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See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/287978163

Daytime Blue Light Enhances the NighttimeCircadian Melatonin Inhibition of Human

Prostate Cancer Growth

ARTICLE in COMPARATIVE MEDICINE DECEMBER 2015

Impact Factor: 0.74

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13 AUTHORS, INCLUDING:

Robert Dauchy

Tulane University

87PUBLICATIONS 2,649CITATIONS

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Steven M Hill

Tulane University


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Victoria P Belancio

Tulane University


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Erin M Dauchy

Tulane University

27PUBLICATIONS 398CITATIONS

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Available from: Victoria P BelancioRetrieved on: 22 February 2016
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Hill3?enrichId=rgreq-c083878f-449b-4b7c-909d-e92dcd057f36&enrichSource=Y292ZXJQYWdlOzI4Nzk3ODE2MztBUzozMDk4NTQwODQ3NjM2NDhAMTQ1MDg4NjM3ODc2Mg%3D%3D&el=1_x_4https://www.researchgate.net/profile/Robert_Dauchy?enrichId=rgreq-c083878f-449b-4b7c-909d-e92dcd057f36&enrichSource=Y292ZXJQYWdlOzI4Nzk3ODE2MztBUzozMDk4NTQwODQ3NjM2NDhAMTQ1MDg4NjM3ODc2Mg%3D%3D&el=1_x_7https://www.researchgate.net/institution/Tulane_University?enrichId=rgreq-c083878f-449b-4b7c-909d-e92dcd057f36&enrichSource=Y292ZXJQYWdlOzI4Nzk3ODE2MztBUzozMDk4NTQwODQ3NjM2NDhAMTQ1MDg4NjM3ODc2Mg%3D%3D&el=1_x_6https://www.researchgate.net/profile/Robert_Dauchy?enrichId=rgreq-c083878f-449b-4b7c-909d-e92dcd057f36&enrichSource=Y292ZXJQYWdlOzI4Nzk3ODE2MztBUzozMDk4NTQwODQ3NjM2NDhAMTQ1MDg4NjM3ODc2Mg%3D%3D&el=1_x_5https://www.researchgate.net/profile/Robert_Dauchy?enrichId=rgreq-c083878f-449b-4b7c-909d-e92dcd057f36&enrichSource=Y292ZXJQYWdlOzI4Nzk3ODE2MztBUzozMDk4NTQwODQ3NjM2NDhAMTQ1MDg4NjM3ODc2Mg%3D%3D&el=1_x_4https://www.researchgate.net/?enrichId=rgreq-c083878f-449b-4b7c-909d-e92dcd057f36&enrichSource=Y292ZXJQYWdlOzI4Nzk3ODE2MztBUzozMDk4NTQwODQ3NjM2NDhAMTQ1MDg4NjM3ODc2Mg%3D%3D&el=1_x_1https://www.researchgate.net/publication/287978163_Daytime_Blue_Light_Enhances_the_Nighttime_Circadian_Melatonin_Inhibition_of_Human_Prostate_Cancer_Growth?enrichId=rgreq-c083878f-449b-4b7c-909d-e92dcd057f36&enrichSource=Y292ZXJQYWdlOzI4Nzk3ODE2MztBUzozMDk4NTQwODQ3NjM2NDhAMTQ1MDg4NjM3ODc2Mg%3D%3D&el=1_x_3https://www.researchgate.net/publication/287978163_Daytime_Blue_Light_Enhances_the_Nighttime_Circadian_Melatonin_Inhibition_of_Human_Prostate_Cancer_Growth?enrichId=rgreq-c083878f-449b-4b7c-909d-e92dcd057f36&enrichSource=Y292ZXJQYWdlOzI4Nzk3ODE2MztBUzozMDk4NTQwODQ3NjM2NDhAMTQ1MDg4NjM3ODc2Mg%3D%3D&el=1_x_2

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Comparative MedicineCopyright 2015by the American Association for Laboratory Animal Science

Vol 65, No 6December 2015Pages 473485

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Light profoundly influences circadian, neuroendocrine, andneurobehavioral regulation in all mammals and is essential to lifeon our planet.2,15,28, 40The lightdark cycle entrains the master bio-logic clock, located in the suprachiasmatic nucleus of the brain, inan intensity-, duration-, and wavelength-dependent manner.8-13Photobiologic responses, including circadian rhythms of metabo-lism and physiology, are mediated by organic molecules called

chromophores, which are contained within a small subset ofretinal cells, called the intrinsically sensitive retinal ganglion cells(ipRGC).16,29,31,36,41,49,53,59In humans and rodents light quanta aredetected by the chromophore melanopsin, which detects lightquanta in principally the short-wavelength, blue-appearing por-tion of the spectrum (446 to 477 nm), and transmits its photicinformation via the retinohypothalamic tract to the molecularclock of the suprachiasmatic nucleus. This region of the brainregulates the daily pineal gland production of the circadian neu-rohormone melatonin (N-acetyl-5-methoxytryptamine), which

results in high levels produced at night and low levels duringdaytime.38,54The daily, rhythmic melatonin signal provides tem-poral coordination of normal behavioral and physiologic func-tions including chronobiologic rhythms of locomotor activity,2sleep-wake cycle,2,14dietary and water intake,2,51hormone secre-tion and metabolism.5,44,47,61Alterations in light intensity, duration,and spectral quality at a given time of day,8-13,17,19-22,24,61 such as oc-

curs in night-shift workers exposed to light at night,26,34,46,57acutelysuppresses endogenous melatonin levels in most mammalianspecies9,11,44,45,54,55and may lead to various disease states, includingmetabolic syndrome5,61and carcinogenesis.4-7,17,18

