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A multimodal in vitro approach to assess the safety of oral care products using 2D and 3D cellular models. 使用二维和三维细胞模型评估口腔护理产品安全性的多模式体外方法。
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-11-06 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1474583
S Marceli Leano, Wanderson De Souza, Rodrigo De Vecchi, Amanda Lopes, Tatiana Deliberador, Jose M Granjeiro

Introduction: Periodontitis, affecting approximately 3.9 billion individuals globally, significantly impacts quality of life and has raised interest in its potential systemic effects. Sodium perborate, a common component in oral care products for biofilm control, is widely used, though concerns about its safety persist. This study aimed to evaluate the in vitro toxicity of six commercial oral care products and varying concentrations of sodium perborate, utilizing human gingival fibroblasts (HGF) and keratinocytes (HaCat) as cell models.

Methods: Experiments were performed in both 2D monolayer and 3D cultures using MTT and electrical impedance assays, adhering to the manufacturer's recommended exposure time of 30-60 s for product testing. For the reconstructed epidermis model, a prolonged exposure time of 42 min was applied, following the Organization for Economic Cooperation and Development (OECD) Test Guideline 439.

Results: Results indicated that all products and sodium perborate at 1 mg/mL were cytotoxic in monolayer cultures. However, at concentrations relevant to commercial formulations (0.06 mg/mL sodium perborate), no significant toxicity was observed. In contrast, the 3D culture models, including spheroids and reconstructed epidermis, exhibited minimal to no cytotoxic effects for the commercial products, with sodium perborate showing no significant toxicity below 0.1 mg/mL. The reconstructed epidermis model, used as surrogate for oral mucosa, further confirmed that the products were non-irritating, in compliance with OECD TG 439 standards.

Discussion: This study highlights the importance of considering exposure time, dosage, and cellular model when assessing the safety of oral care products. While 2D models are useful for preliminary screenings, 3D models provide a more physiologically relevant assessment, emphasizing the need for robust testing protocols to ensure product safety.

导言:牙周炎影响着全球约 39 亿人的生活质量,并引起了人们对其潜在全身影响的关注。过硼酸钠是口腔护理产品中用于控制生物膜的常见成分,被广泛使用,但人们对其安全性的担忧依然存在。本研究旨在利用人体牙龈成纤维细胞(HGF)和角质形成细胞(HaCat)作为细胞模型,评估六种商用口腔护理产品和不同浓度过硼酸钠的体外毒性:实验在二维单层和三维培养物中进行,采用 MTT 和电阻抗检测法,并按照制造商建议的 30-60 秒暴露时间进行产品测试。对于重建表皮模型,按照经济合作与发展组织(OECD)测试指南 439,采用了 42 分钟的延长暴露时间:结果表明,所有产品和浓度为 1 毫克/毫升的过硼酸钠在单层培养物中都具有细胞毒性。不过,在与商业制剂相关的浓度(0.06 毫克/毫升过硼酸钠)下,未观察到明显的毒性。相比之下,三维培养模型(包括球体和重建表皮)对商用产品的细胞毒性影响很小甚至没有,过硼酸钠在 0.1 毫克/毫升以下没有明显毒性。作为口腔粘膜替代物的重建表皮模型进一步证实,这些产品无刺激性,符合 OECD TG 439 标准:本研究强调了在评估口腔护理产品安全性时考虑暴露时间、剂量和细胞模型的重要性。虽然二维模型对初步筛选很有用,但三维模型能提供更贴近生理的评估,这强调了为确保产品安全而制定严格测试协议的必要性。
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引用次数: 0
Editorial: Women in environmental toxicology. 社论:环境毒理学领域的女性。
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-11-05 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1490209
Laura M Langan, Michelle Bloor, Amanda Sevcik, Erica D Bruce
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引用次数: 0
Use of serum-free media for peripheral blood mononuclear cell culture and the impact on T and B cell readouts. 使用无血清培养基进行外周血单核细胞培养及其对 T 细胞和 B 细胞读数的影响。
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-11-05 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1462688
Stella Cochrane, Ouarda Saib, David Sheffield

Introduction: As part of a wider programme of work developing next-generation risk assessment approaches (NGRA) using non-animal methods (NAMs) for safety assessment of materials, Unilever SEAC is exploring the use of a peripheral blood mononuclear cell (PBMC) system to investigate how cells from different arms of the human immune system are impacted by different treatments. To maximise human relevance, the cell cultures are supported by human serum, but this came with some challenges, including an inability to measure induced levels of immunoglobulins due to high background levels. Therefore, a study comparing use of human sera containing media with three different chemically defined serum-free media was undertaken.

