Jenny-Anne Sigstad Lie

Night shift work characteristics and 6-sulfatoxymelatonin (MT6s) in rotating night shift nurses and midwives

Objectives Synthesis of melatonin follows a circadian cycle, with high melatonin levels during the night and low levels during the day. Light exposure at night has been hypothesised as one of potential mechanisms of breast carcinogenesis in the night shift workers through inhibition of melatonin synthesis. The aim of the study was to examine a number of determinants for night shift work in relation to 6-sulfatoxymelatonin (MT6s), primary melatonin metabolite. Methods The cross-sectional study included 354 nurses and midwives (aged 40–60 years) currently working on rotating night shifts and 370 working days only. Data from questionnaires and 1-week diaries were used to characterise current job and total occupational history. Associations between rotating night shift work characteristics and MT6s (creatinine adjusted) in spot morning urine were tested in multiple linear regression models. Results No significant differences were found for MT6s concentrations between women currently working on rotating night shifts and those working only day shifts (means 47.2 vs 45.7 ng/mg Cr, respectively). The adjusted means among rotating night shift nurses and midwives varied depending on the department of employment, from 35.1 ng/mg Cr in neonatology to 68.2 ng/mg Cr in the orthopaedics department. Women working eight or more night shifts per month had significantly lower MT6s levels than those having fewer night shifts per month (37.9 vs 47.4 ng/mg Cr, respectively). Total night shift work history was not associated with MT6s. Conclusions The results of this study indicate that working eight or more night shifts per month may disrupt the synthesis of melatonin.

Rotating night shift work and polymorphism of genes important for the regulation of circadian rhythm.

OBJECTIVE People living in industrialized societies have developed specific working schedules during the day and at night, including permanent night shifts and rotating night shifts. The aim of this study was to examine the association between circadian polymorphisms and rotating night shift work. METHODS This cross-sectional study comprised 709 nurses and midwives (348 current rotating and 361 current day workers). Genetic polymorphism of selected clock genes BMAL1 (rs2279287), CLOCK (rs1801260), PER1 (rs2735611), PER2 (rs2304672), PER3 (rs10462020), CRY1 (rs8192440), CRY2 (rs10838527, rs10838527) was determined using real-time polymerase chain reaction (PCR) assays. RESULTS There were no differences in BMAL1, CLOCK, CRY2, PER1, PER2, and PER3 genotypes among nurses and midwives working rotating night and day shifts. The frequency of women with rare CRY1 TT genotype was higher in the group of rotating night shift than day workers (17.0% versus 13.9%, P=0.06). Moreover, CRY1 TT genotype was associated with the total rotating shift-work duration, compared to women rarely working night shifts. CONCLUSIONS These results suggest that CRY1 (rs8192440) polymorphism may influence the adaptation to the rotating night shift work among nurses and midwives.

Circadian gene expression in peripheral blood leukocytes of rotating night shift nurses

OBJECTIVE It has been hypothesized that the underlying mechanism of elevated breast cancer risk among long-term, night-working women involves circadian genes expression alteration caused by exposure to light at night and/or irregular work hours. The aim of the present study was to determine the effect of rotating night shift work on expression of selected core circadian genes. METHODS The cross-sectional study was conducted on 184 matched nurses and midwives, who currently work either day or rotating night shifts, to determine the effect of irregular work at night on circadian gene expression in peripheral blood leukocytes. Transcript levels of BMAL1, CLOCK, CRY1, CRY2, PER1, PER2, and PER3 were determined by means of quantitative real-time polymerase chain reaction (PCR). RESULTS After adjusting for hour of blood collection, there were no statistically significant changes of investigated circadian genes among nurses and midwives currently working rotating night shifts compared to nurses working day shifts. The highest expression of PER1 messenger ribonucleic acid (mRNA) was observed for women currently working shifts who had worked >15 years in rotating night shift work. PER1 gene expression was associated with the lifetime duration of rotating night shift work among women currently working night shifts (P=0.04). PER1 and PER3 transcript levels in blood leukocytes were significantly down-regulated in the later versus early hours of the morning between 06.00-10.00 hours (β-coefficient -0.226, P=0.001 and β-coefficient -0.181, P<0.0001, respectively). CONCLUSIONS These results suggest that current rotating night shift work does not affect circadian gene expression in human circulating leukocytes. In analysis of the peripheral clock in human studies, the hour of blood collection should be precisely specified.