Recent studies from our laboratory5,20,23-25,60,61have demon-strated that relatively small changes in the spectral transmit-tance (color) of light passing through translucent amber (>590nm), blue (>480 nm), and red-tinted (>640 nm) polycarbonatelaboratory rodent cages, compared with standard polycarbon-ate clear cages (390 to 700 nm), during the light phase markedlyinfluenced the normal nighttime melatonin signal and disrupt-ed temporal coordination of metabolism and physiology. 19,24,61Most notable was our discovery that, in both male and female

pigmented nude rats maintained in blue-tinted rodent cages,nighttime melatonin levels were as much as 7 times higher than

Original Research

Daytime Blue Light Enhances the NighttimeCircadian Melatonin Inhibition of Human ProstateCancer Growth

Robert T Dauchy,1,*Aaron E Hoffman,2Melissa A Wren-Dail,1John P Hanifin,3Benjamin Warfield,3George C Brainard,3ShulinXiang,1Lin Yuan,1Steven M Hill,1Victoria P Belancio,1Erin M Dauchy,1Kara Smith,1and David E Blask1

Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in

normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher afterdaytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypoth-esis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, andgrowth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats inblue-tinted cages (with increased transmittance of 462484 nm and decreased red light greater than 640 nm) evinced over 6-foldhigher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO

2, pCO

2, insulin, leptin, and

corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. Afterimplantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates weremarkedly delayed, and tumor cAMP levels, uptakemetabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growthsignaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttimemelatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic,signaling, and proliferative activities.

Abbreviations:A-V, arterialvenous difference; ipRGC, intrinsically photosensitive retinal ganglion cell; LA, linoleic acid; 13-HODE,13-hydroxyoctadecadienoic acid; TFA, total fatty acids.

Received: 27 May 2015. Revision requested: 24 Jun 2015. Accepted: 16 Jul 2015.Departments of Structural and Cellular Biology and 2Epidemiology, Tulane University

School of Medicine, Tulane, Louisiana, and

3

Department of Neurology, Thomas JeffersonUniversity, Philadelphia, Pennsylvania.*Corresponding author. Email: [email protected].

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Use of Laboratory Animals.39All procedures for animal use wereapproved by the Tulane University IACUC.

Rats were maintained as described below in autoclaved cagesusing hardwood maple bedding (catalog no. 7090, Sanichips,Harlan Teklad, Madison, WI; 2 bedding changes weekly). To en-sure that all rats remained infection-free from bacterial and viral

agents and murine parasites, serum samples from sentinel ani-mals were tested quarterly and during the course of this study(Multiplex Fluorescent Immunoassay 2, Idexx Research AnimalDiagnostic Laboratory, Columbia, MO) as described previous-ly.19,22Rats were provided free access to food (5053 Irradiated Lab-oratory Rodent Diet, Purina, Richmond, IN) and acidified water.Quadruplicate determinations of this diet contained (per 100 gof diet) 4.72 g total fatty acid (TFA), composed of 0.92% myris-tic (C14:0), 13.82% palmitic (C16:0), 1.17% palmitoleic (C16:1n7),3.64% stearic (C18:0), 23.90% oleic (C18:1n9), 50.17% linoleic(C18:2n6), 5.98% -linolenic, and 0.29% arachidonic (C20:4n6) ac-ids. Minor amounts of other FA comprised 0.11%. Conjugated LAand trans FA were not found. More than 90% of the TFA was in

the form of triglycerides; more than 5% was in the form of free FA.Caging, lighting regimens, and spectral transmittance measure-

ments.After a 1-wk acclimation period, rats were randomizedinto 2 designated groups of 6 animals each (3 rats per cage) andplaced in standard polycarbonate, translucent laboratory rodentcages (10.5 in. 19.0 in. 8.0 in.; wall thickness, 0.10) of eitherclear (control; catalog no. R20PC, Ancare, Bellmore, NY) or blue(experimental; catalog no. 80778CC; Lab Products, Seaford, DE)in hue. Both cage types used identical stainless steel lids (catalogno. 10SS, Ancare) and were covered with polysulfone translucentmicrofilter tops (catalog no. N10MBT, Ancare). The SPF rats weremaintained in environmentally controlled rooms (25 C; 50% to55% humidity) with diurnal, 12:12-h lighting (lights on, 0600).

