GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth.
GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth.
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DOI：
10.1016/j.ebiom.2015.04.019
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发表时间：
2015-06
期刊：
影响因子：
11.1
通讯作者：
Robbins DJ
中科院分区：
文献类型：
--
作者：
Winterbottom EF;Fei DL;Koestler DC;Giambelli C;Wika E;Capobianco AJ;Lee E;Marsit CJ;Karagas MR;Robbins DJ
尽管大量证据表明子宫内砷暴露会影响儿童的健康，但这些数据主要来自世界上地下水砷含量远远超过世界卫生组织规定的 10 μg/L 限值的地区。我们和其他人发现，更常见的子宫内砷暴露水平也可能影响儿童的健康。然而，人们对潜在的分子机制知之甚少。为了解决这个问题，我们分析了美国地下水砷含量升高地区使用不受管制供水的妇女出生队列中胎儿胎盘中关键发育基因的表达。我们鉴定了几个基因，其表达与胎儿性别特异性的母体砷暴露相关。特别是，女性胎盘中 HEDGEHOG 通路成分 GLI3 的表达既与砷暴露呈负相关，又与婴儿出生体重呈正相关。这表明胎儿胎盘以及其他胎儿组织中 GLI3 的调节会导致砷对胎儿生长产生有害影响。我们之前表明，砷暴露的 NIH3T3 细胞会减少 GLI3 阻遏蛋白。总之，这些研究将 GLI3 确定为受砷影响的关键信号传导节点，介导其对发育信号传导和胎儿健康的部分影响。子宫内砷暴露与胎儿胎盘中几个关键发育基因的表达有关。胎盘基因表达与子宫内砷暴露之间的关联存在广泛的性别二态性。女性胎儿胎盘中的 GLI3 表达与砷暴露相关，并可能介导其对胎儿生长的影响。
Although considerable evidence suggests that in utero arsenic exposure affects children's health, these data are mainly from areas of the world where groundwater arsenic levels far exceed the World Health Organization limit of 10 μg/L. We, and others, have found that more common levels of in utero arsenic exposure may also impact children's health. However, the underlying molecular mechanisms are poorly understood. To address this issue, we analyzed the expression of key developmental genes in fetal placenta in a birth cohort of women using unregulated water supplies in a US region with elevated groundwater arsenic. We identified several genes whose expression associated with maternal arsenic exposure in a fetal sex-specific manner. In particular, expression of the HEDGEHOG pathway component, GLI3, in female placentae was both negatively associated with arsenic exposure and positively associated with infant birth weight. This suggests that modulation of GLI3 in the fetal placenta, and perhaps in other fetal tissues, contributes to arsenic's detrimental effects on fetal growth. We showed previously that arsenic-exposed NIH3T3 cells have reduced GLI3 repressor protein. Together, these studies identify GLI3 as a key signaling node that is affected by arsenic, mediating a subset of its effects on developmental signaling and fetal health. In utero arsenic exposure associates with the expression of several key developmental genes in the fetal placenta. There is extensive sexual dimorphism in the associations between placental gene expression and in utero arsenic exposure. GLI3 expression in the female fetal placenta associates with arsenic exposure and may mediate its effects on fetal growth.