Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, P.O. Box 39040, 69978, Tel Aviv, Israel.
J Bone Miner Metab. 2012 May;30(3):270-80. doi: 10.1007/s00774-011-0311-7. Epub 2011 Sep 30.
Maternal malnutrition during pregnancy was shown by numerous studies to result in the birth of offspring exhibiting altered bone characteristics, which are indicative of bone loss. We hypothesized that not only maternal malnutrition but also some developmental toxicants (teratogens) given at a dose inducing neither structural anomalies nor growth retardation can detrimentally affect skeletal health in adult offspring. To check this hypothesis, pregnant mice were exposed to a single injection of 5-aza-2-deoxycytidine (5-AZA) (a teratogen capable of inducing phocomelia of the hind limbs) at a sub-threshold teratogenic dose. Micro-computed tomography scanning revealed that femora of 5-month-old male offspring exposed in uterus to 5-AZA had trabecular microarchitecture indicative of bone loss. Furthermore, exposure to 5-AZA increased the susceptibility of offspring to postnatal chronic mild stress, which has been shown to induce bone loss in mice. While exploring possible mechanisms underlying this phenomenon, we observed that the expression of some microRNAs, which have been demonstrated as regulators of key osteoblastogenic genes, was altered in hind limb buds of embryos exposed to 5-AZA. Furthermore, the expression of receptor activator of nuclear factor kappa B ligand (RANKL) in femoral stromal/osteoblastic cells of 5-month-old offspring of 5-AZA-treated females was found to be increased. Collectively, this study implies for the first time that single low-dose exposure to a teratogen can induce bone loss in adult offspring, possibly via alteration of embryonic microRNAs and RANKL expression.
孕期母体营养不良已被大量研究证实会导致后代出生时骨骼特征发生改变，表明存在骨质流失。我们假设不仅母体营养不良，而且某些发育毒物（致畸剂）在诱导结构异常或生长迟缓的剂量下，也可能对成年后代的骨骼健康产生不利影响。为了验证这一假设，我们将怀孕的老鼠暴露于单次亚阈值致畸剂量的 5-氮杂-2-脱氧胞苷（5-AZA）（一种能够诱导后肢海豹肢畸形的致畸剂）中。微计算机断层扫描显示，子宫内暴露于 5-AZA 的 5 个月大雄性后代的股骨具有提示骨质流失的小梁微结构。此外，暴露于 5-AZA 增加了后代对产后慢性轻度应激的易感性，这种应激已被证明会导致小鼠骨质流失。在探索这种现象的潜在机制时，我们观察到一些 microRNAs 的表达发生了改变，这些 microRNAs 已被证明是关键成骨基因的调节剂，在暴露于 5-AZA 的胚胎后肢芽中。此外，还发现 5-AZA 处理雌性后代 5 个月大的股骨基质/成骨细胞中核因子 kappa B 配体（RANKL）的表达增加。总的来说，这项研究首次表明，单次低剂量暴露于致畸剂可导致成年后代发生骨质流失，可能是通过改变胚胎 microRNAs 和 RANKL 的表达。