Animal rooms were lighted with a series of 3 overhead luminairescontaining 4 cool-white fluorescent lamps per ballast (Alto Collec-tion 32 W, catalog no. F32T8TL741, Philips, Somerset, NJ); animalrooms were completely devoid of light contamination during thedark phase.5,17

Daily during the course of this experiment, the animal roomwas monitored for normal light-phase lighting intensity at 1 mabove the floor in the center of the room (at rodent eye level)and outside and from within and at the front of the animal cag-es. Irradiance measures used a radiometerphotometer (modelIL1400A, International Light Technologies, Peabody, MA) thathad a silicon-diode detector head (model SEL033, InternationalLight Technologies) and a wide-angle input optic (W6849, Inter-

national Light Technologies); a filter (F23104, International LightTechnologies) provided a flat response across the visible spec-trum. Illuminance measures used a silicon-diode detector head(model SEL033, International Light Technologies) with a wide-angle input optic (W10069, International Light Technologies) anda filter (Y23104, International Light Technologies) to provide aphotopic illuminance response. The meter and associated opticswere calibrated annually, as described previously.19,21,22,24,61Eachday and at the same time (0800), prior to light intensity measure-ments for that day, all cages on the rack shelf were rotated oneposition to the right (placed at an identical, premeasured distanceapart) in the same horizontal plane; the cage at position 4 (lastposition at far right on the shelf) was moved to position 1 (firstposition at far left on the shelf). Although light intensity, as mea-sured outside and from within the front of each cage at each of

normal nighttime peak levels in animals maintained in all othercage types.19An earlier study in human subjects diagnosed withmidwinter insomnia coupled with low nighttime melatonin lev-els demonstrated that daily exposure to intense morning brightpolychromatic light therapy for up to one week resulted in arestoration of nocturnal melatonin levels to those of control sub-

ects.35In another study, exposure to blue-tinted (470 nm) LEDlight (100 lx) for approximately 20 min in the morning after 2sleep-restricted (6 h) nights led to earlier onset of the melatoninsurge at nighttime.30

In the United States alone this year, approximately 240,000men will be diagnosed with prostate cancer, and nearly 30,000will die from this disease (National Cancer Institute;www.can-cer.gov/). Epidemiologic studies have shown that night shiftwork, which involves circadian disruption, including noctur-nal melatonin suppression, markedly increases prostate can-cer risk in men.26,34,46,57,58Both in vitro and in vivo studies havedemonstrated that melatonin inhibits human prostate cancergrowth, including that of androgen-receptornegative, castra-

tion-resistant PC3 human prostate cancer cells.20,29,42,56Cancercells depend primarily on aerobic glycolysis (Warburg effect)over oxidative phosphorylation to meet their bioenergetic needssupporting biomass formation.5The Warburg effect is character-ized by increased cellular uptake of glucose and production oflactate despite an abundance of oxygen. Investigations haveshown that signal transduction pathways that include AKT,MEK, NFB, GS3K, and PDK1 drive the Warburg effect.5,61Inaddition, cancer cells rely on increased uptake of the 6 fattyacid linoleic acid (LA), which is prevalent in the western diet.4-6In most cancers, LA uptake occurs through a cAMP-dependenttransport mechanism, and LA is metabolized to the mitogenicagent 13-hydroxyoctadecadienoic acid (13-HODE). In most tu-

mors, 13-HODE plays an important role in enhancing down-stream phosphorylation of ERK 1/2, AKT, and activation of theWarburg effect, thereby leading to increased cell proliferationand tumor growth.4-6Melatonin, the principal neurohormoneof the pineal gland and whose production is regulated by thesuprachiasmatic nucleus,4,5modulates processes of tumor initia-tion, progression, and growth in vivo.5The circadian nocturnalmelatonin signal not only inhibits LA uptake and metabolism,the Warburg effect in human cancer xenografts, and ultimatelytumor growth, but it actually drives circadian rhythms in tumormetabolism, signal transduction activity, and cell proliferation.These effects are extinguished when melatonin production issuppressed by light exposure at night.5

In the present investigation, we examined the hypothesis thatthe spectral transmittance (color) of short-wavelength (480 nm)bright light passing through blue-tinted standard laboratory ro-dent cages during the light phase not only amplifies the normalcircadian nocturnal melatonin signal but also enhances the inhi-bition of the metabolism, signaling activity, and growth progres-sion of human PC3 androgen-receptornegative human prostatecancer xenografts in male nude rats.

Materials and MethodsAnimals, housing conditions, and diet.Male, pigmented, ho-

mozygous, athymic, inbred nude rats (Crl:NIH-Foxn1rnu), 3 to 4wk of age, used in this study were purchased from Charles River

(Wilmington, MA). Animals were maintained in an AAALAC-accredited facility in accordance with theGuide for the Care and
http://www.can-/http://www.can-/

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ues for glucose and lactate are reported as mg/dL and mmol/Land for pH, pO

2, pCO

2, glucose, and lactate values as, 0.01, 0.1

mm Hg, 0.1 mm Hg, 0.2 mg/dL, and 0.01 mmol/L, respectively.Plasma samples were stored at 20 C until analysis.

PC3 prostate cancer xenograft implantation, determination oftumor growth, and arterial and venous difference measurements.