Materials and methods: PBMC were isolated from healthy donors and cultured in the absence (media alone) or presence of stimulation reagents (CpG-ODN plus IL-15, Pokeweed Mitogen (PWM) or Cytostim (CS)), in RPMI plus human serum, AIM-V, CTS OpTmizer T cell expansion SFM or X-VIVO 15 media. T cell (CD4+ and CD8+) and B cell proliferation and viability were measured after 6 days, along with levels of total IgG in the cell culture supernatants.

Results: Each of the serum-free media tested supported good levels of viable and proliferating T cells and B cells over the 6 days of culture, with only a few, small differences across the media, when there was no stimulation. They also enabled detection of a stimulation-evoked increase in IgG levels. There were however some differences in the viability and proliferation responses of T and B cells, to different stimuli, across the different media.

Discussion: The serum-free media formulations tested in this study offer defined systems for. measuring B cell IgG responses, in vitro, in either a 'T cell-independent' (CpG + IL-15) or "T cell-dependent" (PWM or CS) manner and for assessing B cell proliferation, particularly in response to a "T cell-independent" stimulus. However, there are some characteristics and features endowed by human serum that appear to be missing. Therefore, further work is required to optimise animal-free, chemically defined culture conditions for PBMC based assays for inclusion in tiered safety assessments.

简介:联合利华 SEAC 正在探索使用外周血单核细胞 (PBMC) 系统来研究人体免疫系统不同臂膀的细胞如何受到不同治疗方法的影响,这是开发使用非动物方法 (NAM) 进行材料安全评估的下一代风险评估方法 (NGRA) 的广泛工作计划的一部分。为了最大限度地贴近人体,细胞培养使用了人血清,但这也带来了一些挑战,包括由于本底水平较高而无法测量诱导的免疫球蛋白水平。因此,我们进行了一项研究,比较使用含人血清培养基和三种不同化学定义的无血清培养基:从健康捐献者身上分离出 PBMC,在无刺激试剂(单独培养基)或有刺激试剂(CpG-ODN 加 IL-15、Pokeweed Mitogen (PWM) 或 Cytostim (CS))的情况下,在 RPMI 加人血清、AIM-V、CTS OpTmizer T 细胞扩增 SFM 或 X-VIVO 15 培养基中进行培养。6 天后测量 T 细胞(CD4+ 和 CD8+)和 B 细胞的增殖和活力,以及细胞培养上清中总 IgG 的水平:结果:所测试的每种无血清培养基都能在 6 天的培养过程中支持较高水平的存活和增殖 T 细胞和 B 细胞,在没有刺激的情况下,不同培养基之间的差异很小。它们还能检测到刺激引起的 IgG 水平的增加。不过,不同培养基中的 T 细胞和 B 细胞对不同刺激的活力和增殖反应存在一些差异:本研究中测试的无血清培养基配方为体外测量 B 细胞 IgG 反应提供了明确的系统,这些反应可以是 "T 细胞依赖型"(CpG + IL-15)或 "T 细胞依赖型"(PWM 或 CS),也可用于评估 B 细胞增殖,特别是对 "T 细胞依赖型 "刺激的反应。然而,人类血清所具有的一些特性和特征似乎还存在缺失。因此,需要进一步开展工作,优化基于 PBMC 分析的无动物、化学定义的培养条件,以便纳入分级安全评估。
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引用次数: 0
Identifying non-essential uses to phase out substances of very high concern under REACH. 根据 REACH 法规,确定非必要用途,以逐步淘汰高度关注物质。
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-11-01 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1488336
Flora Borchert, Romain Figuière, Ian T Cousins, Christina Rudén, Marlene Ågerstrand

