Moderate alcohol consumption and 24-hour urinary levels of melatonin in postmenopausal women.

CONTEXT: Low overnight urinary melatonin metabolite concentrations have been associated with increased risk for breast cancer among postmenopausal women. The Postmenopausal Women's Alcohol Study was a controlled feeding study to test the effects of low to moderate alcohol intake on potential risk factors for breast cancer including serum and urinary levels of hormones and other biomarkers. Previously, we observed significant increases in concentrations of serum estrone sulfate and dehydroepiandrosterone sulfate in participants after consumption of 15 or 30 g (one or two drinks) of alcohol per day. OBJECTIVE: In the present analysis, we evaluated the relationship of alcohol consumption with 24-h urinary 6-sulfatoxymelatonin (6-SMT) concentration (micrograms per 24 h). DESIGN AND PARTICIPANTS: Healthy postmenopausal women (n = 51) consumed a controlled diet plus each of three treatments (a nonalcoholic placebo beverage or 15 or 30 g alcohol/d) during three 8-wk periods in random order under conditions of weight maintenance. MEASURES: 6-SMT was measured in 24-h urine samples that were collected at entry into the study (baseline) and at the midpoint (4 wk) and end (8 wk) of each of the three diet periods. RESULTS: Concentration of 6-SMT was not significantly modified by the alcohol treatment after adjustment for body mass index, hours of sleep, daylight hours, and baseline level of 6-SMT. CONCLUSIONS: These results suggest that low to moderate daily alcohol consumption does not significantly affect 24-h urinary levels of melatonin among healthy postmenopausal women.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

In utero alcohol exposure increases mammary tumorigenesis in rats.

Findings in humans and animal models suggest that in utero hormonal and dietary exposures increase later breast cancer risk. Since alcohol intake by adult women consistently increases their breast cancer risk, we wondered whether maternal alcohol consumption during pregnancy increases female offspring's mammary tumorigenesis. In our study, pregnant female rats were pair-fed isocaloric diets containing either 0 (control), 16 or 25 g alcohol kg(-1) feed between days 7 and 19 of gestation. These alcohol exposures generate blood alcohol levels that correspond to low and moderate alcohol consumption and are lower than those that induce foetal alcohol syndrome. Serum oestradiol levels were elevated in pregnant rats exposed to alcohol (P<0.003). When adult, female offspring of alcohol-exposed dams developed significantly more 7,12-dimethylbenz[a]anthracene -induced mammary tumours, compared to the controls (tumour multiplicity; mean+/-s.e.m., controls: 2.0+/-0.3, 16 g alcohol: 2.7+/-0.4 and 25 g alcohol: 3.7+/-0.4; P<0.006). In addition, the mammary epithelial tree of the alcohol-exposed offspring was denser (P<0.004) and contained more structures that are susceptible for the initiation of breast cancer (P<0.001). Immunohistochemical assessment indicated that the mammary glands of 22-week-old in utero alcohol-exposed rats contained elevated levels of oestrogen receptor-alpha (P<0.04) that is consistent with the changes in mammary gland morphology. In summary, maternal alcohol intake during pregnancy increases female offspring's mammary tumorigenesis, perhaps by programming the foetal mammary gland to exhibit persistent alterations in morphology and gene expression. It remains to be determined whether an increase in pregnancy oestradiol levels mediated alcohol's effects on offspring's mammary tumorigenesis.

Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

[Light, melatonin and internal cancers - recent facts and research perspectives]. / Licht, Melatonin und innere Krebserkrankungen - Aktuelle Fakten und Forschungsperspektiven.

