有机磷酸酯代谢物二乙基二硫代磷酸酯（DEDTP）在体内的遗传毒性和免疫毒性作用。,Toxicology and Applied Pharmacology

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有机磷酸酯代谢物二乙基二硫代磷酸酯（DEDTP）在体内的遗传毒性和免疫毒性作用。
Toxicology and Applied Pharmacology ( IF 3.3 ) Pub Date : 2019-01-29 , DOI: 10.1016/j.taap.2019.01.023
D Medina-Buelvas ₁ , E Estrada-Muñiz ₁ , M Flores-Valadez ₁ , L Vega ₁

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二乙基二硫代磷酸酯（DEDTP）是通过有机磷农药和磷酸二烷基酯降解产生的代谢产物，其化学合成方法已广泛用于商业用途。DEDTP是一种稳定的化合物，大多数研究认为它是无害的。但是，一些研究发现了体外不良反应，包括不同类型人类细胞的毒性。但是，尚无体内研究表征DEDTP的毒理作用。因此，我们调查了DEDTP在鼠模型中的遗传毒性和免疫毒性。我们使用暴露于DEDTP ip的C57BL / 6J和Balb / c小鼠（6-8周龄），我们确定DEDTP的中等致死剂量（LD50）为0.537 g / kg。DEDTP在体内具有遗传毒性，因为它增加了0.05 g / kg外周血中多色红细胞中微核的频率。DEDTP对T和自然杀伤细胞具有免疫毒性作用，对巨噬细胞具有免疫调节作用，尤其是M2型，在暴露至0.01 g / kg 20天后增加了1000％。这些作用改变了对肿瘤挑战的反应。DEDTP暴露增加了肿瘤的大小，并减少了淋巴细胞对肿瘤抗原刺激的反应。我们得出的结论是，在环境相关浓度下，暴露于DEDTP会产生遗传毒性和免疫调节作用，从而影响体内肿瘤的生长。这些结果表明，DEDTP可能会降低暴露个体的生活质量，尽管具有稳定性，但仍具有遗传毒性和免疫毒性。这些作用改变了对肿瘤挑战的反应。DEDTP暴露增加了肿瘤的大小，并减少了淋巴细胞对肿瘤抗原刺激的反应。我们得出的结论是，在环境相关浓度下，暴露于DEDTP会产生遗传毒性和免疫调节作用，从而影响体内肿瘤的生长。这些结果表明，DEDTP可能会降低暴露个体的生活质量，尽管具有稳定性，但仍具有遗传毒性和免疫毒性。这些作用改变了对肿瘤挑战的反应。DEDTP暴露增加了肿瘤的大小，并减少了淋巴细胞对肿瘤抗原刺激的反应。我们得出的结论是，在环境相关浓度下，暴露于DEDTP会产生遗传毒性和免疫调节作用，从而影响体内肿瘤的生长。这些结果表明，DEDTP可能会降低暴露个体的生活质量，尽管具有稳定性，但仍具有遗传毒性和免疫毒性。

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Genotoxic and immunotoxic effects of the organophosphate metabolite diethyldithiophosphate (DEDTP) in Vivo.

Diethyldithiophosphate (DEDTP) is a metabolite produced by the degradation of organophosphorus pesticides and a dialkylphosphate that is chemically synthesized with widespread commercial use. DEDTP is a stable compound, and most studies considered it harmless. However, some studies found adverse effects in vitro, including toxicity in different human cell types. However, there are no in vivo studies characterizing the toxicological effects of DEDTP. Therefore, we investigated the genotoxicity and immunotoxicity of DEDTP in a murine model. We used C57BL/6J and Balb/c mice (6-8-weeks-old) exposed to DEDTP i.p. We established that the medium lethal dose (LD50) of DEDTP was 0.537 g/kg. DEDTP was genotoxic in vivo because it increased the frequency of micronuclei in polychromatic erythrocytes in peripheral blood at 0.05 g/kg. DEDTP showed immunotoxic effects on T and Natural Killer cells and immunomodulatory effects on macrophages, especially M2 type that increased 1000% after 20 days of exposure to 0.01 g/kg. These effects modified the response to a tumoural challenge. DEDTP exposure increased tumour size and reduced the response of lymphocytes to tumoural antigen stimulation. We conclude that exposure to DEDTP produced genotoxic and immunomodulatory effects at environmentally relevant concentrations, which affected the growth of tumours in vivo. These results suggest that DEDTP might reduce the quality of life in exposed individuals, and it exhibits genotoxicity and immunotoxicity despite its stability.

更新日期：2019-01-29

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