After a 1-wk recovery period, androgen-receptornegative orandrogen-independent human PC3 prostate xenografts were im-planted in the nude rats and grew as tissue-isolated tumors asdescribed previously,4,6,20,23with a single arterial and single ve-nous connection to the host. The PC3 prostate tumor xenograftswere verified histopathologically to be a grade IV human pros-tate cancer cell line (catalog no. CRL-1435, American Tissue CellCollection, Mannassas, VA). Latency-to-onset of tumor growth(approximately pea-sized) was determined, and estimated tu-mor weights were measured, as described previously.6,20,23Whentumors reached an estimated weight of 6 to 8 g, animals wereprepared for tumor arterial and venous (A-V) difference mea-surements, as previously described.6,20,23In the initial experiment,

all tumor A-V difference measurements in rats in clear or bluecages were taken between 0600 and 0800. Whole blood was col-lected for measurements of pH, pO

2, pCO

2, glucose, and lactate

levels; plasma samples were obtained to analyze Hct, TFA andLA uptake, and 13-HODE production. At the end of the tumorA-V blood collections, tumors were freeze -lamped under liquidnitrogen, weighed, and stored at 80 C until used for analyses.

To determine the effects of normal daytime physiologic (lessthan 10 pg/mL; occurring at 1200) and elevated nighttime (occur-ring at 2400 h) melatonin levels on tumor A-V differences in ratsmaintained in blue-tinted cages, all rats were randomized into 2designated groups of 6 animals each (3 per cage) and maintainedonly in blue-tinted cages. Animal cages were rotated daily as de-

scribed earlier. After a 1-wk acclimation period in the blue cages,all rats were implanted with the tissue-isolated PC3 prostate xe-nograft and measured for latency-to-onset and tumor growth, asdescribed earlier. When tumors reached an estimated weight of 6to 8 g, rats were prepared for tumor A-V difference measurementsat either 1200 or 2400, as described previously.

Melatonin analysis.Arterial plasma melatonin levels were mea-sured by radioimmunoassay (rat melatonin125I-radioimmunoas-say kit, Alpco, Salem, NH; lot 1429.18, prepared by BhlmannLaboratories AG, Schnenbuch, Switzerland) and analyzed byusing an automated gamma counter (Cobra 5005, Packard, PaloAlto, CA) as previously described.21,22,24The minimal level of de-tection for the assay was 1 to 2 pg/mL plasma.

ELISA analysis of corticosterone, insulin, and leptin.Arterialplasma samples were prepared in duplicate for measurement ofcorticosterone, insulin, and leptin levels by using chemilumines-cent ELISA diagnostic kits (ALPCO; corticosterone: catalog no.55-CORMS-E01; mouse or rat; protocol version 4/09/11ALPCO9/13/11); insulin: catalog no. 80-INSRTH-E01; rat, high range;protocol version 2.0ALPCO 12/2/11); and leptin: catalog no.22-LEPMS-E01; mouse or rat; protocol version 030112 version10ALPCO 2/29/2012). Samples were measured at 450 nM byusing a microplate reader (VersaMax, Molecular Devices, Sunny-vale, CA). The detection sensitivity for corticosterone, insulin, andleptin plasma analyses were 4.5 ng/mL, 0.124 ng/mL, and 10 pg/mL, respectively; the lower limits of the assays were 15 ng/mL,0.15 ng/mL, and 10 pg/mL, respectively; and the coefficient ofvariation of all assays was less than 4.0%.

the 4 positions, did not differ among positions, the daily cage shiftfurther ensured uniformity of intensity of ocular light exposureand accounted for the effects of any unforeseen subtle differencesdue to position on the rack shelf.

According to current convention, when discussing human andlaboratory animal environments, we use the term lux to indicate

the amount of light falling on a surface that stimulates the mam-malian eye during daytime (that is, the perceived brightness tothe eye [photometric values]). Measures of lux are appropriatefor human daytime vision but are not appropriate for quantify-ing light stimuli that regulates circadian, neuroendocrine or neu-robehavioral physiology in animals or humans.9,11Consequently,radiometric values of irradiance (W/cm2), a measure of radiantpower or density over a defined bandwidth of light, were mea-sured in the cages by using the same equipment and system as forilluminance. Given these standards, we present the light stimuliin the current investigation in terms of both lux and W/cm2forease of understanding.

Spectral transmittances were quantified by using a handheld

spectroradiometer (ASD FieldSpec, ASD, Boulder, CO). Spectralpower distributions, a measure of the concentration (as a functionof wavelength) of any radiometric quantity (that is, irradiancecompared with wavelength), were recorded when the meter waspointing directly at the overhead fluorescent lighting source andused for a comparison between cages. Pearson correlations wereperformed to determine similarities and differences of the spec-tral power distributions between cages. According to the irradi-ance measures, the correlation coefficient of the spectral powerdistributions from 380 nm to 760 nm was determined. As a moredetailed method of analysis, the spectral power distribution wasdivided into 100-nm bins (that is, 400 to 500 nm), and Pearsoncorrelations were determined between cage conditions. In addi-

tion, we calculated weighted retinal photopigment illuminances(measured in lx) for rats on the basis of the integrated output ofthe S and M cones, rods, and ipRGC regulating nonvisual physi-ology and behavior.49

Calculation of effective rod, cone, and melanopsin photore-ceptor illuminances.To calculate the effective rodent rod, coneand melanopsin photoreceptor illuminances, the spectral powerdistributions of the clear- and blue-cage transmissions were en-tered into a Toolbox worksheet (this software model for rodentphotoreception is freely available online).52The spectral powerdistributions for the experiments shown here were importedinto the worksheet in 1-nm increments between 325 and 782 nm.The spectral range available in Toolbox extends down to 298

nm. However, because the light output from a standard 4000-Kfluorescent bulb at wavelengths below 325 nm approaches 0, allvalues between 298 and 325 nm were set to 0. According to the in-structions for Toolbox, all raw spectral power distribution valuesthat were negative were manually changed to 0.

