School of Nursing, Anhui Medical University, Hefei 230032, China; Anhui Provincial Key Laboratory of Population Health & Aristogenics, Hefei, 230032, China.
School of Nursing, Anhui Medical University, Hefei 230032, China.
Mol Cell Endocrinol. 2018 Oct 15;474:272-283. doi: 10.1016/j.mce.2018.03.019. Epub 2018 Apr 1.
An adverse intrauterine environment may be an important factor contributing to the development of type 2 diabetes in later life. The present study investigated the longitudinal effects of maternal lipopolysaccharide (LPS) exposure during the third trimester on glucose metabolism and sex hormone balance in the offspring. Pregnant mice were intraperitoneally injected with LPS (50 μg/kg) daily from gestational day (GD) 15 to GD17. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were assessed at postnatal day (PND) 60 and PND120. Sex hormones, their receptors, and metabolic enzymes (aromatase) were measured in male offspring at different phases of development (PND14: juvenile; PND35: adolescence; PND60: adulthood; and PND120: middle age). LPS-exposed male offspring exhibited glucose intolerance and insulin resistance by GTT and ITT at middle age, accompanied by an increase in fasting blood glucose and reductions in serum insulin levels and hepatic phosphorylated (p) -AKT/AKT ratio. However, glucose intolerance and insulin resistance were not observed in LPS-exposed female offspring. Maternal LPS exposure upregulated hepatic aromatase proteins and mRNA levels in male offspring at all time points. At adolescence, the testosterone/estradiol ratio (T/E2) was markedly reduced in LPS-exposed male offspring. Moreover, maternal LPS exposure significantly increased hepatic estrogen receptor (ER) α expressions and decreased hepatic androgen receptor (AR) expressions in male offspring. At adulthood, maternal LPS exposure increased serum estradiol levels, decreased serum testosterone levels and elevated hepatic ERβ expressions in male offspring. In conclusion, maternal LPS exposure upregulated aromatase expressions, followed by a reduction in the T/E2 ratio and an alteration in sex hormone receptor activity, which might be involved in the development of glucose metabolism disorders in middle-aged male offspring. This study provides a novel clue and direction to clarify the pathogenesis of maternal infection-related diabetes in male offspring.
不良的宫内环境可能是导致 2 型糖尿病发生的重要因素。本研究探讨了母体脂多糖（LPS）在妊娠晚期暴露对后代葡萄糖代谢和性激素平衡的纵向影响。妊娠小鼠从妊娠第 15 天（GD）到第 17 天（GD）每天腹腔注射 LPS（50μg/kg）。在产后第 60 天（PND60）和第 120 天（PND120）进行葡萄糖耐量试验（GTT）和胰岛素耐量试验（ITT）。在不同发育阶段（PND14：幼年；PND35：青春期；PND60：成年；PND120：中年）测量雄性后代的性激素、其受体和代谢酶（芳香酶）。LPS 暴露的雄性后代在中年时通过 GTT 和 ITT 表现出葡萄糖不耐受和胰岛素抵抗，伴随着空腹血糖升高、血清胰岛素水平降低和肝磷酸化（p）-AKT/AKT 比值降低。然而，LPS 暴露的雌性后代没有观察到葡萄糖不耐受和胰岛素抵抗。母体 LPS 暴露在所有时间点上调雄性后代肝芳香酶蛋白和 mRNA 水平。在青春期，LPS 暴露的雄性后代的睾丸酮/雌二醇比值（T/E2）显著降低。此外，母体 LPS 暴露显著增加雄性后代肝雌激素受体（ER）α的表达并降低肝雄激素受体（AR）的表达。在成年期，母体 LPS 暴露增加了雄性后代的血清雌二醇水平，降低了血清睾丸酮水平，并升高了肝 ERβ 的表达。总之，母体 LPS 暴露上调了芳香酶的表达，随后降低了 T/E2 比值，并改变了性激素受体的活性，这可能与中年雄性后代葡萄糖代谢紊乱的发生有关。本研究为阐明母体感染相关糖尿病在雄性后代中的发病机制提供了新的线索和方向。
