Loss of flavin-containing monooxygenase 3 modulates dioxin-like polychlorinated biphenyl 126-induced oxidative stress and hepatotoxicity.
Loss of flavin-containing monooxygenase 3 modulates dioxin-like polychlorinated biphenyl 126-induced oxidative stress and hepatotoxicity.
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DOI：
10.1016/j.envres.2024.118492
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发表时间：
2024-02
影响因子：
8.3
通讯作者：
Manisha Agarwal;Katherine Roth;Zhao Yang;Rahul Sharma;Krishnarao Maddipati;Judy Westrick;M. Petriell
中科院分区：
文献类型：
--
作者：
Manisha Agarwal;Katherine Roth;Zhao Yang;Rahul Sharma;Krishnarao Maddipati;Judy Westrick;M. Petriell
二恶英类污染物 (DLP)，例如多氯联苯 126 (PCB 126)，是属于持久性有机污染物的合成化学品。它们在脂肪组织中积聚，并与脂肪肝等心脏代谢紊乱有关。这些化合物的毒性与芳烃受体 (Ahr) 的激活有关，导致 I 相代谢酶细胞色素 P4501a1 (Cyp1a1) 的诱导以及随后活性氧 (ROS) 的产生。最近的研究表明，DLP 还可以诱导异生物质解毒酶含黄素单加氧酶 3 (FMO3)，该酶在代谢稳态中发挥作用。我们假设 Fmo3 的基因缺失是否可以保护小鼠，特别是在 Fmo3 最容易诱导的肝脏中，免受 PCB 126 毒性。为了检验这一假设，在为期 12 周的研究中，雄性 C57BL/6 野生型 (WT) 小鼠和 Fmo3 敲除 (Fmo3KO) 小鼠在第 2 周和第 4 周接触 PCB 126 或媒介物（红花油）。进行了各种分析，包括肝组织学、RNA 测序以及 PCB 126 和 F2-异前列腺素浓度的定量。结果表明，PCB 126 暴露导致 WT 小鼠出现大泡和微泡脂肪沉积，但 Fmo3KO 小鼠中不存在这种大泡脂肪变化。此外，在途径水平上，两种基因型之间的肝脏氧化应激反应存在显着差异，仅在WT小鼠中观察到特定基因的诱导。值得注意的是，WT 小鼠中最丰富的 F2-异前列腺素 8-iso-15-keto PGE2 在暴露于 PCB 126 后有所增加。研究结果还表明，与 Fmo3KO 小鼠相比，WT 小鼠肝组织中 PCB 126 的浓度更高。总之，小鼠体内缺乏 FMO3 会导致肝脏对二恶英类污染物暴露产生独特的反应，这可能是由于脂质代谢和储存的改变所致，这强调了遗传因素在对环境毒素的反应中复杂的相互作用。
Dioxin-like pollutants (DLPs), such as polychlorinated biphenyl 126 (PCB 126), are synthetic chemicals classified as persistent organic pollutants. They accumulate in adipose tissue and have been linked to cardiometabolic disorders, including fatty liver disease. The toxicity of these compounds is associated with activation of the aryl hydrocarbon receptor (Ahr), leading to the induction of phase I metabolizing enzyme cytochrome P4501a1 (Cyp1a1) and the subsequent production of reactive oxygen species (ROS). Recent research has shown that DLPs can also induce the xenobiotic detoxification enzyme flavin-containing monooxygenase 3 (FMO3), which plays a role in metabolic homeostasis. We hypothesized whether genetic deletion ofFmo3could protect mice, particularly in the liver, whereFmo3is most inducible, against PCB 126 toxicity. To test this hypothesis, male C57BL/6 wild-type (WT) mice andFmo3knockout (Fmo3KO) mice were exposed to PCB 126 or vehicle (safflower oil) during a 12-week study, at weeks 2 and 4. Various analyses were performed, including hepatic histology, RNA-sequencing, and quantitation of PCB 126 and F2-isoprostane concentrations. The results showed that PCB 126 exposure caused macro and microvesicular fat deposition in WT mice, but this macrovesicular fatty change was absent inFmo3KO mice. Moreover, at the pathway level, the hepatic oxidative stress response was significantly different between the two genotypes, with the induction of specific genes observed only in WT mice. Notably, the most abundant F2-isoprostane, 8-iso-15-keto PGE2, increased in WT mice in response to PCB 126 exposure. The study's findings also demonstrated that hepatic tissue concentrations of PCB 126 were higher in WT mice compared toFmo3KO mice. In summary, the absence of FMO3 in mice led to a distinctive response to dioxin-like pollutant exposure in the liver, likely due to alterations in lipid metabolism and storage, underscoring the complex interplay of genetic factors in the response to environmental toxins.