Arterial blood collection.After a 2-wk exposure to the de-scribed lighting regimens, rats underwent a series of 6 low-volume blood draws by cardiocentesis to collect left ventriculararterial blood4-6,17-19,21-25over a period of 30 d. Briefly, blood collec-tions were designated at 4-h intervals to include the 24-h feedingperiod; each rat was tested only once every 5 d to eliminate the ef-fects of feeding, stress, and potential mortality. Samples of wholeblood were collected for the measurements of pH, pO

2, pCO

2,

glucose, and lactate levels and Hct (iSTAT1 Analyzer with CG4+and CG8+ cartridges, Abbott Laboratories, East Windsor, NJ). Val-

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were assessed by using an unpaired Student ttest. Differencesin the slopes of regression lines (that is, tumor growth rates) be-tween groups were determined by linear regression analysis andtests for parallelism (Student ttest). Differences among the groupmeans were considered statistically different at a P value of 0.05.

ResultsAnimal-room illumination and cage spectral transmittance.

Animal room illumination during the daytime at the center ofthe room and at 1 m above the floor (with the detector facingupward toward the luminaires) varied minimally (n= 252 mea-surements) and was 425.93 16.43 lx (174.63 6.73 W/cm2).Measurements of photometric illuminance (lux) and radiometricirradiance (W/cm2) from outside and inside the front of eachcage (Figure 1) showed little to no intercage variability, and theaveraged values (n= 294 measurements) for clear and blue cages,respectively, were 133.37 7.41 lx (54.68 3.04 W/cm2) outsideand at the front of the cage and 91.31 2.21 lx (37.44 0.91 W/cm2) inside and at the front of the cage. Spectral power distribu-tions of light measured through the wall of these cages are shownin (Figure 2). The data are typical of this fluorescent-lamp type,with signature peaks in the appropriate wavelengths. Differencesin the amplitude of these peaks are apparent between cage types.The blue cage contained the highest peak amplitude in the shorter(400 to 550 nm) wavelength segments. As expected, in the lon-ger wavelength ranges (550 to 700 nm), there was a shift in peakamplitude, with the clear cage demonstrating larger peak ampli-tudes than those of the blue cage at wavelengths longer than 550nm. The Pearson correlation coefficient between cage conditionsdid not demonstrate a significant difference, given the linearityof the curves.

(Table 1) provides the calculated photon densities, irradiances,

and weighted rodent photopigment illuminances for the standardwhite fluorescent light transmitted through the clear and bluerodent cages (Figure 1). The data illustrate that the blue plasticattenuates both the transmission of both total photon flux and ir-radiance.52In contrast, the light transmitted through the blue plas-tic cage to the rodents inside has a higher capacity for stimulatingeach of the rodent photoreceptors (Table 2). Measurements madein the animal room and within the cages of both groups duringthe dark phase were 0 lx (0 W/cm2).

Animal food and water intakes and growth measurements.Foodand water intakes and body growth rates did not differ signif-icantly between the rats maintained in either the clear or bluecages during the course of this study and are reported here as the

combined means. Values for rats in both groups of the presentstudy were in good agreement with those determined for healthyyoung male Hsd:RH-Foxn1rnunude rats in previous investiga-tions.20Mean (n= 90 measurements) daily dietary intake was21.14 0.64 g daily, and water intake was 29.87 0.86 mL daily.The mean (n= 83 measurements per group) body growth ratewas 3.88 0.28 g daily.

Plasma melatonin levels.Circadian rhythms in concentrationsof plasma melatonin for rats in clear and blue cages (n= 12 pergroup) prior to xenograft implantation are shown in (Figure 3).The overall pattern of daily plasma melatonin level rhythms wassimilar for both groups: low during daytime (less than 10 pg/mL)and significantly (P

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clear (control) cages. A phase advance was defined as a shift ina group peak level to an earlier time (for example, from 1600 to1200), whereas a phase delay was defined as a shift in a groupto a later time (for example, from 0800 to 1200), as compared withcontrol values. Daily rhythms for arterial glucose and lactate con-centrations (Figure 5 A and B) were similar between groups, with

peaks for both constituents occurring at 1200 and 2000 for thecontrol rats but phase-advanced 4 h at 0800 in the experimentalgroup. However, values over the 24-h day were higher (P

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was delayed by more than 90% in rats in blue cages (day 46 afterimplantation) compared with control rats (day 24).

Tumor A-V measurements.We tested whether tumor xenograftsthemselves exhibited differences in cAMP levels, TFA and LAuptake, 13-HODE release, [3H]thymidine incorporation into tu-mor DNA, and Warburg effect as a result of daytime blue-lightexposure and altered arterial plasma melatonin levels at the timeof harvest (Table 4). None of the tumor levels of these constit-uents in controls at 0800 differed from those of the experimen-

tal group at 1200, when arterial plasma melatonin levels werenot significantly different from one another and were at normalphysiologic daytime concentrations (greater than 3 pg/mL). Tu-mor cAMP levels, TFA and LA uptake, 13-HODE release, [3H]thymidine incorporation into tumor DNA at 0800 were decreasedsignificantly (P

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els were lowest in rats in blue-tinted cages (1200), compared withthose of animals in both clear and blue cages at 0800 and 2400.

