Jugan Juliann A, Jackson Kyle B, Elmore Sarah E, La Merrill Michele A
Department of Environmental Toxicology, University of California, Davis, Davis, CA 95616, United States.
Environ Epigenet. 2024 Aug 23;10(1):dvae011. doi: 10.1093/eep/dvae011. eCollection 2024.
The insecticide dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite, dichlorodiphenyldichloroethylene (DDE), have been associated with increased adiposity and obesity in multiple generations of rodents and humans. These lipophilic pollutants accumulate in adipose tissue and appear to decrease energy expenditure through the impairment of thermogenesis in brown adipose tissue (BAT). We hypothesized that impaired thermogenesis is due to persistent epigenetic modifications of BAT. To address this, we exposed C57BL/6 J mice to DDT or DDE from gestational day (GD) 11.5 to postnatal day (PND) 5, evaluated longitudinal body temperature, and performed reduced representation bisulfite sequencing and RNA sequencing of BAT from infant and adult offspring. Exposure to DDT or DDE reduced core body temperature in adult mice, and differential methylation at the pathway and gene level was persistent from infancy to adulthood. Furthermore, thermogenesis and biological pathways essential for thermogenic function, such as oxidative phosphorylation and mechanistic target of rapamycin kinase (mTOR) signaling, were enriched with differential methylation and RNA transcription in adult mice exposed to DDT or DDE. PAZ6 human brown preadipocytes were differentiated in the presence of DDT or DDE to understand the brown adipocyte-autonomous effect of these pollutants. exposure led to limited changes in RNA expression; however, mitochondrial membrane potential was decreased with 0.1 µM and 1 µM doses of DDT or DDE. These results demonstrate that concentrations of DDT and DDE relevant to human exposure have a significant effect on thermogenesis, the transcriptome, and DNA methylome of mouse BAT and the mitochondrial function of human brown adipocytes.
杀虫剂二氯二苯三氯乙烷（DDT）及其持久性代谢物二氯二苯二氯乙烯（DDE）与多代啮齿动物和人类的肥胖及超重增加有关。这些亲脂性污染物在脂肪组织中蓄积，并似乎通过损害棕色脂肪组织（BAT）的产热作用来降低能量消耗。我们推测产热受损是由于BAT的持久性表观遗传修饰所致。为了验证这一点，我们在妊娠第11.5天（GD 11.5）至出生后第5天（PND 5）期间，将C57BL/6 J小鼠暴露于DDT或DDE中，评估其纵向体温，并对幼年和成年子代的BAT进行了简化代表性亚硫酸氢盐测序和RNA测序。暴露于DDT或DDE会降低成年小鼠的核心体温，并且从幼年到成年，途径和基因水平的差异甲基化一直持续存在。此外，在暴露于DDT或DDE的成年小鼠中，产热及产热功能所必需的生物学途径，如氧化磷酸化和雷帕霉素激酶机制靶点（mTOR）信号传导，富含差异甲基化和RNA转录。在DDT或DDE存在的情况下，对PAZ6人棕色前脂肪细胞进行分化，以了解这些污染物对棕色脂肪细胞的自主作用。暴露导致RNA表达变化有限；然而，0.1µM和1µM剂量的DDT或DDE会降低线粒体膜电位。这些结果表明，与人类暴露相关的DDT和DDE浓度对小鼠BAT的产热、转录组和DNA甲基化组以及人类棕色脂肪细胞的线粒体功能有显著影响。
