Bui-Nguyen Tri M, Baer Christine E, Lewis John A, Yang Dongren, Lein Pamela J, Jackson David A
ORISE Postdoctoral Fellow, Fort Detrick, MD, 21702, USA.
Current address: US Food and Drug Administration, Silver Spring, MD, 20993, USA.
BMC Genomics. 2015 Oct 24;16:853. doi: 10.1186/s12864-015-1941-2.
Exposure to dichlorvos (DDVP), an organophosphorus pesticide, is known to result in neurotoxicity as well as other metabolic perturbations. However, the molecular causes of DDVP toxicity are poorly understood, especially in cells other than neurons and muscle cells. To obtain a better understanding of the process of non-neuronal DDVP toxicity, we exposed zebrafish to different concentrations of DDVP, and investigated the resulting changes in liver histology and gene transcription.
Functional enrichment analysis of genes affected by DDVP exposure identified a number of processes involved in energy utilization and stress response in the liver. The abundance of transcripts for proteins involved in glucose metabolism was profoundly affected, suggesting that carbon flux might be diverted toward the pentose phosphate pathway to compensate for an elevated demand for energy and reducing equivalents for detoxification. Strikingly, many transcripts for molecules involved in β-oxidation and fatty acid synthesis were down-regulated. We found increases in message levels for molecules involved in reactive oxygen species responses as well as ubiquitination, proteasomal degradation, and autophagy. To ensure that the effects of DDVP on energy metabolism were not simply a consequence of poor feeding because of neuromuscular impairment, we fasted fish for 29 or 50 h and analyzed liver gene expression in them. The patterns of gene expression for energy metabolism in fasted and DDVP-exposed fish were markedly different.
We observed coordinated changes in the expression of a large number of genes involved in energy metabolism and responses to oxidative stress. These results argue that an appreciable part of the effect of DDVP is on energy metabolism and is regulated at the message level. Although we observed some evidence of neuromuscular impairment in exposed fish that may have resulted in reduced feeding, the alterations in gene expression in exposed fish cannot readily be explained by nutrient deprivation.
已知接触有机磷农药敌敌畏（DDVP）会导致神经毒性以及其他代谢紊乱。然而，DDVP毒性的分子机制尚不清楚，尤其是在神经元和肌肉细胞以外的细胞中。为了更好地理解非神经元DDVP毒性的过程，我们将斑马鱼暴露于不同浓度的DDVP中，并研究由此导致的肝脏组织学和基因转录变化。
对受DDVP暴露影响的基因进行功能富集分析，确定了肝脏中许多与能量利用和应激反应有关的过程。参与葡萄糖代谢的蛋白质转录本丰度受到深刻影响，这表明碳通量可能转向磷酸戊糖途径，以补偿对能量和解毒所需还原当量的需求增加。引人注目的是，许多参与β-氧化和脂肪酸合成的分子转录本下调。我们发现参与活性氧反应以及泛素化、蛋白酶体降解和自噬的分子的信息水平增加。为确保DDVP对能量代谢的影响不仅仅是由于神经肌肉损伤导致摄食不良的结果，我们让鱼禁食29或50小时，并分析它们肝脏中的基因表达。禁食和暴露于DDVP的鱼的能量代谢基因表达模式明显不同。
我们观察到大量参与能量代谢和氧化应激反应的基因表达发生协调变化。这些结果表明，DDVP的相当一部分作用是对能量代谢的影响，并且在信息水平上受到调节。虽然我们在暴露的鱼中观察到一些神经肌肉损伤的证据，这可能导致摄食减少，但暴露鱼中基因表达的变化不能轻易用营养剥夺来解释。