DiscussionGiven our previous observation that the spectral transmittance

of blue-appearing light during the daytime markedly augmentsthe peak amplitude of the nocturnal circadian melatonin signalin male nude rats and circadian rhythms of plasma measures ofmetabolism and physiology,19,61we tested the hypothesis that thedaytime exposure of these rats to blue light similarly enhances

melatonin-induced suppression of PC3 human prostate cancerxenograft metabolism, signaling activity, and growth progres-

keeping protein -actin in human prostate tumor xenografts.5Phosphorylated forms of AKT, GSK3, ERK 1/2, and CREB weredecreased in the presence of melatonin in the arterial blood of tu-mors harvested at 0800 (greater than 30 pg/mL) and 2400 (greaterthan 900 pg/mL) from rats in blue-tinted cages compared withthe levels of these constituents when exposed to normal daytimelevel of melatonin (less than 10 pg/mL) in control tumors har-vested at 0800, whereas total protein concentrations were eithersimilar (AKT, NFB, GSK3, and CREB) between groups or el-evated (PDK1) in rats in blue compared with clear cages. Concen-

trations of phosphorylated and total forms of AKT, NF

B, GSK3

,ERK 1/2, CREB, and PDK1 were all elevated when melatonin lev-

Figure 3.Diurnal plasma melatonin levels (pg/mL; mean 1 SD) of male pigmented nude rats (n= 12 per group) maintained for 6 wk in standardpolycarbonate, translucent, clear cages (control; solid red circles) or blue cages (experimental; solid blue squares) under 12:12-h photoperiods. Bothgroups were exposed similarly during the light phase (300 lx, 123 W/cm2); during the 12-h dark phase (1800 to 0600; dark bars), rats had no exposureto light. Data are plotted twice to better demonstrate rhythmicity (panel A) and clarity of scale (panel B). Rhythmicity analysis (Table 3) revealed robustand highly significant (P

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be completely ruled out as a contributing factor. Interestingly, thehigh melatonin concentrations achieved early in the dark phase(at 2000) were equivalent to the peak levels reached 4 h later inthe control group during the middark phase (at 2400). Moreover,the markedly elevated nocturnal melatonin levels persisted be-yond the dark phase into the light phase (0800) by at least 4 h,

because they were still 30-fold higher than those in the controlsat the same circadian time point. Therefore, the early and robustnocturnal rise in melatonin coupled with its high concentrationswell into the light phase prolonged the duration of the melatoninsignal and, in effect, extended the length of the biological nightinto the daytime period. One might speculate that the extensionof elevated melatonin titers into the light phase could have beenattributed to slower hepatic melatonin metabolism relative topineal melatonin production. Because light has a gating effect onpineal melatonin synthesis, melatonin levels would have been ex-pected to plummet in response to lights-on at 0600 if the extendedmelatonin duration was due exclusively to persistent, albeit, di-minishing pineal melatonin production.

With the exception of the circadian rhythm for blood TFA, in-cluding LA levels, all physiologic and metabolic rhythms in hostanimals (prior to tumor implantation) were changed to a lesser orgreater degree in response to the altered spectral transmittance oflight of bright, blue-appearing light compared with broad-spec-trum light during the light phase. Depending on the circulatingfactor measured, the alterations included changes in rhythm am-plitude, phasing, or duration or combinations of these circadianrhythm characteristics. These altered rhythms appeared to becompletely independent from those generated by the suprachi-asmatic nucleus in the dietary intake of TFA, which were nearlyidentical for both the control and experimental groups, indicatingthat the phasing of overall rhythmicity of the suprachiasmatic

nucleus was intact and unaffected by short wavelengths duringthe light phase. This inference is further corroborated by the factthat although the melatonin amplitudes were markedly different,the acrophases of the suprachiasmatic-nucleusdriven melatoninrhythms in both groups were identical.

In rats exposed to blue light, circadian oscillations in arterialplasma glucose and lactate levels and in arterial pO

2and pCO

2

were, in general, phase-advanced by 4 h, whereas overall 24-hintegrated levels were decreased, as previously observed in fe-male nude rats,19suggesting lower rates of basal metabolism inthese animals as compared with the control group. Similarly,circadian variations in the phasing, amplitude, and duration ofcorticosterone, insulin, and leptin, which all have crucial effects

on whole-animal metabolism, were altered in response to expo-sure to daytime short wavelengths, again corroborating the samechanges in these parameters demonstrated in our previous studyin nude female rats.19

Melatonin exerts regulatory effects on glucose and lactate me-tabolism as well as on corticosterone, insulin, and leptin levelsin humans9,43,54and rats.18,27,42,47,48 Arguably, the marked circadianchanges in melatonin levels in rats exposed to blue light mayhave been responsible for some of the circadian changes in thesehormones as observed in the present study in nude male rats andour previous study in female nude rats. This contention is furthersupported, in part, by our previous observations in nude rats19,22,24that the spectral transmittance of longer wavelength light througheither amber- or red-tinted cages resulted in circadian melatoninas well as metabolic and hormonal profiles that markedly differed

sion. This study is the first to show that long-term exposure ofPC3 prostate cancer-bearing nude male rats to supra-physiologicnighttime melatonin levels induced by blue-appearing light dur-

ing the daytime resulted in a marked downregulation of tumorcAMP levels, LA uptake, 13-HODE production, the Warburg ef-fect (for example, glucose uptake and lactate production), rel-evant signal transduction pathways (for example, cAMP, CREB,AKT, ERK 1/2, GSK3, NFB, and PDK1), and cell proliferativeactivity that culminated in tumor growth rates that were sub-stantially slower (for example, more than 50%) than those of xe-nografts inhibited by the normal physiologic melatonin signal.

