animals tested to confirm safety of a new dietary ingredient and this study showed the data from in vivo mutagenicity test for the first time.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100171"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000240/pdfft?md5=d2d93c1852cab16f8d024b14ecbbfef2&pid=1-s2.0-S2666027X24000240-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140906755","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":"Disruptive consequences of monosodium glutamate on male reproductive function: A review","authors":"David Tolulope OLUWOLE ,&nbsp;Oladipupo`Samuel EBIWONJUMI ,&nbsp;Lydia Oluwatoyin AJAYI ,&nbsp;Olubunmi Dupe ALABI ,&nbsp;Victor AMOS ,&nbsp;Grace AKANBI ,&nbsp;Wale Johnson ADEYEMI ,&nbsp;Ayodeji Folorunsho AJAYI","doi":"10.1016/j.crtox.2024.100148","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100148","url":null,"abstract":"<div><p>Monosodium glutamate (MSG) is one of the most extensively used flavour enhancers worldwide. Although it is widely regarded as a safe food additive with no recommended daily dosage, its over-consumption has been associated with notably pathophysiological events in various tissues and organs of the body. Previous studies have reported of the neuro- cardio- and hepato- toxic effects of its excessive exposure. Moreover, the food additive instigates metabolic dysfunction. It has been established that MSG damages male reproductive accessory organs like prostate glands and epididymis. In addition, it impairs serum enzymatic activities and serum levels of testosterone, gonadotropin-releasing hormone, luteinizing hormone and cholesterol. Reduced sperm count, sperm motility, sperm morphology, and sperm viability, imbalances in male reproductive hormones, alongside alteration in the histoarchitecture of the testes and other male reproductive tissues have also been connected with excessive exposure to MSG. Literature reports affirm the link between the over-consumption of MSG and reproductive organ weight and male sexual behaviour. This review article addresses the multi-systemic effects of exposure to MSG and the possible mechanism of action of the compound with a focus on the negative implications of the food additive on male reproductive functions and the possible role of natural antioxidants in male reproductive functions. carefully selected keywords were used during the literature search to gather credible and up-to-date information about the subject matter.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100148"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X2400001X/pdfft?md5=44f680ca120bc4503db1bb33cb5420a5&pid=1-s2.0-S2666027X2400001X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139434489","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":"Roles of oxidative stress/JNK/ERK signals in paraquat-triggered hepatic apoptosis","authors":"Kuan-I Lee ,&nbsp;Kai-Min Fang ,&nbsp;Chun-Ying Kuo ,&nbsp;Chun-Fa Huang ,&nbsp;Shing-Hwa Liu ,&nbsp;Jui-Ming Liu ,&nbsp;Wei-Cheng Lai ,&nbsp;Kai-Chih Chang ,&nbsp;Chin-Chuan Su ,&nbsp;Ya-Wen Chen","doi":"10.1016/j.crtox.2024.100155","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100155","url":null,"abstract":"<div><p>Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1–2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome <em>c</em> release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant <em>N</em>-Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100155"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000082/pdfft?md5=e145215fad560b32c819d99cb92a7fe9&pid=1-s2.0-S2666027X24000082-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139737551","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":"A wide survey of heavy metals-induced in-vitro DNA replication stress characterized by rate-limited replication","authors":"Qidong Ren ,&nbsp;Xuejun Guo ,&nbsp;Dong Yang ,&nbsp;Chuanfang Zhao ,&nbsp;Xiangyuan Zhang ,&nbsp;Xinghui Xia","doi":"10.1016/j.crtox.2024.100152","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100152","url":null,"abstract":"<div><p>Heavy metals (HMs) are environmental pollutants that pose a threat to human health and have been accepted to cause various diseases, including cancer and developmental disorders. DNA replication stress has been identified to be associated with such diseases. However, the effect of HMs exclusively on DNA replication stress is still not well understood. In this study, DNA replication stress induced by thirteen HMs was assessed using a simplified <em>in-vitro</em> DNA replication model. Two parameters, <em>Ct_e/Ct_c</em> reflecting the cycle threshold value alteration and <em>K_e/K_c</em> reflecting the linear phase slope change, were calculated based on the DNA replication amplification curve to evaluate the rate of exponential and linear phases. These parameters were used to detect the replication rate reflecting <em>in-vitro</em> DNA replication stress induced by tested HMs. According to the effective concentrations and rate-limiting degree, HMs were ranked as follows: Hg, Ce &gt; Pb &gt; Zn &gt; Cr &gt; Cd &gt; Co &gt; Fe &gt; Mn, Cu, Bi, Sr, Ni. Additionally, EDTA could relieve the DNA replication stress induced by some HMs. In conclusion, this study highlights the potential danger of HMs themselves on DNA replication and provides new insight into the possible links between HMs and DNA replication-related diseases.