MIXTURE TERATOGENESIS--RELATION TO MECHANISMS AND QSARS

混合致畸--机制与QSARS的关系

• 批准号: 3253675
• 负责人: DOUGLAS A DAWSON
• 金额: $ 6.79万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3253675
• 关键词: Xenopus; carboxylate; drug interactions; histology; microscopy; organic chemicals; physical chemical interaction; teratogens; toxicant interaction; toxicant screening

Teratological evaluation of chemical mixtures have shown four basic joint action types, but the nature of these joint actions is not understood. Similar work in acute toxicity indicates that the type of joint action may be related to the mode(s) of action of the toxicants. Therefore, work proposed herein will focus on determining if a consistent relationship exists between teratogenic joint actions and the mechanism(s) of chemical teratogens. Since 65 to 70% of human malformations cannot be attributed to any one cause, the possibility of multiple causative agents may become increasingly important in hazard assessment. To examine these ideas, FETAX (Frog Embryo Teratogenesis Assay: Xenopus) will be used to evaluate the teratogenic joint action of chemical combinations, both among and between each of two groups of chemical teratogens. Each group of chemicals: 1) osteolathyrogens, 2) short-chain carboxylic acids (SCCAs), is thought to represent a different, distinct mode of teratogenesis. In accordance with the present hypothesis, any combination of osteolathyrogens or any combination of SCCAs should show a strictly additive teratogen joint action. In contrast, any combination of an osteolathyrogen and an SCCA should have less than additive rates of malformation. Preliminary data indicates this is the case, but determination of the consistency of the relationship is needed. If a consistent teratogenic joint action is observed when only one teratogenic mechanism is represented while a different joint action is seen when two mechanisms are represented, the testing strategy could be valuable in hazard assessment of chemical mixtures; especially when used in conjunction with quantitative structure- activity relationships (QSARs) for teratogenesis. This is so, because a simple QSAR represents a single biological endpoint (e.g., teratogenesis) for a single mechanism of action (e.g., osteolathyrism). In this study, 6 binary combinations of osteolathyrogens, 6 binary combinations of SCCAs, and 8 combinations of an osteolathyrogen and an SCCA will be evaluated with FETAX to determine if consistent teratogenic joint actions are observed in each of the three cases. FETAX is ideal to examine the joint actions since confounding factors, such as metabolism and protein-toxicant binding, can be controlled. This work should lead to a better understanding of the nature of teratogenic joint actions and provide a basis for developing a more efficient safety testing strategy for developmental toxicity of chemical mixtures.

化学混合物的曲折评估显示了四个基本关节 行动类型，但是这些联合行动的性质尚不理解。 急性毒性的类似工作表明，联合作用的类型可能 与有毒物质的作用模式有关。 因此，工作 本文提出的将重点侧重于确定是否存在一致的关系 在致病性关节作用与化学机制之间存在 Teratogens。 由于65％至70％的人畸形不能归因于 任何原因，多种因果剂的可能性可能会变成 在危险评估中越来越重要。 要检查这些想法，胎儿 （Frog胚胎致化测定法：Xenopus）将用于评估 化学组合的致化关节作用，包括 两组化学畸胎组中的每一组。 每组化学物质：1） 骨肌元，2）短链羧酸（SCCAS），被认为是 代表一种不同的，不同的变性方式。 依据 目前的假设，骨质拉蒙元的任何组合或任何组合 SCCAS的组合应显示严格的添加性破坏点关节 行动。 相比之下，骨雌激素和SCCA的任何组合 畸形率应少于加性率。 初步数据 表明是这种情况，但是确定 需要关系。 如果一致的致畸关节作用是 当仅表示一个致化机制时观察到 当表示两种机制时，可以看到不同的联合作用 测试策略对于化学危害评估可能很有价值 混合物；特别是与定量结构一起使用时 活动关系（QSARS）用于致病。 是这样，因为 简单的QSAR代表一个单个生物学终点（例如，变性） 单一的作用机理（例如，骨层理由）。 在这项研究中，6 骨质拉元的二元组合，6种SCCAS的二元组合， 以及8种骨肌原和SCCA的组合将与 胎儿确定是否在 三个案例中的每一个。 胎儿是检查联合行动的理想选择 混杂因素（例如代谢和蛋白质刺激性结合）可以 被控制。 这项工作应该可以更好地理解 致病性关节行动的性质，并为开发 更有效的安全测试策略的发育毒性 化学混合物。