The essential use concept aims to better protect consumers, vulnerable groups, and the environment from the most harmful chemicals by phasing out uses considered non-essential for society. Given the lack of empirical research evaluating this novel approach for chemical management in real-world settings, the aims of the present analysis were to 1) investigate if the information provided in applications for authorisation under REACH allowed for the identification of non-essential uses of substances of very high concern (SVHCs), and 2) identify data gaps, challenges and potential needs for revising the assessment criteria to effectively implement the essential use concept in the REACH authorisation. In total, 100 uses covering 11 SVHCs were analysed. 4-(1,1,3,3-tetramethylbutyl) phenol (OPnEO) and chromium trioxide were among the most frequently used substances, covering 42% and 35% of the analysed uses. Using the current essential use criteria, 55% of all analysed uses were categorised as essential, while 10% were categorised as non-essential. Potentially, authorisations would not have been granted for the identified non-essential uses under REACH if the concept had been implemented at the time. However, for 35% of the uses it was not possible to assess their essentiality and these uses were therefore categorised as "complex." These challenges were due to the multiple purposes of the technical function, lack of detailed information on the spectrum of end-uses, and difficulties in interpreting the essential use criteria. Consequently, for a successful implementation of the essential use concept, we recommend the European Commission to develop guidance for applicants and refine the essential use criteria to ensure a transparent and resource-efficient authorisation procedure under REACH.

必要用途概念旨在通过逐步淘汰被认为对社会非必要的用途,更好地保护消费者、弱势群体和环境免受最有害化学品的危害。鉴于缺乏实证研究来评估这种在现实环境中进行化学品管理的新方法,本分析报告的目的是:1)调查 REACH 法规授权申请中提供的信息是否允许识别高度关注物质(SVHC)的非必要用途;2)确定数据差距、挑战和潜在需求,以修订评估标准,在 REACH 法规授权中有效实施必要用途概念。总共分析了 11 种高关注度物质的 100 种用途。4-(1,1,3,3-四甲基丁基)苯酚 (OPnEO) 和三氧化二铬是使用最频繁的物质,分别占分析用途的 42% 和 35%。根据目前的必要用途标准,所有分析用途中有 55% 被归类为必要用途,10% 被归类为非必要用途。根据 REACH 法规,如果当时实施了这一概念,则可能不会对已确定的非必要用途进行授权。然而,对于 35% 的用途,无法评估其必要性,因此这些用途被归类为 "复杂"。这些挑战是由于技术功能的多种用途、缺乏有关最终用途范围的详细信息以及难以解释必要用途标准造成的。因此,为了成功实施必要用途概念,我们建议欧盟委员会为申请人制定指南,并完善必要用途标准,以确保 REACH 法规下的授权程序透明且资源高效。
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引用次数: 0
A toxicological assessment of Ganoderma lucidum and Cordyceps militaris mushroom powders. 灵芝和冬虫夏草蘑菇粉的毒理学评估。
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-10-30 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1469348
Paola P Chrysostomou, Elaine Freeman, Mary M Murphy, Ankit Chaudhary, Nazia Siddiqui, Julie Daoust

Gonoderma lucidum (G. lucidum) and Cordyceps militaris (C. militaris) are among the many mushrooms known for their long history of use in traditional medicine. Wildcrafted sources of mushrooms including G. lucidum and C. militaris can be limited from a scarcity and quality perspective, but solid fermentation processes in cultivation settings can provide an efficient way to deliver whole mushroom preparations of a consistent composition. Despite the historical use of these mushrooms, few published reports have explored their potential subchronic oral toxicity or genotoxicity, either from specific components or whole mushroom preparations. The purpose of this study was to assess the potential for acute toxicity, subchronic toxicity, and genotoxicity of powders produced from G. lucidum mycelial biomass and fruiting body ("Organic Reishi M2-102-02 powder") cultured on oats, and C. militaris mycelial biomass, stroma, and fruiting body ("Organic Cordyceps M2-116-04 powder") cultured on oats. Results of the testing demonstrate that both Organic Reishi M2-102-02 powder and Organic Cordyceps M2-116-04 powder were not acutely toxic, did not exhibit subchronic oral toxicity in rats at doses up to the highest dose tested of 2,000 mg/kg bw/day, and did not have genotoxic potential based on in vitro and in vivo genotoxicity assays.