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100152"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000057/pdfft?md5=f119fe5f30e69c128acda54cd1a6475d&pid=1-s2.0-S2666027X24000057-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139674448","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":"Mono-(2-ethylhexyl) phthalate induces trophoblast hypoxia and mitochondrial dysfunction through HIF-1α-miR-210-3p axis in HTR-8/SVneo cell line","authors":"Sunitha Meruvu,&nbsp;Zehuan Ding,&nbsp;Mahua Choudhury","doi":"10.1016/j.crtox.2024.100188","DOIUrl":"10.1016/j.crtox.2024.100188","url":null,"abstract":"<div><p>The exposure to the ubiquitous phthalate metabolite mono-(2-ethylhexyl) phthalate (MEHP) is connected to dysregulated trophoblast function and placenta health; however, the underlying mechanisms preluding this scenario remain to be elucidated. In this study, we explored the hypoxemic effects of MEHP on a human placental first-trimester trophoblast cell line (HTR-8/Svneo). MEHP-treated trophoblast cells displayed significantly increased levels of oxidative stress and hypoxia-inducible factor-1 alpha (HIF-1α) attributed by the induction of hypoxia. Further, HIF-1α exhibited higher DNA binding activity and upregulated gene expression of its downstream target vascular endothelial growth factor A (VEGFA). The hypoxia-induced microRNA miR-210-3p was also significantly increased upon MEHP treatment followed by disrupted mitochondrial ATP generation and membrane potential. This was identified to possibly be facilitated by lowered mitochondrial DNA copy number and inhibited expression of electron transport chain subunits, such as mitochondrial complex-IV. These results suggest potential adverse effects of MEHP exposure in a trophoblast cell line mediated by HIF-1α and the epigenetic modulator miR-210-3p. Chronic placental hypoxia and oxidative stress have long been implicated in the pathogenesis of pregnancy complications such as preeclampsia. As we’ve revealed genetic and epigenetic factors underscoring a potential mechanism induced by MEHP, this brings to light another significant implication of phthalate exposure on maternal and fetal health.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100188"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000410/pdfft?md5=9232c7cf93c3879dc45fd371b48a8926&pid=1-s2.0-S2666027X24000410-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141841856","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":"The dynamic face of cadmium-induced Carcinogenesis: Mechanisms, emerging trends, and future directions","authors":"Mohamed Ali Hussein ,&nbsp;Abishek Kamalakkannan ,&nbsp;Kamyab Valinezhad ,&nbsp;Jhishnuraj Kannan ,&nbsp;Nikhila Paleati ,&nbsp;Rama Saad ,&nbsp;André Kajdacsy-Balla ,&nbsp;Gnanasekar Munirathinam","doi":"10.1016/j.crtox.2024.100166","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100166","url":null,"abstract":"<div><p>Cadmium (Cd) is a malleable element with odorless, tasteless characteristics that occurs naturally in the earth’s crust, underground water, and soil. The most common reasons for the anthropological release of Cd to the environment include industrial metal mining, smelting, battery manufacturing, fertilizer production, and cigarette smoking. Cadmium-containing products may enter the environment as soluble salts, vapor, or particle forms that accumulate in food, soil, water, and air. Several epidemiological studies have highlighted the association between Cd exposure and adverse health outcomes, especially renal toxicity, and the impact of Cd exposure on the development and progression of carcinogenesis. Also highlighted is the evidence for early-life and even maternal exposure to Cd leading to devastating health outcomes, especially the risk of cancer development in adulthood. Several mechanisms have been proposed to explain how Cd mediates carcinogenic transformation, including epigenetic alteration, DNA methylation, histone posttranslational modification, dysregulated non-coding RNA, DNA damage in the form of DNA mutation, strand breaks, and chromosomal abnormalities with double-strand break representing the most common DNA form of damage. Cd induces an indirect genotoxic effect by reducing p53′s DNA binding activity, eventually impairing DNA repair, inducing downregulation in the expression of DNA repair genes, which might result in carcinogenic transformation, enhancing lipid peroxidation or evasion of antioxidant interference such as catalase, superoxide dismutase, and glutathione. Moreover, Cd mediates apoptosis evasion, autophagy activation, and survival mechanisms. In this review, we decipher the role of Cd mediating carcinogenic transformation in different models and highlight the interaction between various mechanisms. We also discuss diagnostic markers, therapeutic interventions, and future perspectives.