Mechanisms of breast cancer risk in shift workers: association of telomere shortening with the duration and intensity of night work

Occupational factors such as shiftwork and especially night work that involves disruption of the circadian rhythm may contribute to increased breast cancer risk. Circadian disruption may also affect telomere length (TL). While short TL generally is associated with increased cancer risk, its association with breast cancer risk is inconclusive. We suggest that working schedules might be an important factor in assessment of effects of TL on breast cancer risk. Moreover, telomere shortening might be a potential mechanism for night work‐related breast cancer. In this study, effects of shift work on TL and its association with breast cancer risk were investigated in a nested breast cancer case–control study of Norwegian nurses. TL was assessed by qPCR in DNA from 563 breast cancer patients and 619 controls. Here, we demonstrate that TL is affected by intensive night work schedules, as work with six consecutive night for a period of more than 5 years was associated with decreased telomere lengths (−3.18, 95% CI: −6.46 to −0.58, P = 0.016). Furthermore, telomere shortening is associated with increased breast cancer risk in workers with long periods of consecutive night shifts. Thus, nurses with longer telomere lengths had a lower risk for breast cancer if they had worked more than four (OR: 0.37, 95% CI: 0.16–0.79, P = 0.014) or five (OR: 0.31, 95% CI: 0.10–0.83, P = 0.029) consecutive night shifts for a period of 5 years or more. These data suggest that telomere shortening is associated with the duration and intensity of night work and may be a contributing factor for breast cancer risk among female shift workers.

Mechanisms of Breast Cancer in Shift Workers: DNA Methylation in Five Core Circadian Genes in Nurses Working Night Shifts

Shift work has been suggested to be associated with breast cancer risk, and circadian disruption in shift workers is hypothesized as one of the mechanisms of increased cancer risk. There is, however, insufficient molecular evidence supporting this hypothesis. Using the quantitative methodology of pyrosequencing, epigenetic changes in 5-methyl cytosine (5mC) in five circadian genes CLOCK, BMAL1, CRY1, PER1 and PER2 in female nurses working night shift work (278 breast cancer cases, 280 controls) were analyzed. In breast cancer cases, a medium exposure to night work was associated with increased methylation levels of the CLOCK (p=0.050), BMAL1 (p=0.001) and CRY1 (p=0.040) genes, compared with controls. Within the cases, analysis of the effects of shift work on the methylation patterns showed that methylation of CRY1 was lower in those who had worked night shift and had a high exposure (p=0.006) compared with cases that had worked only days. For cases with a medium exposure to night work, an increase in BMAL1 (p=0.003) and PER1 (p=0.035) methylation was observed compared with day working (unexposed) cases. The methylation levels of the five core circadian genes were also analyzed in relation to the estrogen and progesterone receptors status of the tumors in the cases, and no correlations were observed. Furthermore, nineteen polymorphisms in the five circadian genes were assessed for their effects on the methylation levels of the respective genes, but no associations were found. In summary, our data suggest that epigenetic regulation of CLOCK, BMAL1, CRY1 and PER1 may contribute to breast cancer in shift workers.

Night shift work and other determinants of estradiol, testosterone, and dehydroepiandrosterone sulfate among middle-aged nurses and midwives