灵芝(Gonoderma lucidum,G. lucidum)和冬虫夏草(C. militaris,C. militaris)是众多传统医学中使用历史悠久的蘑菇之一。从稀缺性和质量的角度来看,野生蘑菇(包括金针菇和冬虫夏草)的来源可能有限,但栽培环境中的固体发酵过程可以提供一种有效的方法,提供成分一致的全蘑菇制剂。尽管这些蘑菇的使用历史悠久,但很少有公开报道探讨其潜在的亚慢性口服毒性或遗传毒性,无论是特定成分还是整个蘑菇制剂。这项研究的目的是评估用燕麦培养的灵芝菌丝体和子实体("有机灵芝 M2-102-02 粉")以及用燕麦培养的冬虫夏草菌丝体、基质和子实体("有机冬虫夏草 M2-116-04 粉")制成的粉末的潜在急性毒性、亚慢性毒性和遗传毒性。測試結果顯示,有機靈芝 M2-102-02 粉和「有機冬蟲夏草 M2-116-04 粉」沒有急性毒性,對大鼠的亞慢 性口服毒性測試最高劑量為每日每公斤體重 2,000 毫克,而根據體外和體內基因毒 性測試,兩者也沒有潛在的基因毒性。
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引用次数: 0
Assessment of pulmonary fibrosis using weighted gene co-expression network analysis. 利用加权基因共表达网络分析评估肺纤维化
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-10-24 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1465704
Christina Drake, Walter Zobl, Sylvia E Escher

For many industrial chemicals toxicological data is sparse regarding several regulatory endpoints, so there is a high and often unmet demand for NAMs that allow for screening and prioritization of these chemicals. In this proof of concept case study we propose multi-gene biomarkers of compounds' ability to induce lung fibrosis and demonstrate their application in vitro. For deriving these biomarkers we used weighted gene co-expression network analysis to reanalyze a study where the time-dependent pulmonary gene-expression in mice treated with bleomycin had been documented. We identified eight modules of 58 to 273 genes each which were particularly activated during the different phases (inflammatory; acute and late fibrotic) of the developing fibrosis. The modules' relation to lung fibrosis was substantiated by comparison to known markers of lung fibrosis from DisGenet. Finally, we show the modules' application as biomarkers of chemical inducers of lung fibrosis based on an in vitro study of four diketones. Clear differences could be found between the lung fibrosis inducing diketones and other compounds with regard to their tendency to induce dose-dependent increases of module activation as determined using a previously proposed differential activation score and the fraction of differentially expressed genes in the modules. Accordingly, this study highlights the potential use of composite biomarkers mechanistic screening for compound-induced lung fibrosis.

对于许多工业化学品来说,有关几个监管终点的毒理学数据非常稀少,因此对能够筛选这些化学品并确定其优先次序的 NAMs 的需求很高,而且往往得不到满足。在这项概念验证案例研究中,我们提出了化合物诱导肺纤维化能力的多基因生物标志物,并在体外演示了其应用。为了得出这些生物标志物,我们利用加权基因共表达网络分析重新分析了一项研究,该研究记录了博莱霉素治疗小鼠肺部基因表达的时间依赖性。我们确定了由 58 至 273 个基因组成的八个模块,这些基因在纤维化发展的不同阶段(炎症、急性和晚期纤维化)被特别激活。通过与 DisGenet 中已知的肺纤维化标志物进行比较,我们证实了这些模块与肺纤维化的关系。最后,我们基于对四种二酮类化合物的体外研究,展示了这些模块作为肺纤维化化学诱导剂生物标记的应用。根据之前提出的差异激活评分和模块中差异表达基因的比例,可以发现诱导肺纤维化的二酮类化合物和其他化合物在诱导模块激活的剂量依赖性增加方面存在明显差异。因此,本研究强调了复合生物标志物机理筛选在化合物诱导肺纤维化方面的潜在用途。
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引用次数: 0
Cannabinoid hyperemesis syndrome: genetic susceptibility to toxic exposure. 大麻素剧吐症综合征:遗传易感性毒性暴露。
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-10-23 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1465728
Ethan B Russo, Venetia L Whiteley

Cannabinoid hyperemesis syndrome presents as a complex of symptoms and signs encompassing nausea, vomiting, abdominal pain, and hot water bathing behavior, most typically in a heavy cannabis user. Its presentation is frequently associated with hypothalamic-pituitary-adrenal axis activation with stress and weight loss. Recent investigation has identified five statistically significant mutations in patients distinct from those of frequent cannabis users who lack the symptoms, affecting the TRPV1 receptor, two dopamine genes, the cytochrome P450 2C9 enzyme that metabolizes tetrahydrocannabinol, and the adenosine triphosphate-binding cassette transporter. The syndrome is associated with escalating intake of high potency cannabis, or alternatively, other agonists of the cannabinoid-1 receptor including synthetic cannabinoids. Some patients develop environmental triggers in scents or foods that suggest classical conditioned responses. Various alternative "causes" are addressed and refuted in the text, including exposure to pesticides, neem oil or azadirachtin. Nosological confusion of cannabinoid hyperemesis syndrome has arisen with cyclic vomiting syndrome, whose presentation and pathophysiology are clearly distinct. The possible utilization of non-intoxicating antiemetic cannabis components in cannabis for treatment of cannabinoid hyperemesis syndrome is addressed, along with future research suggestions in relation to its genetic foundation and possible metabolomic signatures.

