Arsenic exposure during embryonic development alters the expression of the long noncoding RNA growth arrest specific-5 (Gas5) in a sex-dependent manner.
Arsenic exposure during embryonic development alters the expression of the long noncoding RNA growth arrest specific-5 (Gas5) in a sex-dependent manner.
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DOI：
10.1016/j.ntt.2017.11.003
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发表时间：
2018-03
影响因子：
2.9
通讯作者：
Allan AM
中科院分区：
文献类型：
--
作者：
Caldwell KK;Hafez A;Solomon E;Cunningham M;Allan AM
我们以前的研究表明，产前暴露(50 Ppb)改变了发育中小鼠大脑中糖皮质激素受体(GR)信号系统编程的表观遗传控制。这些缺陷可能会导致长期的后果，包括学习和记忆障碍，类似抑郁的行为增加，以及一生中GR反馈的设定值改变。为了了解砷诱导的GR系统内的变化，我们评估了宫内砷暴露对小鼠GR编程的关键妊娠期(妊娠天数，GD14-18)GR和生长抑制特异性5(Gas5)水平的影响，Gas5是一种非编码RNA。Gas5含有一个糖皮质激素反应元件(GRE)样序列，它与GR结合，从而减少GR-GRE依赖的基因转录，并可能改变GR编程。出生前砷暴露导致胎儿端脑GR和Gas5表达水平随性别和年龄的变化。在测试的所有妊娠时间点，男性的核GR水平降低，但女性的核GR水平没有变化。在GD16和18岁时，暴露于砷的雄性细胞Gas5的总水平较低，而暴露于砷的雌性Gas5没有变化。在GD14暴露的雌性细胞中，细胞总的Gas5水平随着细胞核水平的增加而增加，这表明Gas5的细胞区划存在不同的调节。RIP分析显示，在砷暴露的男性和女性的细胞核部分中，与GD14上的GR相关的Gas5减少。这种GR-Gas5结合水平的下降只在GD18的雌性中持续。因此，在出生前暴露于砷的男性中，核GR信号潜势降低，而在出生前暴露于砷的雌性中，核GR信号潜势升高或维持在接近正常的水平。这些发现表明，暴露在砷中的女性，而不是男性，能够通过改变Gas5水平来调节无核GR的水平，从而使GR核信号更接近对照(未暴露)水平。
Our previous studies suggest that prenatal arsenic exposure (50 ppb) modifies epigenetic control of the programming of the glucocorticoid receptor (GR) signaling system in the developing mouse brain. These deficits may lead to long-lasting consequences, including deficits in learning and memory, increased depressive-like behaviors, and an altered set-point of GR feedback throughout life. To understand the arsenic-induced changes within the GR system, we assessed the impact of in utero arsenic exposure on the levels of the GR and growth arrest-specific-5 (Gas5), a noncoding RNA, across a key gestational period for GR programming (gestational days, GD 14–18) in mice. Gas5 contains a glucocorticoid response element (GRE)-like sequence that binds the GR, thereby decreasing GR-GRE-dependent gene transcription and potentially altering GR programming. Prenatal arsenic exposure resulted in sex-dependent and age-dependent shifts in the levels of GR and Gas5 expression in fetal telencephalon. Nuclear GR levels were reduced in males, but unchanged in females, at all gestational time points tested. Total cellular Gas5 levels were lower in arsenic-exposed males with no changes seen in arsenic-exposed females at GD16 and 18. An increase in total cellular Gas-5 along with increased nuclear levels in GD14 arsenic-exposed females, suggests a differential regulation of cellular compartmentalization of Gas5. RIP assays revealed reduced Gas5 associated with the GR on GD14 in the nuclear fraction prepared from arsenic-exposed males and females. This decrease in levels of GR-Gas5 binding continued only in the females at GD18. Thus, nuclear GR signaling potential is decreased in prenatal arsenic-exposed males, while it is increased or maintained at levels approaching normal in prenatal arsenic-exposed females. These findings suggest that females, but not males, exposed to arsenic are able to regulate the levels of nuclear free GR by altering Gas5 levels, thereby keeping GR nuclear signaling closer to control (unexposed) levels.
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