Vezina Chad M, Allgeier Sarah Hicks, Moore Robert W, Lin Tien-Min, Bemis Jeffrey C, Hardin Heather A, Gasiewicz Thomas A, Peterson Richard E
School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, USA.
Toxicol Sci. 2008 Dec;106(2):488-96. doi: 10.1093/toxsci/kfn183. Epub 2008 Sep 8.
Prostate ductal development is initiated by androgen-dependent signals in fetal urogenital sinus (UGS) mesenchyme that stimulate prostatic bud formation in UGS epithelium. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, 5 microg/kg maternal dose) inhibited ventral and dorsolateral but not anterior prostatic budding. We sought to determine which stage of budding, specification or initiation, was inhibited. Ventral prostatic bud formation was maximally inhibited when TCDD exposure spanned E15.5-16.5 and dorsolateral prostatic bud formation when it spanned E14.5-15.5. Because ventral and dorsolateral buds are specified at these times, TCDD impaired bud specification. We hypothesized that TCDD inhibited ventral bud specification by forming a continuous smooth muscle barrier between UGS mesenchyme and epithelium in the ventral prostatic UGS region, blocking mesenchymal-epithelial signaling, but no such barrier was found. We hypothesized that increased aryl hydrocarbon receptor (AHR) signaling in ventral and dorsolateral UGS increased their sensitivity to TCDD, but levels of AHR nuclear translocator (ARNT) protein, Ahr mRNA, and AHR-dependent gene expression were not higher than in anterior UGS where budding was unaffected. However, we identified overlapping expression of Ahr, ARNT, and AHR-induced transcripts in the periprostatic mesenchyme which intimately contacts UGS epithelium where buds are specified. This was considered the putative TCDD site of action in the UGS for inhibition of ventral and dorsolateral prostatic bud specification. Thus, hyperactivation of AHR signaling appears to disrupt dorsoventral patterning of the UGS, reprogramming where prostatic buds are specified, and prostate lobes are formed. Disrupted axial patterning provides a new paradigm for understanding how in utero TCDD exposure causes ventral prostate agenesis and may shed light on how TCDD impairs development of other organs.
前列腺导管发育由胎儿泌尿生殖窦（UGS）间充质中雄激素依赖信号启动，这些信号刺激UGS上皮中的前列腺芽形成。2,3,7,8-四氯二苯并对二恶英（TCDD，母体剂量5微克/千克）抑制腹侧和背外侧前列腺芽形成，但不抑制前侧前列腺芽形成。我们试图确定是芽形成的哪个阶段，即特化或起始阶段受到了抑制。当TCDD暴露时间跨度为E15.5 - 16.5时，腹侧前列腺芽形成受到最大抑制；当暴露时间跨度为E14.5 - 15.5时，背外侧前列腺芽形成受到最大抑制。由于腹侧和背外侧芽在这些时间点被特化，所以TCDD损害了芽的特化。我们推测TCDD通过在腹侧前列腺UGS区域的UGS间充质和上皮之间形成连续的平滑肌屏障来抑制腹侧芽特化，从而阻断间充质 - 上皮信号传导，但未发现这样的屏障。我们推测腹侧和背外侧UGS中芳烃受体（AHR）信号增加会增加它们对TCDD的敏感性，但AHR核转运体（ARNT）蛋白水平、Ahr mRNA和AHR依赖基因表达并不高于芽形成未受影响的前侧UGS。然而，我们在前列腺周围间充质中发现了Ahr、ARNT和AHR诱导转录本的重叠表达，该区域与芽被特化的UGS上皮紧密接触。这被认为是UGS中TCDD抑制腹侧和背外侧前列腺芽特化的假定作用位点。因此，AHR信号的过度激活似乎破坏了UGS的背腹模式，重新编程了前列腺芽的特化位置和前列腺叶的形成。轴向模式的破坏为理解子宫内TCDD暴露如何导致腹侧前列腺发育不全提供了一个新的范例，并可能揭示TCDD如何损害其他器官的发育。