大麻素催吐综合征是一种症状和体征复杂的疾病,包括恶心、呕吐、腹痛和热水澡行为,最典型的表现是大量吸食大麻。其表现通常与压力和体重下降导致的下丘脑-垂体-肾上腺轴激活有关。最近的调查发现,患者体内有五种具有统计学意义的突变,这些突变影响了 TRPV1 受体、两个多巴胺基因、代谢四氢大麻酚的细胞色素 P450 2C9 酶以及三磷酸腺苷结合盒转运体,这些突变与那些经常吸食大麻但没有上述症状的患者不同。该综合征与高浓度大麻或大麻素-1 受体的其他激动剂(包括合成大麻素)的摄入量不断增加有关。有些患者会在气味或食物中出现环境诱因,这表明他们出现了典型的条件反射。文中讨论并驳斥了各种替代 "原因",包括接触杀虫剂、楝树油或氮芥。大麻素催吐综合征与周期性呕吐综合征在命名上产生了混淆,后者的表现和病理生理学明显不同。本研究探讨了利用大麻中的非致毒止吐成分治疗大麻素催吐综合征的可能性,以及有关其遗传基础和可能的代谢组特征的未来研究建议。
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引用次数: 0
Editorial: Global excellence in Toxicology: Central and South America. 社论:全球卓越毒理学:中美洲和南美洲。
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-10-22 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1494491
Miriam Beatriz Virgolini, Ricardo Bastos Cunha
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引用次数: 0
A systematic review and meta-analysis of the impact of triclosan exposure on human semen quality. 关于接触三氯生对人类精液质量影响的系统回顾和荟萃分析。
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-10-17 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1469340
Cecilia Adedeji Adegbola, Tunmise Maryanne Akhigbe, Adetomiwa Ezekiel Adeogun, Eva Tvrdá, Alica Pizent, Roland Eghoghosoa Akhigbe

Introduction: Triclosan is an antibacterial and antifungal compound that is frequently found in personal care and consumer products, and its its impact on male reproductive health is a growing concern. Despite existing experimental studies demonstrating its potential threats to male fertility, reports on its effects on human semen quality remains limited and inconsistent. Therefore, this study presents a systematic review and meta-analysis assessing the relationship between triclosan exposure and semen quality.

Methods: This study was registered with PROSPERO (CRD42024524192) and adhered to PRISMA guidelines.

Results: The study analyzed 562 screened studies, out of which five articles including 1,312 male subjects were finally included in the study. The eligible studies were geographically diverse, with three from China, one from Belgium, and one from Poland. More so, the eligible studies were both case-control and cross-sectional. The meta-analysis revealed that triclosan exposure significantly reduced sperm concentration (Standard Mean Difference (SMD) -0.42 [95% CI: -0.75, -0.10], P = 0.01) and sperm total motility (SMD -1.30 [95% CI: -2.26, -0.34], P = 0.008). Mechanistic insights from animal and in vitro studies showed that oxidative stress may mediate the adverse effects of triclosan on semen quality.

Discussion: This meta-analysis is the first comprehensive evaluation of the impact of triclosan on human semen quality, highlighting its potential to impair male fertility through reductions in sperm concentration and motility. However, the high heterogeneity among the included studies underscores the need for further high-quality research to establish more definitive conclusions regarding the effects of triclosan exposure on human reproductive health.