Visible light of sufficient intensity inhibits melatonin biosynthesis and numerous experimental studies suggest that melatonin may protect against cancer. From a public health point of view it is important to verify or falsify the hypothesis that artificial light - or even sunlight itself - suppresses melatonin production sufficiently to increase the risk of developing cancers of internal organs. Since humans are exposed universally, even small risk elevations could lead to numerous cases. Recent epidemiological studies of people exposed to anthropogenic light-at-night in the course of shift work and first evaluations of natural light experiments in blind people and in residents of the Arctic are compatible with the possibility that light can influence - at least hormone- dependent - cancer developments via melatonin. To systematically investigate the effect of geographically different light intensities on melatonin production in man, a pan-European study is suggested. Further epidemiological investigations can contribute to the understanding of the patho-physiological relationships between light, melatonin and human biology.

Residential magnetic fields, light-at-night, and nocturnal urinary 6-sulfatoxymelatonin concentration in women.

Exposure to 60-Hz magnetic fields may increase breast cancer risk by suppressing the normal nocturnal rise in melatonin. This 1994-1996 Washington State study investigated whether such exposure was associated with lower nocturnal urinary concentration of 6-sulfatoxymelatonin in 203 women aged 20-74 years with no history of breast cancer. Each woman was interviewed and provided data on the following for a 72-hour period at two different seasons of the year: 1) magnetic field and ambient light measured every 30 seconds in her bedroom, 2) personal magnetic field measured at 30-second intervals, and 3) complete nighttime urine samples on three consecutive nights. Lower nocturnal urinary 6-sulfatoxymelatonin level was associated with more hours of daylight, older age, higher body mass index, current alcohol consumption, and current use of medications classified as beta blockers, calcium channel blockers, or psychotropics. After adjustment for these factors, higher bedroom magnetic field level was associated with significantly lower urinary concentration of 6-sulfatoxymelatonin during the same night, primarily in women who used these medications and during times of the year with the fewest hours of darkness. These results suggest that exposure to nighttime residential 60-Hz magnetic fields can depress the normal nocturnal rise in melatonin.

Night shift work, light at night, and risk of breast cancer.

BACKGROUND: Exposure to light at night may increase the risk of breast cancer by suppressing the normal nocturnal production of melatonin by the pineal gland, which, in turn, could increase the release of estrogen by the ovaries. This study investigated whether such exposure is associated with an increased risk of breast cancer in women. METHODS: Case patients (n = 813), aged 20-74 years, were diagnosed from November 1992 through March 1995; control subjects (n = 793) were identified by random-digit dialing and were frequency matched according to 5-year age groups. An in-person interview was used to gather information on sleep habits and bedroom lighting environment in the 10 years before diagnosis and lifetime occupational history. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by use of conditional logistic regression, with adjustment for other potential risk factors. RESULTS: Breast cancer risk was increased among subjects who frequently did not sleep during the period of the night when melatonin levels are typically at their highest (OR = 1.14 for each night per week; 95% CI = 1.01 to 1.28). Risk did not increase with interrupted sleep accompanied by turning on a light. There was an indication of increased risk among subjects with the brightest bedrooms. Graveyard shiftwork was associated with increased breast cancer risk (OR = 1.6; 95% CI = 1.0 to 2.5), with a trend of increased risk with increasing years and with more hours per week of graveyard shiftwork (P =.02, Wald chi-squared test). CONCLUSION: The results of this study provide evidence that indicators of exposure to light at night may be associated with the risk of developing breast cancer.

Light in the built environment: potential role of circadian disruption in endocrine disruption and breast cancer.

Life in industrialized societies is primarily life inside buildings. Illumination from electric lighting in the built environment is quite different from solar radiation in intensity, spectral content, and timing during the 24-hour daily period. Humans evolved over millions of years with the day-night pattern of solar radiation as the primary circadian cue. This pattern maintained a 24-hour rhythm of melatonin release, as well as a host of other physiological rhythms including the sleep-wake cycle. Electric lighting in the built environment is generally more than sufficient for visual performance, but may be inappropriate for the maintenance of normal neuroendocrine rhythms in humans; e.g., insufficient during the day and too much at night. Lighting standards and engineering stress visual performance, whereas circadian function is not currently emphasized. The molecular biological research on the circadian clock and on mechanisms of phototransduction makes it clear that light for vision and light for circadian function are not identical systems. In particular, if electric lighting as currently employed contributes to 'circadian disruption' it may be an important cause of 'endocrine disruption' and thereby contribute to a high risk of breast cancer in industrialized societies.

