MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, 4, rue Larrey, 49933, Angers, France.
Laboratoire d'Etude des Résidus et Contaminants dans les Aliments (LABERCA), Oniris, INRA, Université Bretagne Loire, 44307, Nantes, France.
Environ Sci Pollut Res Int. 2020 Nov;27(33):40953-40962. doi: 10.1007/s11356-019-04353-5. Epub 2019 Feb 1.
In situ chemical reduction (ISCR) has been identified as a possible way for the remediation of soils contaminated by chlordecone (CLD). Evidences provided by the literature indicate an association between the development of prostate cancer and CLD exposure (Multigner et al. 2010). In a previous in vitro study, we demonstrated that the two main dechlorinated CLD derivatives formed by ISCR, CLD-1Cl, and CLD-3Cl have lower cytotoxicity and proangiogenic properties than CLD itself (Legeay et al. 2017). By contrast, nothing is known on the in vivo proangiogenic effect of these dechlorinated derivatives. Based on in vitro data, the aims of this study were therefore to evaluate the in vivo influence of CLD and three of its dechlorinated metabolites in the control of neovascularization in a mice model of prostate cancer. The proangiogenic effect of CLD and three of its dechlorinated derivatives, CLD-1Cl, CLD-3Cl, and CLD-4Cl, was evaluated on a murine model of human prostate tumor (PC-3) treated, at two exposure levels: 33 μg/kg and 1.7 μg/kg respectively reflecting acute and chronic toxic exposure in human. The results of serum measurements show that, for the same ingested dose, the three metabolite concentrations were significantly lower than that of CLD. Dechlorination of CLD lead therefore to molecules that are biologically absorbed or metabolized, or both, faster than the parent molecule. Prostate tumor growth was lower in the groups treated by the three metabolites compared to the one treated by CLD. The vascularization measured on the tumor sections was inversely proportional to the rate of dechlorination, the treatment with CLD-4Cl showing no difference with control animals treated with only the vehicle oil used for all substances tested. We can therefore conclude that the proangiogenic effect of CLD is significantly decreased following the ISCR-resulting dechlorination. Further investigations are needed to elucidate the molecular mechanisms by which dechlorination of CLD reduces proangiogenic effects in prostate tumor.
原位化学还原 (ISCR) 已被确定为修复受十氯酮 (CLD) 污染土壤的一种可行方法。文献提供的证据表明，前列腺癌的发展与 CLD 暴露之间存在关联（Multigner 等人，2010 年）。在之前的一项体外研究中，我们证明了 ISCR 形成的两种主要脱氯 CLD 衍生物，CLD-1Cl 和 CLD-3Cl，其细胞毒性和促血管生成特性低于 CLD 本身（Legeay 等人，2017 年）。相比之下，对于这些脱氯衍生物的体内促血管生成作用，目前还知之甚少。基于体外数据，因此本研究的目的是评估 CLD 及其三种脱氯代谢物在控制前列腺癌小鼠模型中新生血管形成方面的体内影响。在两个暴露水平下，评估 CLD 及其三种脱氯衍生物，CLD-1Cl、CLD-3Cl 和 CLD-4Cl，对人前列腺肿瘤（PC-3）模型的促血管生成作用：分别为 33μg/kg 和 1.7μg/kg，分别反映了人类急性和慢性毒性暴露。血清测量结果表明，对于相同的摄入剂量，三种代谢物的浓度明显低于 CLD。CLD 的脱氯导致生物吸收或代谢更快的分子，或两者兼而有之，比母体分子更快。与用 CLD 处理的组相比，用三种代谢物处理的前列腺肿瘤生长较低。肿瘤切片上的血管化与脱氯率成反比，用 CLD-4Cl 处理与用仅用于所有测试物质的载体油处理的对照动物没有差异。因此，我们可以得出结论，CLD 的促血管生成作用在 ISCR 导致的脱氯后显著降低。需要进一步研究阐明 CLD 脱氯降低前列腺肿瘤促血管生成作用的分子机制。