The apparent paradox of bright blue light during the day stim-ulating a nearly 6-fold increase in the peak amplitude (approxi-mately 900 pg/mL) of the nocturnal plasma melatonin surge overthe normal nocturnal melatonin peak (approximately 150 pg/mL) both in the present and our previous study 19is not withoutprecedent. For example, other investigators noted similar find-ings in nocturnal pineal levels of melatonin in male rats exposedto bright sunlight (rich in blue wavelengths) over a 13-h day, ascompared with the light emitted by cool-white fluorescent lu-minaires in an animal room for the same period of time duringthe day.4,7The underlying mechanism, however, by which eitherlight spectral transmittance (wavelength) or intensity during thelight phase induces enhanced melatonin production during thesubsequent dark phase of a 24-h day is unknown. In addition,decreased long wavelength (red) was seen during the blue-tintedspectral power distribution measurements (Figure 2) and cannotbe ruled out as a causative factor. The remarkably high nocturnallevels of circulating melatonin concentrations observed here arepresumably due to a stimulation of melatonin synthesis, albeit aconcomitant inhibition of hepatic melatonin metabolism cannot

Figure 4.Diurnal changes in the blood plasma total fatty (TFA) and li-noleic (LA) levels (g/mL; mean 1 SD) of male pigmented nude rats(n= 12 per group) with unrestricted access to normal chow and main-tained on either control (TFA, solid black circles; LA, solid red trian-gles) or experimental (TFA, solid blue squares; LA, solid inverted ambertriangles) lighting conditions. Rats were exposed to dark-phase light-ing conditions (see Methods) from 1800 to 0600 (dark bars). TFA values(mean 1 SD; n= 12 per group) are the sums of myristic, palmitic, pal-mitoleic, stearic, oleic, linoleic, and arachidonic acid concentrations col-lected at the various time points. Data are plotted twice to better dem-onstrate rhythmicity. Rhythmicity analysis (Table 3) revealed robust andhighly significant (P

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occurs during the light phase. Exposure of tumor-bearing ratsto dim light at night suppresses melatonin production nearlycompletely, resulting in the further activation of signaling, me-tabolism, and cell proliferation 24 h daily, thus culminating in a

more than 2-fold increase in tumor growth rates.5,7,18,21,50,61Con-versely, in the current investigation, the marked suppression ofprostate cancer metabolism, signaling, and growth in responseto short wavelength light probably can be attributed primarilyto the rapid early dark-phase increase and extended duration ofthe nocturnal melatonin signal rather than to its exaggeratedpeak amplitude. The strong suppression of tumor growth andmetabolism was most likely due to the prolonged presence oftumor-inhibitory blood levels of melatonin rather than to its in-creased amplitude (nearly 5 nM) and is supported by the fact thatthe inhibition of tumor proliferative activity and metabolism bymelatonin during short-term tumor perfusion in situ saturates atapproximately 1 nM (that is, 232 pg/mL).7Perhaps the enhanced

tumor inhibition would not have occurred in the same way hadthe xenografts been exposed to a longer duration of elevated noc-

from the circadian profiles seen here and in our previous blue-light study.19This pattern suggests that each circadian responseis dependent on exposure to a specific wavelength as conveyedto peripheral tissues by a corresponding wavelength-dependent

melatonin signature. Because the exact mechanism by which thiseffect might occur is unknown, other wavelength-dependent butmelatonin-independent factors that influence circadian hormonaland neural outputs from the suprachiasmatic nucleus should beconsidered.

We have previously demonstrated that the normal physiolog-ic nocturnal blood concentrations of melatonin that peak duringthe middark phase under 12:12-h light:dark conditions in animalrooms are sufficient to significantly slow the rates of cell prolifera-tion and overall growth of human breast cancer xenografts, whichare characteristically rapid during the daytime in the presence ofwhite fluorescent light.5,22This effect occurs via the ability of thephysiologic nocturnal melatonin signal to stymie the increased

activation of tumor signal transduction activity, LA uptake andmetabolism to 13-HODE, and the Warburg effect that normally

Figure 5.Diurnal changes in arterial blood (A) glucose, (B) lactate, (C) pO2, and (D) pCO

2levels (mean 1 SD; n= 12 per group) of male nude rats

maintained under either control (solid black circles) or experimental (solid blue triangles) lighting conditions. Rats were exposed to dark-phase light-ing conditions from 1800 to 0600 (dark bars). Data are plotted twice to better visualize rhythmicity. Rhythmicity analysis (Table 3) revealed robust andhighly significant (P