Measuring temporal variability in residential magnetic field exposures.

Considerable interest has developed during the past ten years regarding the hypothesis that living organisms may respond to temporal variability in ELF magnetic fields to which they are exposed. Consequently, methods to measure various aspects of temporal variability are of interest. In this paper, five measures of temporal variability were examined: Arithmetic means (D(mean)) and rms values (D(rms)) of the first differences (i.e., absolute value of the difference between consecutive measurements) of magnetic field recordings; "standardized" forms of D(rms), denoted RCMS, obtained by dividing D(rms) by the standard deviations of the magnetic field data; and mean (F(mean)) and rms (F(rms)) values of fractional first differences. Theoretical investigations showed that D(mean) and D(rms) are virtually unaffected by long-term systematic trends (changes) in exposure. These measures thus provide rather specific measures of short-term temporal variability. This was also true to a lesser extent for F(mean) and F(rms). In contrast, the RCMS metric was affected by both short-term and long-term exposure variabilities. The metrics were also investigated using a data set consisting of twice-repeated two-calendar-day recordings of bedroom magnetic fields and personal exposures of 203 women residing in the western portion of Washington State. The predominant source of short-term temporal variability in magnetic field exposures arose from the movement of subjects through spatially varying magnetic fields. Spearman correlations between TWA bedroom magnetic fields or TWA personal exposures and five measures of temporal variability were relatively low. Weak to moderate levels of correlation were observed between temporal variability measured during two different sessions separated in time by 3 or 6 months. We conclude that first difference and fractional difference metrics provide specific and fairly independent measures of short-term temporal variability. The RCMS metric does not provide an easily interpreted measure of short-term or long-term temporal variability. This last result raises uncertainties about the interpretation of published studies that use the RCMS metric.

Characterisation of pea cytosolic glutathione reductase expressed in transgenic tobacco.

Expression in transgenic tobacco (Nicotiana tabacum L.) of a pea (Pisum sativum L.) GOR2 cDNA, encoding an isoform of glutathione reductase (GOR2), resulted in a 3- to 7-fold elevation of total foliar glutathione reductase (GR) activity. The enzyme encoded by GOR2 was confirmed to be extraplastidial in organelle fractionation studies and was considered most likely to be localised in the cytosol. A partial purification of GOR2 was achieved but a standard affinity chromatography step, using adenosine-2',5'-diphosphate-Sepharose and often employed in the purification of GR from diverse sources, was unsuccessful with this isoform. Preparative isoelectric focussing was employed as part of the purification procedure of GOR2 and a complete separation from plastidial/mitochondrial glutathione reductase (GOR1) was achieved. The isoform GOR2 was shown to have a slower migration on non-denaturing polyacrylamide gels compared with GOR1 and properties typical of GR enzymes from plant sources.

Alcohol consumption and urinary concentration of 6-sulfatoxymelatonin in healthy women.