简介三氯生是一种抗菌和抗真菌化合物,经常出现在个人护理和消费品中,它对男性生殖健康的影响日益受到关注。尽管现有的实验研究表明三氯生对男性生育能力有潜在威胁,但有关三氯生对人类精液质量影响的报告仍然有限且不一致。因此,本研究对三氯生暴露与精液质量之间的关系进行了系统回顾和荟萃分析:本研究已在 PROSPERO(CRD42024524192)注册,并遵守 PRISMA 指南:结果:本研究分析了 562 项筛选过的研究,其中有 5 篇文章(包括 1,312 名男性受试者)最终被纳入研究。符合条件的研究具有地域多样性,其中三篇来自中国,一篇来自比利时,一篇来自波兰。此外,符合条件的研究既有病例对照研究,也有横断面研究。荟萃分析表明,暴露于三氯生会显著降低精子浓度(标准均差(SMD)-0.42 [95% CI:-0.75,-0.10],P = 0.01)和精子总活力(SMD-1.30 [95% CI:-2.26,-0.34],P = 0.008)。动物和体外研究的机理研究表明,氧化应激可能是三氯生对精液质量产生不良影响的介导因素:这项荟萃分析首次全面评估了三氯生对人类精液质量的影响,强调了三氯生可能通过降低精子浓度和活力来损害男性生育能力。然而,所纳入研究的高度异质性突出表明,需要进一步开展高质量的研究,才能就三氯生暴露对人类生殖健康的影响得出更明确的结论。
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引用次数: 0
A new approach methodology to identify tumorigenic chemicals using short-term exposures and transcript profiling. 利用短期暴露和转录本特征分析确定致癌化学品的新方法。
IF 3.6 Q2 TOXICOLOGY Pub Date : 2024-10-17 eCollection Date: 2024-01-01 DOI: 10.3389/ftox.2024.1422325
Victoria Ledbetter, Scott Auerbach, Logan J Everett, Beena Vallanat, Anna Lowit, Gregory Akerman, William Gwinn, Leah C Wehmas, Michael F Hughes, Michael Devito, J Christopher Corton

Current methods for cancer risk assessment are resource-intensive and not feasible for most of the thousands of untested chemicals. In earlier studies, we developed a new approach methodology (NAM) to identify liver tumorigens using gene expression biomarkers and associated tumorigenic activation levels (TALs) after short-term exposures in rats. The biomarkers are used to predict the six most common rodent liver cancer molecular initiating events. In the present study, we wished to confirm that our approach could be used to identify liver tumorigens at only one time point/dose and if the approach could be applied to (targeted) RNA-Seq analyses. Male rats were exposed for 4 days by daily gavage to 15 chemicals at doses with known chronic outcomes and liver transcript profiles were generated using Affymetrix arrays. Our approach had 75% or 85% predictive accuracy using TALs derived from the TG-GATES or DrugMatrix studies, respectively. In a dataset generated from the livers of male rats exposed to 16 chemicals at up to 10 doses for 5 days, we found that our NAM coupled with targeted RNA-Seq (TempO-Seq) could be used to identify tumorigenic chemicals with predictive accuracies of up to 91%. Overall, these results demonstrate that our NAM can be applied to both microarray and (targeted) RNA-Seq data generated from short-term rat exposures to identify chemicals, their doses, and mode of action that would induce liver tumors, one of the most common endpoints in rodent bioassays.

目前的癌症风险评估方法耗费大量资源,而且对于成千上万种未经检测的化学品来说并不可行。在早期的研究中,我们开发了一种新的方法(NAM),利用基因表达生物标志物和相关的致癌活化水平(TALs),在大鼠短期暴露后识别肝脏肿瘤原。生物标志物用于预测六种最常见的啮齿动物肝癌分子启动事件。在本研究中,我们希望确认我们的方法是否可用于仅在一个时间点/剂量识别肝脏肿瘤原,以及该方法是否可应用于(靶向)RNA-Seq 分析。雄性大鼠每天灌胃接触 15 种已知慢性结果剂量的化学品 4 天,使用 Affymetrix 阵列生成肝脏转录本图谱。我们的方法使用从 TG-GATES 或 DrugMatrix 研究中获得的 TALs 预测准确率分别为 75% 或 85%。在一个由雄性大鼠肝脏生成的数据集中,我们发现我们的 NAM 与靶向 RNA-Seq(TempO-Seq)相结合,可用于识别致癌化学物质,预测准确率高达 91%。总之,这些结果表明,我们的 NAM 可以应用于从短期大鼠暴露中生成的微阵列和(靶向)RNA-Seq 数据,以识别会诱发肝脏肿瘤(啮齿动物生物测定中最常见的终点之一)的化学品、其剂量和作用模式。
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Frontiers in toxicology
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