A neuroanatomical mechanism linking perinatal chemical exposure to prostate smooth muscle hyperactivity and altered voiding function

The historical focus of male lower urinary tract dysfunction (LUTD) has been benign prostatic enlargement and other aging-related processes. Little attention has been directed towards the influence of early life events on urinary physiology in advancing age. Here, we identify the intrauterine environment as a modifier of adult voiding function and risk factor for male LUTD. To model environmental chemical exposures, we exposed pregnant mice to the environmental contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD, 1 µg/kg), coinciding with initiation of lower urinary tract development in male fetuses. Fetal TCDD exposure incites abnormal urodynamics in adult male mice, including increased urinary voiding frequency. TCDD also enhances adult prostate sensitivity to electrically evoked muscle contraction, suggesting increased autonomic tone. IUL TCDD exposure stably increases noradrenergic axon density beginning in the fetal period and persisting into adulthood. These changes are accompanied by increased abundance of a neurotrophin, Artemin (Artn), in the fetal prostate. This is the first evidence that intrauterine chemical exposures can reprogram prostate neuroanatomical development and drive prostatic smooth muscle hyperactivity in adulthood, which may create a susceptible phenotype for aging-related male lower urinary tract dysfunction.

长期以来，男性下尿路功能障碍（lower urinary tract dysfunction, LUTD）的研究焦点集中于良性前列腺增生（benign prostatic enlargement）及其他衰老相关病理进程，却鲜有研究关注生命早期事件对衰老过程中尿路生理状态的影响。本研究证实，宫内环境可调控成年个体的排尿功能，同时也是男性下尿路功能障碍的风险因素。为模拟环境化学暴露场景，我们在雄性胎儿下尿路发育启动阶段，令孕鼠暴露于环境污染物2,3,7,8-四氯二苯并对二恶英（2,3,7,8 tetrachlorodibenzo-p-dioxin, TCDD，1 µg/kg）。胎儿期暴露于TCDD会导致成年雄性小鼠出现异常尿动力学（urodynamics）特征，包括排尿频次增加。此外，TCDD还会增强成年小鼠前列腺对电刺激诱发肌肉收缩的敏感性，提示自主神经张力升高。宫内（intrauterine, IUL）TCDD暴露可从胎儿期开始稳定增加去甲肾上腺素能轴突（noradrenergic axon）密度，并持续至成年阶段。上述变化伴随胎儿前列腺内神经营养因子（neurotrophin）Artemin（Artn）表达丰度的提升。本研究首次证实，宫内化学暴露可重塑前列腺神经解剖发育，并在成年后诱发前列腺平滑肌高反应性，这可能为衰老相关的男性下尿路功能障碍构建易感表型。