Consumption of alcoholic beverages may suppress circulating melatonin levels at night, possibly resulting in an increase in circulating estrogen. An increased estrogen burden could increase the risk of breast cancer. This study was designed to investigate whether alcohol consumption is associated with a decrease in nighttime melatonin levels in a group of healthy women. A total of 203 randomly selected healthy women between the ages of 20 and 74 years were recruited for a broader study of the effects of exposure to power-frequency magnetic fields on nocturnal levels of urinary 6-sulfatoxymelatonin. For the purposes of this analysis, data collection consisted of the following during two seasons of the year: (1) an in-person interview, (2) a daily activity diary, and (3) nocturnal urine collection for each of 3 consecutive nights. We found that the nocturnal urinary concentration of the primary metabolite of melatonin (6-sulfatoxymelatonin) decreased in a dose-dependent manner with increasing consumption of alcoholic beverages in the preceding 24-hour period, after taking into account the independent effects on melatonin of age, hours of darkness, use of medications that affect melatonin levels, and body mass index. A categorical analysis revealed no effect of one drink, but a 9% reduction with two drinks, a 15% reduction with three drinks, and a 17% reduction with four or more drinks. It remains unknown whether such a change could affect estrogen levels or breast cancer risk.

A prospective study of estradiol and breast cancer in Japanese women.

Few studies have prospectively examined endogenous hormone levels as risk factors for breast cancer. The present study compares prediagnostic hormone levels using stored serum from breast cancer cases and controls selected from the Life Span Study population of the Radiation Effects Research Foundation in Hiroshima and Nagasaki, Japan. Stored serum samples collected in 1968-1970 were assayed for 72 women subsequently diagnosed with breast cancer and 150 control subjects in 72 case-control sets matched on age, date of blood collection, exposure, radiation dose, and city. Serum levels were determined for sex hormone binding globulin, total estradiol (E2), bioavailable E2, dehydroepiandrosterone sulfate, and prolactin. Matched case-control comparisons of hormone levels were carried out by conditional logistic regression and were adjusted for menopausal status at the time of blood drawing. The odds ratio per unit log change in bioavailable E2 was 2.2 [95% confidence interval (CI), 1.02-5.31 for all subjects, and 2.3 (95% CI, 0.55-6.8) and 2.1 (95% CI, 0.55-9.7), respectively, based only on premenopausal or postmenopausal serum. The estimated odds ratios in each quintile of bioavailable E2 level, using the lowest quintile as referent, were 1.00, 1.89, 1.43, 3.45, and 3.37 (P for trend = 0.035). For sex hormone binding globulin, the overall odds ratio was 0.58 (95% CI, 0.14-2.26), and 1.00 (95% CI, 0.19-5.45) and 0.21 (95% CI, 0.02-1.88) based on premenopausal and postmenopausal serum, respectively. This study offers further prospective support for the hypothesis that a high level of biologically available E2 is a risk factor for the subsequent development of breast cancer.

Hemochromatosis heterozygotes may constitute a radiation-sensitive subpopulation.

A primary mechanism of radiation-induced DNA damage is by generation of free radicals. Chronically increased oxidative stress from elevated levels of iron in the body may increase radiation sensitivity by decreasing cellular oxygen radical scavenging capability. Hemochromatosis heterozygotes have elevated body iron. Low-level radiation sensitization by iron may be particularly pertinent for risk of breast cancer. Since 10% of the population appears to be heterozygous for the hemochromatosis gene, a radiosensitizing effect would have pervasive implications.

Effect of constant light on DMBA mammary tumorigenesis in rats.

A study of light, and mammary tumorigenesis was conducted in rats. One-hundred female Sprague-Dawley rats were divided by weight into two groups. One group was exposed to constant light (LL) from 26 days of age, and the second group was exposed to 8 h light and 16 h dark per day (LD). Both groups received an 8 mg dose of a chemical carcinogen, dimethylben-zanthracene (DMBA) at 52 days of age. At 13 weeks post-DMBA, there were significantly fewer mammary tumors in the LL group compared with the LD group. Constant light was clearly demonstrated to have a profound effect on mammary tissue development. Although virgin, the majority of the LL rats (29/50) had gross evidence of lactation at 141 days of age. None of the LD rats (0/50) showed evidence of milk production. These results suggest that constant light not only substantially accelerated mammary gland development, but pushed development of the tissue past the stage normally observed in virgin animals (to the lactation stage).

Nocturnal 6-hydroxymelatonin sulfate excretion in female workers exposed to magnetic fields.

