Journal of Applied Toxicology最新文献

{"title":"Exploring developmental MeHg impact on extraembryonic and cardiac vessels and its effect on cardiomyocyte contractility","authors":"Nathália Ronconi-Krüger,&nbsp;Yara Maria Rauh Müller,&nbsp;Evelise Maria Nazari","doi":"10.1002/jat.4661","DOIUrl":"10.1002/jat.4661","url":null,"abstract":"<p>The toxicity of methylmercury (MeHg) during embryonic development is a relevant issue that remains unclear and deserves investigation. In this sense, there is evidence that links the intake of contaminated food with cardiovascular pathologies in human adults and children. Thus, this study aimed to verify the impact of MeHg on the structure and integrity of extraembryonic and cardiac blood vessels and the contractile function of cardiomyocytes, also evaluating embryonic weight and the cardiosomatic index (CSI). Thus, chicken embryos, used as an experimental model, were exposed to a single dose of 0.1 μg MeHg/50 μl saline at E1.5 and analyzed at E10. After exposure, an increase in the number of extraembryonic blood vessels and the veins of the cardiac tissue was observed. These increases were accompanied by a reduction in the content of VEGF and VCAM proteins related to vessel growth and adhesiveness. Together, these results were related to reduced nitrite (NOx) levels. Furthermore, MeHg reduces the number of sarcomeres and increases the content of cardiac troponin I (cTnI), a protein that regulates contraction. In general, exposure to MeHg affected the integrity of extraembryonic and cardiac vessels and the contractile function of cardiomyocytes, which had a systemic impact evidenced by the reduction in embryonic weight gain and CSI.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 11","pages":"1679-1688"},"PeriodicalIF":2.7,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An evaluation of the genotoxicity and 90-day repeated dose oral toxicity in rats of Porphyridium purpureum","authors":"Timothy S. Murbach,&nbsp;Róbert Glávits,&nbsp;John R. Endres,&nbsp;Gábor Hirka,&nbsp;Adél Vértesi,&nbsp;Erzsébet Béres,&nbsp;Ilona Pasics Szakonyiné","doi":"10.1002/jat.4665","DOIUrl":"10.1002/jat.4665","url":null,"abstract":"<p>Interest in microalgae products for use in food is increasing, as demands for sustainable and cost-effective food choices grow due to the escalating global population and increase in climate-related struggles with agriculture. Toxicological assessments of some species of microalgae have been conducted, but there were little data available for the oral consumption of the red microalgae <i>Porphyridium purpureum</i> and no data on genotoxicity. This article articulates a genotoxicity assessment and a 90-day repeated dose oral toxicity study in rats performed according to OECD guidelines. Under the experimental conditions applied, the test item did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used in the bacterial reverse mutation test. Similarly, the test item did not induce structural chromosomal aberrations in V79 hamster lung cells. The test item also did not cause chromosomal damage in bone marrow of mice in the mammalian micronucleus test. The no observed adverse effect level (NOAEL) of the 90-day repeated dose oral toxicity study in rats was determined to be the highest dose tested, 3000 mg/kg bw/day. These data add to the body of evidence regarding the safety of <i>P. purpureum</i> for human consumption.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 10","pages":"1616-1632"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is micronucleus assay a useful marker in gingiva, tongue, and palate for evaluating cytogenetic damage induced by chemical, physical, and biological agents in vivo? A systematic review with meta-analysis.","authors":"Thiago Guedes Pinto, Wilton Mitsunari Takeshita, Ana Claudia Muniz Renno, Patricia Ramos Cury, Jean Junes Dos Santos, Daniel Araki Ribeiro","doi":"10.1002/jat.4662","DOIUrl":"https://doi.org/10.1002/jat.4662","url":null,"abstract":"<p><p>The present systematic review (SR) aims to evaluate manuscripts in order to help further elucidate the following question: is the micronucleus assay (MA) also a useful marker in gingiva, tongue, and palate for evaluating cytogenetic damage in vivo? A search was performed through the electronic databases PubMed/Medline, Scopus, and Web of Science, all studies published up to December 2023. The comparisons were defined as standardized mean difference (SMD), and 95% confidence intervals (CIs) were established. Full manuscripts from 34 studies were carefully selected and reviewed in this setting. Our results demonstrate that the MA may be a useful biomarker of gingival tissue damage in vivo, and this tissue could be a useful alternative to the buccal mucosa. The meta-analysis analyzing the different sites regardless of the deleterious factor studied, the buccal mucosa (SMD = 0.69, 95% CI, - 0.49 to 1.88, p = 0.25) and gingiva (SMD = 0.31, 95% CI, - 0.11 to 0.72, p = 0.15), showed similar results and different outcome for the tongue (SMD = 1.19, 95% CI, 0.47 to 1.91, p = 0.001). In summary, our conclusion suggests that the MA can be a useful marker for detecting DNA damage in gingiva in vivo and that this tissue could be effective site for smearing.