Sleep interruption associated with house staff work schedules alters circadian gene expression.
BACKGROUND
Epidemiological studies indicate that disruption of circadian rhythm by shift work increases the risk of breast and prostate cancer. Our studies demonstrated that carcinogens disrupt the circadian expression of circadian genes (CGs) and circadian-controlled genes (CCGs) during the early stages of rat mammary carcinogenesis. A chemopreventive regimen of methylselenocysteine (MSC) restored the circadian expression of CGs and CCGs, including PERIOD 2 (PER2) and estrogen receptor β (ERS2), to normal. The present study evaluated whether changes in CG and CCG expression in whole blood can serve as indicators of circadian disruption in shift workers.


METHODS
Fifteen shift workers were recruited to a crossover study. Blood samples were drawn before (6 PM) and after (8 AM) completing a night shift after at least seven days on floating night-shift rotation, and before (8 AM), during (1 PM), and after (6 PM) completing seven days on day shift. The plasma melatonin level and messenger RNA (mRNA) expression of PER2, nuclear receptor subfamily 1, group d, member 1 (NR1D1), and ERS2 were measured, and the changes in levels of melatonin and gene expression were evaluated with statistical analyses.


RESULTS
The mRNA expression of PER2 was affected by shift (p = 0.0079); the levels were higher in the evening for the night shift, but higher in the morning for the day shift. Increased PER2 expression (p = 0.034) was observed in the evening on the night versus day shifts. The melatonin level was higher in the morning for both day shifts (p = 0.013) and night shifts (p <0.0001).


CONCLUSIONS
Changes in the level of PER2 gene expression can serve as a biomarker of disrupted circadian rhythm in blood cells. Therefore, they can be a useful intermediate indicator of efficacy in future MSC-mediated chemoprevention studies.
Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Piscataway, NJ, USA; National Institute for Environmental Health Sciences (NIEHS) Center for Environmental Exposures and Disease, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, USA; Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Ming Zhu
MZ
Fang
National Institute for Environmental Health Sciences (NIEHS) Center for Environmental Exposures and Disease, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, USA; Department of Biostatistics, School of Public Health, Piscataway, NJ, USA.
Pamela
P
Ohman-Strickland
Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Piscataway, NJ, USA; National Institute for Environmental Health Sciences (NIEHS) Center for Environmental Exposures and Disease, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, USA.
Kathie
K
Kelly-McNeil
Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Piscataway, NJ, USA; National Institute for Environmental Health Sciences (NIEHS) Center for Environmental Exposures and Disease, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, USA.
Howard
H
Kipen
Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Family Medicine, Robert Wood Johnson Medical School, Piscataway, NJ, USA.
Benjamin F
BF
Crabtree
Children's National Medical Center, Washington, DC 20010, USA.
Jenny Pan
JP
Lew
Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Piscataway, NJ, USA; National Institute for Environmental Health Sciences (NIEHS) Center for Environmental Exposures and Disease, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, USA; Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. Electronic address: zarbl@eohsi.rutgers.edu.
Helmut
H
Zarbl
D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D057906:Circadian Clocks; D002940:Circadian Rhythm / Q000502:physiology*; D018592:Cross-Over Studies; D005260:Female; D015870:Gene Expression; D006801:Humans; D007396:Internship and Residency; D008297:Male; D008550:Melatonin / Q000097:blood*; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020178:Sleep Disorders, Circadian Rhythm / Q000235:genetics*; D014940:Work Schedule Tolerance; D055815:Young Adult
D015415:Biomarkers; C421902:PER2 protein, human; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D008550:Melatonin
Biomarker; Breast cancer; Circadian rhythm; PERIOD 2; Shift worker