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Currently, a standardized, single measurement unit for quanti-fying light that regulates the circadian, neuroendocrine, and neu-robehavioral effects of light is not available. A recent consensusposition was developed across many of the laboratories that havestudied wavelength regulation of the biologic and behavioral ef-fects of light in rodents, humans, and other species for best prac-tices for measuring and reporting experimental light stimuli.49With that consensus, a freely available web-based toolbox52wasprovided that permits the calculation of the effective irradianceexperienced by each of the rodent ipRGC, cone, and rod photo-receptors that are capable of driving circadian, neuroendocrineand neurobehavioral effects.36It is interesting that the clear cagestransmit more total light to rats inside the cages but less effec-

tive stimulation to each of the retinal photoreceptors. Abundantdata have illustrated that the melanopsin-containing ipRGC areanatomically and functionally interconnected with the rods andcones that support vision. Physiologic responses to light reflectinput from all of the retinal photoreceptor classes, with the rela-tive importance of each being labile within and between responsetypes. Therefore, the spectral sensitivity of this photoreceptivesystem is fundamentally context-dependent.1,16,30,32,33,35,41,42,48,49,53,61It is important for different groups of investigators to use com-monly accepted metrics for reporting spectral response functionsto be able to pool results, such as those shown in Table 1. As datausing this measurement system accumulate from different labo-ratories, it will become possible to generate testable hypotheses

that predict the spectral characteristics for a targeted physiologicresponse to light.Light intensity, spectral quality, and duration are of para-

mount importance in regulation of mammalian circadianrhythms. Variations in any of these parameters affect virtuallyevery biologic process associated with animal physiology andmetabolism. The nocturnal melatonin signal represents the in-ternal zeitgeber responsible for normal host circadian rhythmsof metabolism, as well as tumor rhythms in metabolism, sig-naling, and proliferation. The present investigation providescompelling evidence for the hypothesis that supraphysiologicnocturnal levels of melatonin, as evinced in rats exposed to bluespectrum light during the daytime, may contribute to the circa-

dian reorganization of the host metabolic and hormonal milieuas they greatly enhance the suppression of tumor metabolism,

Figure 6.Diurnal changes in plasma (A) corticosterone, (B) insulin, and(C) leptin concentrations (mean 1 SD; n= 12 per group) in the arterialblood of rats maintained on either control (solid black circles) or experi-mental (solid blue squares) lighting conditions. Data are plotted twiceto better demonstrate rhythmicity. Rats were exposed to dark-phaselighting conditions from 1800 to 0600 (dark bars). Rhythmicity analysis(Table 3) revealed robust and highly significant (P

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signaling activity, proliferative activity, and growth. Additionalstudies in both rats and human subjects are warranted to betterunderstand the potentially beneficial effects of daytime blue-light exposure and high nocturnal melatonin levels in the hostand the inhibition of human tumor metabolic signaling mecha-

nisms, metabolism, and proliferative activity that could leadto novel therapeutic interventions and/or cancer preventivemeasures.

AcknowledgmentsThis work was supported in part by a Tulane University School of

Medicine and Louisiana Cancer Research Consortium Startup Grant(no. 631455 to DEB) and by an American Association for LaboratoryAnimal Science Grants for Laboratory Animal Science Award (to RTDand DEB). Additional support for the Jefferson coinvestigators (JPH,BW, and GCB) was from The Institute for Integrative Health (Baltimore,MD) and the National Science Foundation (no. EEC-0812056 to GCB).We acknowledge and are grateful for the technical support of DrGeorgina Dobek, Ms Lynell Dupepe, Ms Patricia Beavers, and MrMichael Webb.

Table 4.Effects of daytime (0800 and 1200) and nighttime (2400) arterial blood plasma melatonin concentration on tumor cAMP level, TFA and LAuptake, 13-HODE production, and tumor [3H]thymidine incorporation and DNA content (mean 1 SD, n = 12) measured across PC3 human prostatetumor xenografts in situ

cAMP(nmol/g

tissue)

TFA uptake(g/min/g)(% of arterial

supply)

LA uptake(g/min/g)(% of arterial

supply)

13-HODE (ng/min/g)[3H]thymidineincorporation

(dpm/g DNA)

DNAcontent

(mg/g)

Plasmamelatonin

(pg/mL)

Arterial

supply

Venous

outputClear cages,

08001.295 0.078 6.61 1.08

(30.4% 2.3%)1.52 0.12

(31.0% 1.6%)not detectable 29.43 1.98 45.6 1.5 3.2 0.1 1.50 0.40

Blue cages,0800

0.758 0.041 2.01 0.28a(9.0% 1.2%)

0.74 0.11a(10.1% 1.2%)

not detectable 15.33 0.99a 23.2 1.4a 2.8 0.07a 31.24 2.34a

Blue cages,1200

1.307 0.085a,b 5.60 1.81a,b(31.7% 2.9%)

1.54 0.25a,b(31.0% 2.5%)

not detectable 30.86 2.31b 46.2 1.7b 3.2 0.1b 7.79 1.81a,b

Blue cages,2400

0.394 0.058a,b,c 0.05 0.06a,b,c(0.02% 0.03%)

0.02 0.03a,b,c(-0.2% 0.3%)

not detectable not detectablea,b,c 5.6. 1.0a,b,c 2.80.09a,b,c 968.3 102.2a,b,c

Tumor weight, 7.40 + 0.28 g.aP

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