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Possible pathogenic mechanisms for doxorubicin-induced splenic atrophy in a human breast cancer xenograft mouse model","authors":"Jianjie Xue,&nbsp;Bing Ye,&nbsp;Mengqi Sun","doi":"10.1002/jat.4666","DOIUrl":"10.1002/jat.4666","url":null,"abstract":"<p>Doxorubicin-based chemotherapy is a widely used first-line treatment for breast cancer, yet it is associated with various side effects, including splenic atrophy. However, the pathogenic mechanisms underlying doxorubicin-induced atrophy of the spleen remain unclear. This study investigates that doxorubicin treatment leads to splenic atrophy through several interconnected pathways involving histological changes, an inflammatory response, and apoptosis. Immunohistochemical and western blot analyses revealed reduced size of white and red pulp, decreased cellularity, amyloidosis, and fibrotic remodeling in the spleen following doxorubicin treatment. Additionally, increased secretion of pro-inflammatory cytokines was detected using an antibody array and enzyme-linked immunosorbent assay (ELISA), which triggers inflammation through the regulation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-κB) signaling pathways. Further analysis revealed that the loss of regulators and effectors of the oxidative defense system, including sirtuin (Sirt)3, Sirt5, superoxide dismutase (SOD)1, and SOD2, was implicated in the upstream regulation of caspase-dependent cellular apoptosis. These findings provide insights on the pathogenic mechanisms underlying doxorubicin-induced splenic atrophy and suggest that further investigation may be warranted to explore strategies for managing potential side effects in breast cancer patients treated with doxorubicin.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 10","pages":"1606-1615"},"PeriodicalIF":2.7,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of oxidative stress induced by heavy metals on ovarian function.","authors":"Chengqi Xiao, Dongmei Lai","doi":"10.1002/jat.4664","DOIUrl":"https://doi.org/10.1002/jat.4664","url":null,"abstract":"<p><p>As a crucial organ of the female reproductive system, the ovary has both reproductive and endocrine functions. Oxidative stress refers to an increase in intracellular reactive oxygen species (ROS), which play a role in the normal physiological activity of the ovary. However, excessive ROS can cause damage to the ovary. With the advancement of human industrial activities, heavy metal pollution has become increasingly severe. Heavy metals cause oxidative stress through both direct and indirect mechanisms, leading to changes in signal transduction pathways that damage the ovaries. This review aims to outline the adverse effects of oxidative stress on the ovaries triggered by heavy metals such as copper, arsenic, cadmium, mercury, and lead. The detrimental effects of heavy metals on ovaries include follicular atresia and decreased estrogen production in experimental animals, and they also cause premature ovarian insufficiency in women. Additionally, this review discusses the role of antioxidants, provides some treatment methods, summarizes the limitations of current research, and offers perspectives for future research directions.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining the hepatotoxic potential of cannabidiol, cannabidiol-containing hemp extract, and cannabinol at consumer-relevant exposure concentrations in primary human hepatocytes","authors":"Anneliese Striz,&nbsp;Yang Zhao,&nbsp;Estatira Sepehr,&nbsp;Cory Vaught,&nbsp;Kirsten Eckstrum,&nbsp;Kyra Headrick,&nbsp;Jeffrey Yourick,&nbsp;Robert Sprando","doi":"10.1002/jat.4646","DOIUrl":"10.1002/jat.4646","url":null,"abstract":"<p>Hemp extracts and consumer products containing cannabidiol (CBD) and/or other phytocannabinoids derived from hemp have entered the marketplace in recent years. CBD is an approved drug in the United States for the treatment of certain seizure disorders. While effects of CBD in the liver have been well characterized, data on the effects of other cannabinoids and hemp extracts in the liver and methods for studying these effects in vitro are limited. This study examined the hepatotoxic potential of CBD, CBD concentration-matched hemp extract, and cannabinol (CBN), at consumer-relevant concentrations determined by in silico modeling, in vitro using primary human hepatocytes. Primary human hepatocytes exposed to between 10-nM and 25-μM CBD, CBN, or hemp extract for 24 and 48 h were evaluated by measuring lactate dehydrogenase release, apoptosis, albumin secretion, urea secretion, and mitochondrial membrane potential. Cell viability was not significantly affected by CBD, CBN, or the hemp extract at any of the concentrations tested. Exposure to hemp extract induced a modest but statistically significant decrease in albumin secretion, urea secretion, and mitochondrial membrane potential at the highest concentration tested whereas CBD only induced a modest but statistically significant decrease in albumin secretion compared with vehicle control. Although this study addresses data gaps in the understanding of cannabinoid hepatoxicity in vitro, additional studies will be needed to determine how these results correlate with relevant consumer exposure and the biological effects of cannabinoids in human liver.