Effects of the circadian clock and light on the production of estrogens

描述(申请人提供)：2007年12月，世界卫生组织(WHO)根据流行病学研究提供的越来越多的证据，将倒班工作归类为可能的致癌因素，这些研究表明，倒班工作人员患乳腺癌和前列腺癌的风险增加。然而，倒班工作如何影响癌症风险的潜在机制尚不清楚。已经提出了几个候选机制。一种假说认为松果体激素褪黑激素在轮班工人的癌症风险中起着关键作用。褪黑激素是一种只在夜间产生的荷尔蒙，但会因暴露在阳光下而受到抑制。在体外和动物研究中，褪黑激素具有抑癌作用，而且由于倒班工人经常在夜间暴露在光线下，因此有可能长期抑制褪黑素，从而导致观察到的癌症风险增加。褪黑激素也被认为与雌激素的产生呈负相关。鉴于长期接触雌激素是激素依赖型癌症的一个公认的风险因素，如果光对褪黑素的长期抑制导致雌激素或其代谢物的慢性升高，这种机制也可能导致倒班工人患乳腺癌的风险增加。褪黑素和雌激素是简单地负相关，还是有更直接的负反馈关系，还有待确定。我们已经收集了一些初步证据，表明尿中雌酮-3-葡萄糖醛酸苷存在内源性昼夜节律，其昼夜峰值与褪黑素的主要代谢物6-硫代谢素的昼夜节律相差12小时。然而，尿液标志物的性质意味着它们在确定节律的确切峰值方面缺乏精确度。在目前的提案中，我们希望利用以前的联邦基金(NIH/NASA)收集的尿样和血浆样本。我们有一个独特的机会来研究光线、昼夜节律、轮班工作以及褪黑素和雌激素内分泌学之间的关系，这是在严格控制的实验室条件下进行的价值100万美元的先前研究。这些数据将使我们能够检验以下特定假设：i)血浆和尿液雌二醇和尿雌二醇以及尿液雌酮-3-葡萄糖醛酸苷的产生存在显著的24小时昼夜节律和昼夜节律；ii)这些节律分别与血浆褪黑素和尿液6-硫氧基黑素成反比；iii)血浆雌二醇将在血浆褪黑素被抑制后急剧升高；以及iv)在模拟轮班工作方案中，雌二醇的昼夜节律将与褪黑素节律平行地相移。如果我们的假设被证实，这些研究将提供关于光、昼夜节律去同步化和轮班工作对褪黑素和雌激素内分泌学的影响的重要数据。未来的研究将在更大的现场和实验室病例对照研究中调查它们与癌症风险的关系。与公共健康相关：我们最新的工作表明，在衡量尿雌激素产生的指标中，可能存在24小时的昼夜节律。我们将检验这样的假设，即更频繁采样的血浆雌二醇中存在昼夜节律，以及这些节律是否与昼夜节律相反 褪黑素产生的节律，或受光线或模拟轮班工作时间的影响。最终，我们的目标是更全面地了解轮班工作对褪黑素和雌二醇内分泌的潜在破坏性影响，以及这些问题可能如何与观察到的女性轮班工人患乳腺癌风险的增加有关。

DESCRIPTION (provided by applicant): In December 2007, the World Health Organization (WHO) classified shift work as a probable carcinogen, based on growing evidence from epidemiological studies that show an increased risk of breast and prostate cancer in shift-workers. The mechanism underlying how shift work affects cancer risk is unknown, however. Several candidate mechanisms have been proposed. One hypothesis states that that the pineal hormone melatonin plays a key role in shift workers' cancer risk. Melatonin is a hormone that is produced only at night, but is suppressed by exposure to light. In vitro and in animal studies, melatonin is oncostatic and, as shift workers are often exposed to light at night and are at risk of chronic melatonin suppression, it has been hypothesized that a chronic suppression of melatonin underlies the increased cancer risk observed. Melatonin has also been hypothesized to be inversely related to estrogen production. Given that increased chronic exposure to estrogen is a well-established risk factor for hormone-dependent cancers, if chronic suppression of melatonin by light leads to chronic elevation of estrogen or its metabolites, this mechanism may also contribute to the increased risk of breast cancer in shift workers. Whether melatonin and estrogen are simply inversely associated or have a more direct negative feedback relationship has yet to be established. We have gathered some preliminary evidence to suggest that there is an endogenous circadian rhythm in urinary estrone-3-glucuronide with a day-time peak that is 12 hours out of phase with the urinary 6- sulphatoxymelatonin rhythm, the major metabolite of melatonin. The nature of the urinary markers means that they lack precision, however, in determining the exact peak of the rhythm. In the current proposal, we would like to take advantage of urine and plasma samples collected under previous federal funds (NIH/NASA). We have a unique opportunity to study the relationships between light, circadian rhythms, shift work and melatonin and estrogen endocrinology from $1M-worth of prior research conducted under strictly controlled laboratory conditions. These data will allow us to test the specific hypotheses that; i) there are significant 24-hour diurnal and circadian rhythms in plasma and urinary estradiol and urinary estrone-3-glucuronide production; and ii) that these rhythms are inversely related to plasma melatonin and urinary 6-sulfatoxymelatonin, respectively; iii) plasma estradiol will be acutely elevated following suppression of plasma melatonin; and iv) that the circadian rhythm of estradiol will phase-shift in parallel with the melatonin rhythm during a simulated shift-work protocol. Should our hypotheses be proven, these studies would provide important data on the effects of light, circadian desynchrony, and shift-work on melatonin and estrogen endocrinology. Future studies would then investigate their relationship to cancer risk in larger field- and laboratory based case-controlled studies. PUBLIC HEALTH RELEVANCE: Our most recent work suggests that there may be a 24-hour circadian rhythm in a measure of urinary estrogen production. We will test the hypotheses that there is a circadian rhythm in more frequently-sampled plasma estradiol and whether these rhythms are opposite to the circadian rhythms of melatonin production, or affected by light or simulated shift-work schedules. Ultimately, we aim to understand more fully the potential damaging effects of shift-work on melatonin and estradiol endocrinology and how these problems may relate to the observed increased risk of breast cancer in female shift workers.