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100166"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000197/pdfft?md5=c08f999a224581b582db3eea858bbc40&pid=1-s2.0-S2666027X24000197-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140643964","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":"Investigation of inflammatory mechanisms induced by croton oil in mouse ear","authors":"Ganming Mao ,&nbsp;Dalon Douglas ,&nbsp;Milankumar Prajapati ,&nbsp;Trishaal Janardhanam Raghavendra Rao ,&nbsp;Haiyan Zheng ,&nbsp;Caifeng Zhao ,&nbsp;Blase Billack","doi":"10.1016/j.crtox.2024.100184","DOIUrl":"10.1016/j.crtox.2024.100184","url":null,"abstract":"<div><p>Croton oil is liquid at room temperature, with a pale-yellow color and spicy odor. It is commonly used in combination with phenol as a chemical peeling agent in dermatology, which reveals its caustic exfoliating effects. Topical use of croton oil at a high dose produces skin irritation, inflammation, swelling, pain, and even tumors. Therefore, croton oil has been widely used for inflammation, pain, and tumor related research, with different animal models having been established. However, mechanistic studies through which croton oil induces skin swelling, injury and activates tissue repair/regeneration are limited. The present study used croton oil to induce mouse ear edema and examined tissue responses 4 h after exposure. To this end, croton oil was applied to the ventral side of mouse ears, followed by tissue collection. Samples were analyzed by hematoxylin and eosin (H&amp;E) staining, toluidine blue staining, and immunohistochemistry staining for myeloperoxidase (MPO) and matrix metalloproteinase-9 (MMP-9). Western blotting and ELISA were also carried out for MMP-9 together with unbiased proteomic analysis using mass-spectrometry. Results from our study demonstrated that as soon as 4 h of exposure to 2.5 % croton oil, the expression levels of MPO and MMP-9 in the dermis significantly increased compared to acetone-treated (vehicle) control ears, as did other inflammatory reactions such as swelling and neutrophil aggregation and infiltration. Subsequently, proteomic analysis confirmed that croton oil treatment resulted in significant upregulation of proteins such as myeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9), and matrix metalloproteinase-8 (MMP-8) in the ear skin. Interestingly, mouse ears treated with acetone vehicle showed differential expression of 2,478 proteins relative to naïve tissues; among those differentially expressed in acetone-treated samples were members of the phosphatidylinositol-glycan biosynthesis class N, T and U proteins (PIGN, PIGT, and PIGU). Overall, this work confirms the presence of neutrophil-derived MPO and MMP-9 and extends the body of knowledge to show that MMP-8 is also present during croton oil-mediated skin inflammation in the mouse ear; moreover, we find that acetone vehicle is not inert and has effects on the skin that should be considered moving forward.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100184"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000379/pdfft?md5=065ccacf3dd535d6119a2638ba46a403&pid=1-s2.0-S2666027X24000379-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122759","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":"Evaluation of the diphenyl herbicide, oxyfluorfen, for effects on thyroid hormones in the juvenile rat","authors":"T.E. Stoker ,&nbsp;G.D. DeVane ,&nbsp;A.R. Buckalew ,&nbsp;J.R. Bailey ,&nbsp;J.L. Ford ,&nbsp;A.S. Murr","doi":"10.1016/j.crtox.2023.100146","DOIUrl":"10.1016/j.crtox.2023.100146","url":null,"abstract":"<div><p>Recently, oxyfluorfen, a pre- and post-emergent diphenyl ether herbicide, was identified in our laboratory as an inhibitor of iodide uptake by the sodium iodide symporter (NIS), the first key step in the synthesis of thyroid hormones (THs). This inhibition was observed <em>in vitro</em>, using both a human NIS engineered cell line (hNIS-HEK293T-EPA) and a rat thyroid follicular cell line (FRTL-5). Oxyfluorfen was found to be a potent inhibitor of NIS activity with an EC50 of approximately 2 µM in both cell lines with no observed cytotoxicity at any concentration tested up to 100 μM. The current research tested the hypothesis that oxyfluorfen alters circulating concentrations of THs. This hypothesis was first tested in a pilot study with both juvenile male and female rats exposed to oxyfluorfen for 4 days at 0, 125, 250 and 500 mg/kg/day. Once we identified that this short-term 4-day oxyfluorfen exposure suppressed both total serum thyroxine (T4) and triiodothyronine (T3) at all doses, we tested seven lower concentrations of oxyfluorfen (0.8125 to 62.5 mg/kg day) in an 8-day exposure paradigm to more closely evaluate the dose–response. We found that oxyfluorfen suppressed serum T4 with a LOEL of 3.25 mg/kg/day and T3 with a LOEL 62.5 mg/kg/day. Analytical chemistry of the serum showed an accumulation over time following oral exposure to oxyfluorfen in both the 4- and 8-day groups. Analytical chemistry of the thyroid glands in the 8-day study revealed higher accumulation in the thyroid as compared to the serum (2 to 3- fold at 62.5 mg/kg). No changes in thyroid weight or serum TSH were observed following the 8-day exposure. This study is the first to demonstrate an effect of oxyfluorfen on serum thyroid hormones in the rat. Additional studies are needed to further evaluate the effects on thyroid homeostasis with extended exposures and the potential implications of the observed effects.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100146"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000440/pdfft?md5=ac2684b7e8b3b845fb41ef3cd791c35d&pid=1-s2.0-S2666027X23000440-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139019388","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}