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Defining embryonic developmental effects of chemical mixtures using the embryonic stem cell test.
Food and Chemical Toxicology ( IF 3.9 ) Pub Date : 2020-03-20 , DOI: 10.1016/j.fct.2020.111284
Conny Tm van Oostrom 1 , Wout Slob 2 , Leo Tm van der Ven 1
Affiliation  

The embryonic stem cell test (EST) was applied to evaluate dose addition in combined exposures of teratogenic compounds in the EFSA-defined cumulative assessment group "craniofacial malformations", which was one of the selected cases in the EU-H2020 project "EuroMix". Test compounds were selected through reported effects in rodents, and represented a wide variety of chemical families and modes of action (MOA), including triazoles to inhibit CYP26; (synthetic) retinoids, to activate RAR/RXR; valproic acid, to inhibit histone deacetylase; dithiocarbamates, to disrupt extracellular matrix formation; dioxin (-like) compounds, to activate the aryl hydrocarbon receptor; 17alpha-ethynylestradiol, to activate the estrogen receptor; 5-fluorouracil, to disrupt DNA-synthesis; MEHP and PFOS, to activate peroxisome proliferation activated receptors; and methyl mercury, to induce oxidative stress and inhibit protein function. The EST appeared particularly useful to evaluate differentiation-inhibiting effects of compounds targeting early processes in craniofacial development, possibly related to the early fate of neural crest cells. Mixtures, designed as equipotent concentrations of two compounds with similar or dissimilar MOA, and single compounds showed overlapping dose-responses. This observation is consistent with dose addition in the EST in all studied binary mixtures, irrespective of MOA, and thereby supports the application of dose-addition as a default in cumulative risk assessment.

中文翻译:

使用胚胎干细胞测试定义化学混合物的胚胎发育作用。

胚胎干细胞试验(EST)用于评估EFSA定义的累积评估组“颅面畸形”中致畸化合物的联合暴露的剂量增加,这是EU-H2020项目“ EuroMix”中选定的案例之一。通过报道的对啮齿动物的作用选择受试化合物,它们代表了多种化学家族和作用模式(MOA),包括抑制CYP26的三唑;(合成的)类维生素A,以激活RAR / RXR;丙戊酸,抑制组蛋白脱乙酰基酶;二硫代氨基甲酸酯,破坏细胞外基质的形成;二恶英类化合物,以激活芳烃受体;17α-乙炔基雌二醇,激活雌激素受体;5-氟尿嘧啶,破坏DNA合成;MEHP和PFOS,激活过氧化物酶体增殖激活受体;和甲基汞,可诱导氧化应激并抑制蛋白质功能。EST似乎对于评估针对颅面发育早期过程的化合物的分化抑制作用特别有用,可能与神经rest细胞的早期命运有关。设计成等效浓度的两种具有相似或不同MOA的化合物和单一化合物的混合物显示出重叠的剂量反应。该观察结果与所有研究的二元混合物中EST中的剂量添加一致,而与MOA无关,从而支持在累积风险评估中将剂量添加作为默认应用。EST似乎对于评估针对颅面发育早期过程的化合物的分化抑制作用特别有用,可能与神经rest细胞的早期命运有关。设计成等效浓度的两种具有相似或不同MOA的化合物和单一化合物的混合物显示出重叠的剂量反应。该观察结果与所有研究的二元混合物中EST中的剂量添加一致,而与MOA无关,从而支持在累积风险评估中将剂量添加作为默认应用。EST似乎对于评估针对颅面发育早期过程的化合物的分化抑制作用特别有用,可能与神经rest细胞的早期命运有关。设计成等效浓度的两种具有相似或不同MOA的化合物和单一化合物的混合物显示出重叠的剂量反应。该观察结果与所有研究的二元混合物中EST中的剂量添加一致,而与MOA无关,从而支持在累积风险评估中默认使用剂量添加。单个化合物显示出重叠的剂量反应。该观察结果与所有研究的二元混合物中EST中的剂量添加一致,而与MOA无关,从而支持在累积风险评估中默认使用剂量添加。单个化合物显示出重叠的剂量反应。该观察结果与所有研究的二元混合物中EST中的剂量添加一致,而与MOA无关,从而支持在累积风险评估中将剂量添加作为默认应用。
更新日期:2020-03-21
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