The objective of this study was to determine whether daytime occupational exposure to extremely low frequency magnetic fields (MFs) suppresses nocturnal melatonin production. Sixty female volunteers were recruited. Thirty-nine worked in a garment factory, and 21 office workers served as a reference group. Exposure assessment was based on the type of sewing machine used and MF measurements around each type of machine. Eye-level MF flux density was used to classify the operators to higher (>1 microT) and lower (0.3-1 microT) exposure categories. A third group of factory workers had diverse MF exposures from other sources. The reference group had average exposure of about 0.15 microT. Urine samples were collected on Friday and Monday for three consecutive weeks. Melatonin production was assessed as urinary 6-hydroxymelatonin sulfate (6-OHMS) excretion. The ratio of Friday morning/Monday morning 6-OHMS was used to test the hypothesis that melatonin production is suppressed after 4 days of occupational MF exposure with significant recovery during the weekend. Possible chronic suppression of melatonin production was evaluated by studying exposure-related differences in the Friday values by multivariate regression analysis. The Monday/Friday ratios were close to 1.0, suggesting that there is no increase in melatonin production over the weekend. The average 6-OHMS excretion on Friday was lower among the factory workers than in the reference group, but no monotonous dose-response was observed. Multivariate regression analysis identified MF exposure, smoking, and age as significant explanatory variables associated with decreased 6-OHMS excretion.

Morning urinary assessment of nocturnal melatonin secretion in older women.

We evaluated the feasibility of using morning urine samples in epidemiological studies aimed at clarifying the relationship between nocturnal melatonin levels and breast cancer risk. Initially, a laboratory-based study of 29 women (40- 70 yr old) was performed to examine the correlation between plasma melatonin levels in hourly nocturnal blood samples and both melatonin and its major enzymatic metabolite, 6-hydroxymelatonin-sulfate (6-OHMS) in morning urine samples. In a companion field study, morning urine samples were collected from 203 healthy women to assess similarities and differences in laboratory versus field measures. Taken together, our results indicate: 1) levels of melatonin and of creatinine-corrected 6-OHMS in the first morning void urine are strongly correlated with total nocturnal plasma melatonin output (P < 0.001) and also with peak nocturnal melatonin values (P < 0.001); 2) similar ranges for 6-OHMS were found in the laboratory and the field; and 3) neither menopausal status nor hormonal replacement therapy altered 6-OHMS values in morning void urine. The inclusion of morning urine samples in epidemiological studies of cancer could allow cost-effective, widespread testing of the role played by melatonin in human health and disease.

Inverse association between breast cancer incidence and degree of visual impairment in Finland.

A total of 10935 women with visual impairment were identified from the Finnish Register of Visual Impairment and followed up for cancer through the Finnish Cancer Registry for years 1983-1996. Breast cancer risk decreased by degree of visual impairment (P for trend 0.04) which suggests a dose-response relationship between visible light and breast cancer risk.

Cloning and characterisation of a cytosolic glutathione reductase cDNA from pea (Pisum sativum L.) and its expression in response to stress.

A second glutathione reductase (GR) cDNA has been cloned and sequenced from pea (Pisum sativum L. cv. Birte). This new GR cDNA (GOR2) does not encode a pre-protein with a transit peptide and therefore is most likely to represent a cytosolic GR. It is significantly different at the DNA level from the previously cloned chloroplastidial/mitochondrial pea GR (GOR1), but retains the features characteristic of GRs from all sources and has GR activity when expressed in Escherichia coli. GOR2 maps to linkage group 6 on the pea genome map and it seems likely that this is the only locus for this gene. In contrast to GOR1, transcript levels of GOR2 increase in the recovery (post-stress) phases of both drought and chilling by about ten- and three-fold respectively. GOR2 therefore may play a role in the restoration of the post-stress redox state of the cytosolic glutathione pool.