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 10","pages":"1595-1605"},"PeriodicalIF":2.7,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4646","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141457147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic β cell models for screening insulin secretagogues and cytotoxicity","authors":"Pranjali Potdar, Avinash Kharat, Avinash Sanap, Supriya Kheur, Ramesh Bhonde","doi":"10.1002/jat.4658","DOIUrl":"https://doi.org/10.1002/jat.4658","url":null,"abstract":"In the past 2–3 decades, numerous attempts have been made to create an insulin‐secreting β cell line that maintains normal insulin secretion. However, primary β cell cultures have finite life and, therefore, cannot be used for long‐term experiments. The most widely used insulin‐secreting cell lines are Insulinoma‐1, rat insulinoma cell line, hamster pancreatic β cell line, mouse insulinoma, and β tumor cell line. Insulinoma‐derived cell lines show infinite growth in tissue culture but exhibit varying differences in their insulin responsiveness to glucose levels compared to normal β cells. Despite difficulties with β cell cultures, these cell lines have offered some useful insights in diabetes research concerning physiological functions and pathological investigations. In this review, we describe insulinoma cell lines used for drug screening, insulin secretion, cell viability, proliferation, and other relevant cellular functions. In addition, we have also incorporated recently developed human β cell lines. These cell lines have provided some helpful insights into physiological activities and pathology in diabetes research, despite challenges with β cell culturing. We propose that these cell lines could also be explored for screening Ayurvedic Rasayanas and homeopathy preparations for their cytotoxicity and insulin secretagogue activities to have evidence‐based data on alternative and complementary medicines.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"9 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141506564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential consequences of nitric oxide release: An improved model informing worker safety","authors":"Gautham Venugopalan,&nbsp;Rocco Casagrande,&nbsp;Noah Gunther,&nbsp;Rashmi Prasad,&nbsp;Shawn Jackson","doi":"10.1002/jat.4660","DOIUrl":"10.1002/jat.4660","url":null,"abstract":"<p>Both nitric oxide (NO) and nitrogen dioxide (NO₂) gasses are toxic to humans but are commonly found in industrial settings such as semiconductor manufacturing sites. Due to the spontaneous oxidation of NO to NO₂ under ambient conditions, individuals working with NO may in fact be exposed to both gasses in the case of an accidental release. Unfortunately, most safety materials provided to NO users do not address the potential for associated NO₂ toxicity, and, until now, models developed to predict health consequences following a release of NO have not appropriately considered the oxidation kinetics nor the toxicity of both NO and NO₂ in their assessments. This paper describes an improved multi-module model that addresses these limitations and explores whether facilities using NO should consider adopting measures that can mitigate the simultaneous health effects of both gasses. The model predicts the morbidity (intoxication/injury), mortality (death), and treatment outcomes that may arise following an industrial NO release by first calculating the doses of both NO and NO₂ received by exposed individuals and then applying newly defined toxicity parameters for NO and NO₂ to assign dose-dependent probabilities for the onset of intoxication and/or death and the ability of appropriate treatment(s) to save lives. Modeling results indicate low risk to worker health in the likeliest release scenarios while identifying less likely situations that carry substantially higher risk. Moreover, these results indicate that risks to worker health can be mitigated with simple measures like maintaining reliable alarms, adequate ventilation, and on-site supplies of methylene blue, as well as encouraging quick responses by personnel. With appropriate parameterization, the improved modeling framework is generalizable to any chemical release, especially multi-hazard releases resulting from the conversion of one toxic compound into another under likely environmental conditions. By directly addressing the toxicities of multiple compounds, the improved model presents a more realistic picture of the potential health consequences of a chemical release. This generalizable framework for modeling of multi-hazard chemical releases can inform preparedness and risk mitigation strategies for NO release events.