Background

The incidence of obesity has soared over the last several decades. There is mounting evidence suggesting that the increased presence of environmental endocrine disruptors (EEDs), including nonylphenol (NP), plays an important role in the incidence of lipid metabolism disorders. The aim of this work was to determine whether chronical exposure to NP could induce obesity and lipid metabolism disorders, both in vivo in Sprague–Dawley rats, and in vitro in 3T3-L1 preadipocytes. Forty rats (n = 10 per group) were gavaged with NP in corn oil at dose levels of 0.02 μg/kg/day (low dose, L), 0.2 μg/kg/day (middle dose, M), and 2.00 μg/kg/day (high dose, H) or corn oil alone (vehicle control, C) for 180 days. In vitro study, 3T3-L1 preadipocytes were exposed to NP at concentrations of 0, 40 pM, 40 nM, or 40 μM for 12 days.

Results

In vivo, the fat weight (F = 103.605, P < 0.001) and fat coefficient (F = 169.807, P < 0.001) of NP-exposed rats were higher than those of control group rats. The serum levels of TC (F = 3.798, P < 0.05), LDL-C (F= 4.946,P < 0.05), and TG (F = 14.117,P < 0.05) in the H group were higher than those in the control group. Protein concentrations of CEBPα (F = 189.104, P < 0.001), FAS (F = 51.011, P < 0.001), PPARγ (F = 114.306,P < 0.001), and SREBP1 (F = 30.432,P < 0.001) in serum in the NP group were higher than those in the control group. The concentration of NP in adipose tissues of rats increased with an increase in NP exposure dose in a dose–response manner (F = 561.353,P < 0.001). The numbers of adipocytes in the M and H groups decreased, and the volume of a single cell increased with cells’ membranes ruptured. With the increase in NP exposure dose, the number of adipocytes per microscope decreased gradually (F = 85.873, P < 0.001). The expression levels of PPARγ (F = 169.936, P < 0.001) and FAS (F = 295.249, P < 0.001) proteins in the H group were higher than those in the control group. CEBPα (F = 101.086, P < 0.001) mRNA expression was up-regulated in the M and H groups; and FAS (F = 439.600, P < 0.001), PPARγ (F = 10.540, P < 0.001), and SREBP1 (F = 123.499, P < 0.001) mRNA expression in NP-exposed groups were significantly higher than those in the control group. In vitro, compared with the control group, the Oil Red Staining of adipocytes in the NP groups was darker, the fat cells were more densely distributed, and some of them fused into large lipid droplets. Expressions of CEBPα (F = 539.103, P < 0.001), FAS (F = 715.740, P < 0.001), PPARγ(F = 114.783, P < 0.001), and SREBP1 (F = 139.600, P < 0.001) proteins in 3T3-L1 preadipocytes were higher in group exposed to 40 μM NP than those in the control group.

Conclusions

The results of this in vivo and in vitro experiment were consistent, and both have demonstrated that NP exposure interfered with the expression of proteins and/or mRNAs of lipid metabolism-related regulators (CEBPα, FAS, SREBP1, PPARγ), promoted the proliferation and differentiation of adipocytes and intracellular accumulation of lipids, and eventually lead to blood lipid disorders and obesity in rats.

中文翻译：

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长期暴露于壬基酚对脂质代谢的体内和体外影响

背景

在过去的几十年中，肥胖症的发病率飙升。越来越多的证据表明，包括壬基酚（NP）在内的环境内分泌干扰物（EED）的增加在脂质代谢紊乱的发生中起重要作用。这项工作的目的是确定在Sprague-Dawley大鼠体内以及在3T3-L1前脂肪细胞中体外长期暴露于NP是否会引起肥胖和脂质代谢异常。40只大鼠（ñ 每组= 10）在玉米油中分别以0.02μg/ kg /天（低剂量，L），0.2μg/ kg /天（中剂量，M）和2.00μg/ kg /天（高剂量（H）或仅玉米油（车辆对照C）180天。在体外研究中，将3T3-L1前脂肪细胞以0、40 pM，40 nM或40μM的浓度暴露于NP达12天。

结果

在体内， 暴露于NP的大鼠的脂肪重量（F  = 103.605，P  <0.001）和脂肪系数（F  = 169.807，P <0.001）高于对照组。H组的血清TC（F  = 3.798，P <  0.05），LDL-C（F = 4.946，P  <0.05）和TG（F  = 14.117，P <  0.05）高于对照组组。CEBPα（F  = 189.104，P  <0.001），FAS（F = 51.011，P  <0.001），PPARγ（F  = 114.306，P  <0.001）和SREBP1（FNP组的血清 = 30.432，P  <0.001）高于对照组。大鼠脂肪组织中NP的浓度随NP暴露剂量的增加而呈剂量反应（F  = 561.353，P  <0.001）。M和H组的脂肪细胞数量减少，并且单个细胞的体积随着细胞膜的破裂而增加。随着NP暴露剂量的增加，每个显微镜下的脂肪细胞数量逐渐减少（F  = 85.873，P  <0.001）。PPARγ（F  = 169.936，P  <0.001）和FAS（F  = 295.249，P H组中的<0.001）蛋白高于对照组。 M和H组CEBPα（F  = 101.086，P <0.001）mRNA表达上调;  NP暴露组的FAS（F  = 439.600，P  <0.001），PPARγ（F  = 10.540，P  <0.001）和SREBP1（F  = 123.499，P <0.001）mRNA表达显着高于对照组。 。在体外，与对照组相比，NP组的脂肪细胞油红色染色更深，脂肪细胞分布更密集，其中一些融合成大的脂质液滴。CEBPα的表达（F  = 539.103，P  <0.001），FAS（˚F  = 715.740，P  <0.001），PPARγ（˚F  = 114.783，P  <0.001），和SREBP1（˚F  = 139.600，P  <0.001）在3T3-L1前脂肪细胞蛋白是在暴露于组高NP比对照组低40μM。

结论

该体内和体外实验的结果是一致的，并且都证明了NP暴露会干扰脂质代谢相关调节剂（CEBPα，FAS，SREBP1，PPARγ）的蛋白质和/或mRNA的表达，促进其增殖和增殖。脂肪细胞的分化和脂质在细胞内的积累，最终导致大鼠血脂异常和肥胖。