Departamento de Bioquímica y Biología Molecular, Campus de Excelencia Internacional Agroalimentario CeiA3, Universidad de Córdoba, Campus de Rabanales, Edificio Severo Ochoa, E-14071, Córdoba, Spain.
College of Arts and Science, Khalifa University of Science and Technology, PO Box 127788, Abu Dhabi, United Arab Emirates.
Environ Pollut. 2018 Jul;238:150-167. doi: 10.1016/j.envpol.2018.03.005. Epub 2018 Mar 20.
The use of DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane) in some countries, although regulated, is contributing to an increased worldwide risk of exposure to this organochlorine pesticide or its derivative p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene]. Many studies have associated p,p'-DDE exposure to type 2 diabetes, obesity and alterations of the reproductive system, but their molecular mechanisms of toxicity remain poorly understood. We have addressed this issue by using commercial microarrays based on probes for the entire Mus musculus genome to determine the hepatic transcriptional signatures of p,p'-DDE in the phylogenetically close mouse species Mus spretus. High-stringency hybridization conditions and analysis assured reliable results, which were also verified, in part, by qRT-PCR, immunoblotting and/or enzymatic activity. Our data linked 198 deregulated genes to mitochondrial dysfunction and perturbations of central signaling pathways (kinases, lipids, and retinoic acid) leading to enhanced lipogenesis and aerobic glycolysis, inflammation, cell proliferation and testosterone catabolism and excretion. Alterations of transcript levels of genes encoding enzymes involved in testosterone catabolism and excretion would explain the relationships established between p,p´-DDE exposure and reproductive disorders, obesity and diabetes. Further studies will help to fully understand the molecular basis of p,p´-DDE molecular toxicity in liver and reproductive organs, to identify effective exposure biomarkers and perhaps to design efficient p,p'-DDE exposure counteractive strategies.
在一些国家，尽管对滴滴涕（1,1,1-三氯-2,2-双（对氯苯基）乙烷）的使用进行了监管，但这仍导致全世界接触这种有机氯农药或其衍生物 p,p'-DDE[1,1-二氯-2,2-双（对氯苯基）乙烯]的风险增加。许多研究将 p,p'-DDE 暴露与 2 型糖尿病、肥胖和生殖系统改变联系起来，但它们的毒性分子机制仍知之甚少。我们使用基于整个 Mus musculus 基因组探针的商业微阵列来解决这个问题，以确定在进化上密切相关的小鼠物种 Mus spretus 中 p,p'-DDE 的肝转录特征。高严格杂交条件和分析确保了可靠的结果，这些结果部分通过 qRT-PCR、免疫印迹和/或酶活性得到了验证。我们的数据将 198 个失调基因与线粒体功能障碍和中央信号通路（激酶、脂质和视黄酸）的扰动联系起来，导致脂肪生成和有氧糖酵解、炎症、细胞增殖以及睾酮分解和排泄增强。参与睾酮分解和排泄的基因转录水平的改变将解释 p,p´-DDE 暴露与生殖障碍、肥胖和糖尿病之间建立的关系。进一步的研究将有助于充分了解 p,p´-DDE 在肝脏和生殖器官中的分子毒性的分子基础，识别有效的暴露生物标志物，并可能设计有效的 p,p'-DDE 暴露对抗策略。
