On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens.
On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens.
复制标题
DOI：
10.1289/ehp.1510352
复制
发表时间：
2016-08
影响因子：
10.4
通讯作者：
Blumberg B
中科院分区：
文献类型：
--
作者：
Janesick AS;Dimastrogiovanni G;Vanek L;Boulos C;Chamorro-García R;Tang W;Blumberg B
在ToxCast™第一阶段，美国环保署委托在一系列高通量测定中筛选了320种杀虫剂、除草剂、杀真菌剂和其他化学品。该机构还开发了毒理学优先级工具ToxPi，以促进使用ToxCast™检测来预测生物功能。我们询问在ToxCast™ I期鉴定的得分最高的PPARγ激活剂是否是真正的PPARγ激活剂和脂肪生成诱导剂。接下来，我们确定了应该预测脂肪形成的ToxCast™测定，开发了脂肪形成ToxPi，并询问ToxPi预测脂肪形成活性的程度。我们使用瞬时转染来测试ToxCast™化学品调节PPARγ和RXRα的能力，并使用3 T3-L1前脂肪细胞和小鼠骨髓源性间充质干细胞（mBMSC）进行分化试验，以评估ToxCast™化学品的成脂能力。在我们的试验中，得分最高的ToxCast™ PPARγ激活剂中只有5/21是激活剂，3个是PPARγ拮抗剂，其余的是无活性的。我们鉴定的真正的PPARγ激活剂在3 T3-L1细胞和mBMSC中诱导脂肪形成。在ToxPi预测具有活性的17种化学物质中，只有7种促进脂肪生成，1种抑制脂肪生成，7种预测阴性物质中有2种也是脂肪生成。在这9种脂肪形成化学物质中，3种激活PPARγ，1种激活RXRα。ToxCast™ PPARγ和RXRα检测与实验室测量的PPARγ和RXRα活性相关性不佳。脂肪形成ToxPi表现不佳，可能是由于ToxCast™测定的性能。我们观察到ToxCast™对PPARγ和RXRα活化和脂肪生成的适度预测价值，并且可能仍有许多致肥胖化学物质有待鉴定。Janesick AS，Dimastrogiovanni G，Vanek L，Boulos C，Chamorro-García R，Tang W，Blumberg B. 2016.关于ToxCast™和ToxPi作为鉴定新致肥胖物的方法的效用。环境健康展望124：1214-1226; http：dx.doi.org/10.1289/ehp.1510352
In ToxCast™ Phase I, the U.S. EPA commissioned screening of 320 pesticides, herbicides, fungicides, and other chemicals in a series of high-throughput assays. The agency also developed a toxicological prioritization tool, ToxPi, to facilitate using ToxCast™ assays to predict biological function. We asked whether top-scoring PPARγ activators identified in ToxCast™ Phase I were genuine PPARγ activators and inducers of adipogenesis. Next, we identified ToxCast™ assays that should predict adipogenesis, developed an adipogenesis ToxPi, and asked how well the ToxPi predicted adipogenic activity. We used transient transfection to test the ability of ToxCast™ chemicals to modulate PPARγ and RXRα, and differentiation assays employing 3T3-L1 preadipocytes and mouse bone marrow-derived mesenchymal stem cells (mBMSCs) to evaluate the adipogenic capacity of ToxCast™ chemicals. Only 5/21 of the top scoring ToxCast™ PPARγ activators were activators in our assays, 3 were PPARγ antagonists, the remainder were inactive. The bona fide PPARγ activators we identified induced adipogenesis in 3T3-L1 cells and mBMSCs. Only 7 of the 17 chemicals predicted to be active by the ToxPi promoted adipogenesis, 1 inhibited adipogenesis, and 2 of the 7 predicted negatives were also adipogenic. Of these 9 adipogenic chemicals, 3 activated PPARγ, and 1 activated RXRα. ToxCast™ PPARγ and RXRα assays do not correlate well with laboratory measurements of PPARγ and RXRα activity. The adipogenesis ToxPi performed poorly, perhaps due to the performance of ToxCast™ assays. We observed a modest predictive value of ToxCast™ for PPARγ and RXRα activation and adipogenesis and it is likely that many obesogenic chemicals remain to be identified. Janesick AS, Dimastrogiovanni G, Vanek L, Boulos C, Chamorro-García R, Tang W, Blumberg B. 2016. On the utility of ToxCast™ and ToxPi as methods for identifying new obesogens. Environ Health Perspect 124:1214–1226; http://dx.doi.org/10.1289/ehp.1510352