Abstract：
Trichothecenes are naturally occurring chemicals, produced by fungi, that can be found in contaminated crops. Trichothecenes have the potential to indirectly damage DNA and exacerbate genotoxic effects of genotoxicants. However, genotoxicity data for most trichothecenes are limited and data gaps remain. Here we use the γH2AX/pH3 assay to evaluate DNA damage in vitro of 13 trichothecenes. Three human cell lines (SH-SY5Y, ACHN, and HepG2) were exposed to each trichothecene (0.001-100 μM) to assess toxicity as models for the brain, kidney, and liver, respectively. Concentration-dependent induction of DNA damage, illustrated by γH2AX induction, was observed for all trichothecenes. In vitro-in vivo extrapolation (IVIVE) modeling was employed to support in vivo equivalent potency ranking and screen for risk potential. Diacetoxyscirpenol, T-2, and HT-2 had the highest genotoxic potency, notably in SH-SY5Y cells. Administered equivalent doses (AEDs) derived from IVIVE were compared against exposure data from French total diet studies to assess risk potential. AEDs derived for T-2 and HT-2 from the SH-SY5Y model were within 100-fold of exposure levels for infants aged one year or less. Overall, the potential for trichothecenes to damage DNA and higher exposures in infants highlights the need to investigate the cumulative effects across the broader trichothecene family.
摘要：
三端孢霉烯是天然存在的化学物质，由真菌产生，可以在受污染的作物中找到。单孢霉烯有可能间接损伤DNA并加剧基因毒性剂的基因毒性作用。然而,大多数单端孢霉烯的遗传毒性数据有限，数据差距仍然存在。在这里，我们使用γH2AX/pH3测定法来评估13种单孢霉烯的体外DNA损伤。三种人类细胞系（SH-SY5Y，ACHN,和HepG2）暴露于每个单端孢菌（0.001-100μM），以评估作为大脑模型的毒性，肾,还有肝脏,分别。浓度依赖性诱导DNA损伤，以γH2AX诱导为例，观察到所有的单端孢霉烯。采用体外-体内外推(IVIVIVE)建模来支持体内等效效能排序和潜在风险筛选。二乙酰氧西林，T-2和HT-2具有最高的基因毒性，特别是在SH-SY5Y细胞。将IVIVE的等效剂量（AED）与法国总饮食研究的暴露数据进行比较，以评估潜在风险。来自SH-SY5Y模型的T-2和HT-2的AED在一岁或更小的婴儿的暴露水平的100倍以内。总的来说,在婴儿中,单端孢霉烯类可能会损伤DNA和更高的暴露量,这突出表明有必要研究整个更广泛的单端孢霉烯家族的累积效应.