OBJECTIVES The aims of our study were to (i) investigate the association between rotating night shift work and blood concentrations of estradiol, testosterone and dehydroepiandrosterone sulfate (DHEAS) and (2) evaluate the role of their non-occupational determinants. METHODS A cross-sectional study was conducted on 345 premenopausal and 187 postmenopausal nurses and midwives (263 women working rotating night shifts and 269 women working during days). Data from in-person interviews were used, anthropometric measurements were performed, and body mass index (BMI) and waist- to-hip ratio were calculated. Morning blood and spot urine samples were collected. Multiple linear regression models were fitted with hormone concentrations as dependent variables, and night shift work characteristics and demographic, reproductive, lifestyle and anthropometric determinants as independent variables. Modification of the effect by chronotype was examined. RESULTS Among postmenopausal women, we observed a statistically significant positive association between the total duration of night shift work >15 years and estradiol level (P<0.05 when compared to night work duration <5 years). Night shift work characteristics were significantly associated with estradiol among morning-type postmenopausal women. The well-established associations between hormones and their major determinants, such as age and BMI, were confirmed. CONCLUSIONS The findings of our study imply that prolonged night shift work may be associated with increased estradiol levels among postmenopausal women, especially among the morning-type postmenopausal women.

Fluctuations in heart rate variability of health care workers during four consecutive extended work shifts and recovery during rest and sleep

The aim of this study was to investigate fluctuations in heart rate variability (HRV), which reflect autonomic nervous system (ANS) function and potential psychological and physical strain, among 24 health care workers during work and sleep during four consecutive extended work shifts. Data included 24/36/12 h of HRV measurements, two logbooks, and a questionnaire. A cross-shift/cross-week design was applied. HRV was measured during work, leisure time, and sleep. The HRV data included time-domain [mean RR, SD of normal to normal R-R intervals (SDNN), and root mean square of the successive differences (RMSSD)] and frequency-domain [low frequency (LF)/high frequency (HF) ratio] parameters. HRV parameters revealed significant differences among work, leisure time, and sleep. Mean RR, RMSSD, and SDNN values were lower and the LF/HF ratio was higher on the first versus last day of the work period; however, the differences were most prominent in the morning hours. The results indicate higher levels of cardiovascular stress on the first versus fourth day of the working period, and measurements at night indicate a satisfactory recovery from the extended shifts.

Characteristics of rotating night shift work and morning 6-sulfatoxymelatonin in nurses and midwives

Objectives 6-sulfatoxymelatonin (MT6s) in the morning urine is a valid biomarker of melatonin synthesis at night. Controlled experimental studies have shown decrease in melatonin synthesis after light exposure at night, however, only few epidemiological studies examined morning MT6s in nurses working rotating night shifts. The aim of our study was to investigate which characteristics of rotating night shift work influence melatonin synthesis. Methods The cross-sectional study included 355 nurses and midwives (aged 40–60) currently working on rotating night shifts. Data on the current job (hospital department, frequency of night shifts, activities, napping) and potential confounders were collected through a personal interview. MT6s concentrations were determined in the morning urine samples after night shift (ELISA assay, adjusted for creatinine). Associations between rotating night shift work characteristics and MT6s were tested in multiple linear regression models. Results The adjusted geometric means (GM) in the rotating night shift nurses and midwives varied depending on the department of employment from GM=32 ng/mg Cr at the neonatology department to GM=72 ng/mg Cr) at the orthopaedics department. Women working 8 or more night shifts per month had significantly lower MT6s than those having on average less night shifts per month (35 ng/mg Cr vs 43 ng/mg Cr respectively). MT6s concentrations were significantly lower in women working for more than 10 h when compared to those working fewer hours (p=0.025). Conclusions Preliminary results of our study indicate that the frequency of night shifts and number of working hours may influence MT6s levels.

Record linkage in occupational cancer studies

Record linkage studies have been used for decades to study occupational diseases and mortality. While low response rates represent an increasing problem in connection with sample surveys, response rates at censuses in the Nordic countries are close to 100%. The linking of census data with data about mortality, emigration and cancer by the unique personal identification numbers, ensures complete information on relevant events. Results from a large census-based Nordic study on cancer incidence by occupation are presented, and advantages and problems related to such type of studies are discussed. In record linkage studies occupational group, socio-economic status or any other characteristic may be used as the exposure indicator. The results of such studies usually must be interpreted in light of established etiologic associations. The two main purposes with record linkage studies are that they may be used as reference material in the general description of cancer incidence and distribution in a population, and that they serve as a basis for generation of hypotheses to be tested in analytical studies with more detailed information.