The effect of short intermittent light exposures on the melatonin circadian rhythm and NMU-induced breast cancer in female F344/N rats.
We investigated the effects of altered endogenous nighttime melatonin concentrations on mammary tumor production in an N-nitroso-N-methylurea (NMU)-induced breast cancer model in female Fischer 344 (F344)/N rats. Experiments were designed 1) to evaluate whether short-duration intermittent exposures to light at night would affect the nocturnal rise of melatonin, resulting in a decrease in nighttime serum melatonin concentrations, 2) to evaluate whether any suppression of nighttime serum melatonin concentrations could be maintained for a period of weeks, and 3) to determine the effects of suppressed serum melatonin concentrations on the incidence and progression of NMU-induced breast cancer. In vivo studies were used to assess serum melatonin concentrations after 1 day and 2 and 10 weeks of nightly administration of short-duration intermittent light exposure at night and incidence of NMU-induced tumors. Five 1-minute exposures to incandescent light every 2 hours after the start of the dark phase of the light: dark cycle decreased the magnitude of the nocturnal rise of serum melatonin concentrations in rats by approximately 65%. After 2 weeks of nightly intermittent light exposures, an average decrease of the peak nighttime serum melatonin concentrations of approximately 35% occurred. The amelioration continued and, at 10 weeks, peak nighttime serum melatonin concentrations were still decreased, by approximately 25%. Because peak endogenous nighttime serum melatonin values could be moderately suppressed for at least 10 weeks, a 26-week NMU mammary tumor study was conducted. Serum melatonin concentrations and incidence, multiplicity, and weight of NMU-induced mammary tumors were assessed. A group of pinealectomized (Px) animals was also included in the tumor study. No effect on the development of mammary tumors in an NMU-induced tumor model in rats occurred when endogenous nighttime serum melatonin concentrations were moderately suppressed by short-duration intermittent light exposures at night. At necropsy, there were no alterations in mammary tumor incidence (28/40 NMU controls, 28/40 NMU + light, 31/40 NMU + Px), multiplicity (2.18 tumors/tumor-bearing NMU control, 1.89 NMU + light, 2.39 NMU + Px), or average tumor weight (1.20 g NMU control, 1.19 g NMU + light, 0.74 g NMU + Px). Tumor burden had no effect on the serum melatonin cycle. At 26 weeks, however, animals exposed to intermittent light at night exhibited approximately 3-fold higher serum melatonin concentrations as compared with controls. Additionally, rats that had been pinealectomized at 4 weeks of age had serum melatonin concentrations that were markedly higher than the expected baseline concentrations for pinealectomized rats (<15 pg/ml), suggesting the reestablishment of a melatonin cycle. This finding was unexpected and suggests that melatonin can be produced by an organ or tissue other than the pineal gland.
Travlos
G S
GS
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. travlos@niehs.nih.gov
Wilson
R E
RE
Murrell
J A
JA
Chignell
C F
CF
Boorman
G A
GA
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D008027:Light; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008550:Melatonin / Q000097:blood / Q000378:metabolism*; D008770:Methylnitrosourea / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010870:Pineal Gland / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D008770:Methylnitrosourea; D008550:Melatonin