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 10","pages":"1583-1594"},"PeriodicalIF":2.7,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141531079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to thiourea during the early stages of development impedes the formation of the swim bladder in zebrafish larvae","authors":"Lakshmi Pillai,&nbsp;Shantanu Karandikar,&nbsp;Kamya Pandya,&nbsp;Aishwarya V.M.,&nbsp;Anjali Singh,&nbsp;Suresh Balakrishnan","doi":"10.1002/jat.4657","DOIUrl":"10.1002/jat.4657","url":null,"abstract":"<p>Thiourea, a widely used agrochemical, is known to inhibit the activity of thyroid peroxidase, a key enzyme in the biosynthetic pathway of thyroid hormones. Thyroid insufficiency compromises the basal metabolic rate in warm-blooded organisms and embryonic development in vertebrates. In this study, we looked for developmental defects by exposing the zebrafish embryos to an environmentally relevant dose of thiourea (3 mg/mL). Liquid chromatography–tandem mass spectrometry (LC-MS/MS) was performed to validate thiourea's presence in the treated zebrafish embryos. Structural anomalies like bent tail and pericardial edema were noticed in 96-h post-fertilization (hpf) larvae. On histological examination, underdeveloped swim bladder was noticed in 96 hpf larvae exposed to 3 mg/mL thiourea. The treated larvae also failed to follow the characteristic swimming behavior in response to stimuli due to defective swim bladder. Swim bladder being homologous to the lung of tetrapod, the role of Bmp4, a major regulator of lung development, was studied along with the associated regulatory genes. Gene expression analysis revealed that thiourea administration led to the downregulation of <i>bmp4</i>, <i>shh</i>, <i>pcna</i>, <i>anxa5</i>, <i>acta2</i>, and the downstream effector <i>snail3</i> but the upregulation of <i>caspase3</i>. The protein expression showed a similar trend, wherein Bmp4, Shh, and Pcna were downregulated, but Cleaved Caspase3 showed an increased expression in the treated group. Therefore, it is prudent to presume that exposure to thiourea significantly reduces the expression of Bmp4 and other key regulators; hence, the larvae fail to develop a swim bladder, a vital organ that regulates buoyancy.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 10","pages":"1572-1582"},"PeriodicalIF":2.7,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral subchronic toxicity study and genetic toxicity evaluation of mitoquinone mesylate","authors":"E. Siobhan Mitchell,&nbsp;Shawna Lemke,&nbsp;Brendon Woodhead,&nbsp;David Coleman","doi":"10.1002/jat.4654","DOIUrl":"10.1002/jat.4654","url":null,"abstract":"<p>Mitochondrial dysfunction and excessive reactive oxygen species production contributes to the pathophysiology of aging. Coenzyme Q10 is thought to protect mitochondria from oxidative damage; thus, mitoquinone was developed as mitochondria-targeted analogue with similar antioxidant activity. Mitoquinone is the oxidized form of mitoquinol. Mitoquinone/mitoquinol mesylate has been proposed as a food ingredient. As part of the safety analysis, we performed genotoxicity assays and a 39-week toxicity study to determine overall toxicity potential. Mitoquinone mesylate showed no evidence of genotoxic potential in two in vitro assays, bacterial reverse mutation and human lymphocyte chromosome aberration, nor in the in vivo micronucleus test in rats. In the 39-week study in dogs, there were no findings observed, which were considered to represent adverse systemic toxicity; therefore, the high dose level (40 mg/kg/day) was considered the NOAEL. The principal findings in this study were fecal disturbances and vomiting. These findings were considered to be due to a local, possibly irritant effect of the test substance on the gastrointestinal tract and were not considered adverse as there were no impacts on clinical or histopathology. This highest dose exceeds the expected daily human intake more than 100-fold. Data from well-designed clinical trials actively collecting safety endpoints corroborate that 20 mg/day can be safely consumed and is not likely to result in significant gastrointestinal complaints. These results support the conclusion that the use of mitoquinone/mitoquinol mesylate as a food ingredient is safe.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 10","pages":"1555-1571"},"PeriodicalIF":2.7,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}