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

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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.