J. Valérie Groß

Light, Clocks, Mood, and Cancer: Consolidation and Novel Tests of Latitude and Instability Hypotheses

The recent investigation by Borisenkov (2011) focused on possible relationships between latitude, as a key determinant of exposures to the natural zeitgeber light, and health and disease. Links like that have been discussed and investigated for a long time and, with regard to mood disorders, culminated in the formulation of “latitude” (Potkin et al., 1986) and “instability” (Goodwin & Jamison, 1990) hypotheses. Intriguingly, a recent report in Nature Neuroscience (Ciarleglio et al., 2010), given the findings can be replicated and substantiated for longer observation periods, would allow one to consolidate the hypotheses of a causal link not only between light and mood disorders, but also between light and cancer development. Incorporating these novel experimental insights could help us with issues of “whitebox” epidemiology (Erren, 2010), where biomedical insights and mechanistic knowledge together are required to design and refine investigations. Elsewhere, we (Erren et al., 2011) proposed that the “latitudehypothesis” (Potkin et al., 1986) and the “instability hypothesis” (Goodwin & Jamison, 1990) represent different facets of the same underlying phenomenon (Erren et al., 2011). Here, we wish to extend the concept of these hypotheses beyond mood disorders and would like to see the development of internal cancers included. A common pathway for the development of mood disorders and of cancers may be differential exposures to light and their impact on circadian systems, in general, and differential exposures to light when and where people are born, in particular. We may be looking, therefore, at four interrelated hypotheses, namely: (a) the 1986 latitude hypothesis of an association between latitude and seasonal affective disorders (Potkin et al., 1986); (b) the 1990 instability hypothesis of bipolar disorder (Goodwin & Jamison, 1990); (c) the 1999 latitude hypothesis of an association between latitude and internal cancers (Erren & Piekarski, 1999); and (d) the 2008 chronodisruption cancer theory (Erren & Reiter, 2008). On the basis of theNature Neuroscience report (Ciarleglio et al., 2010), these seemingly diverse concepts may now be unified and tested in a logical way. Indeed, Ciarleglio and colleagues suggested biologically plausible mechanisms to explain and study the causal links postulated by all four hypotheses. The researchers reported that mice born and raised under “summer light conditions” were physiologically responsive and showed stable and robust timing relationships to varying lightdark transitions that characterize seasonal changes in later life. But mice born and raised under lighting conditions similar to winter photoperiods were unresponsive and evinced instable and variable timing relationships to varying light-dark transitions typical for seasonal light alterations. The cornerstone of the consolidated latitude and instability hypotheses is the interaction of light and circadian rhythmicity at two levels and in different time windows. Light early in life may imprint and “shape the susceptibility” of an individual’s circadian system for later stages in life. Later exposures to light at unusual times—examples being light at night or light exposures in the course of rapid transmeridian flights—could provide confusing timing information and derange the body’s circadian systems, which may bemore or less susceptible depending on the time and location of birth (i.e., season and latitude) and thus early-life light exposure patterns. In other words, light could be a dual determinant of risk of mood disorders and internal cancers: early in life it determines the susceptibility of the circadian systems later in life. Moreover, in later life stages, it determines the very dose of light as a key zeitgeber for circadian rhythms. An underlying instability of the timing relationships of circadian clocks and rhythms to nocturnal light/dark transitions may constitute a unifying link between different endpoints, such as “mood disorders” and “internal cancers.” With regard to the etiology, and the course, ofmooddisorders, it has already been suggested (Erren et al., 2011) to consolidate (a) the “latitude hypothesis for seasonal affective disorders” (Potkin et al., 1986) and (b) the “instability hypothesis of bipolar disorder” (Goodwin & Jamison, 1990). Moreover, ideas have been expressed to use the albeit tentative and unreplicated information and insights provided by Ciarleglio et al. (2010) to sharpen epidemiological studies (Erren et al., 2011). This could be done by exploiting the fact that the likelihood and percentage of individuals born in time windows with rather low lightdark ratios should be higher at the extremes of latitude than, for instance, at the equator.

Chronobiology and competitive sports: recent studies and future perspectives

Pullinger et al. (2013) cast light on the somewhat underexplored importance of chronobiology in competitive sports. We wish to add some notions regarding their study in particular and research into how chronobiology may impact performance in general. The authors aimed to answer the following question: Does time of day impact treadmill performance in teamsport specific tests of repeated sprint ability [RSA], as could be relevant, for instance, for football? Their complex RSA tests in 20 active and motivated individuals on a non-motorized treadmill in morning and evening sessions demonstrated higher performances, such as the distance covered, and both peak and average power and velocity in evenings. Insofar, and adding to prior research, the answer to the study question was ‘‘yes’’. With regard to the ‘‘why’’ the researchers concluded that diurnal differences in human performance result from multiple factors. To zero in on possible determinants of diurnal variations in human performance, we like to propose (i) how the recent study might be expanded and (ii) how it may be built upon in future research. Regarding (i), Pullinger and colleagues might consider additional analyses on the basis of chronotype differences, which may still be distinguishable within their data. Moreover, ‘‘extreme chronotype(s)’’ who were excluded from the study could be invited to perform identical tests for further analyses. In so doing, the authors may provide material for testing the validity of what has recently been conceptualized as a potential chronobiological fallacy (Erren & Morfeld, 2013). The rationale holds that ignoring an individuals’ biological day and night may lead to critical errors (Erren & Morfeld, 2014) when interpreting effects of activities at different local times, be it in animal experiments (Wicht et al., 2014), laboratory studies of athletes (Pullinger et al., 2013) or epidemiological studies of shift-workers (Erren & Reiter, 2013). If the proposed expansion of the study of Pullinger et al. (2013) were to evince that earlier chronotypes perform significantly worse in evening sessions than later chronotypes, this would support the notion that we should avoid the suggested chronobiological fallacy by including internal time in our research. Regarding (ii), beyond including different chronotypes, future studies may apply variable lighting conditions. A recent study showed that both chronotype and bright light significantly affected physical performances on a bicycle ergometer (Kantermann et al., 2012). Therefore, in addition to influences on treadmill performances by the standard laboratory lighting of 200–250 lx in the study by Pullinger and colleagues, environmental light to which participants were exposed before the experiments may have influenced the observed morning–evening RSA differences. It may thus be of interest at what season, at which latitude, at what day-/nighttimes and how long study individuals were exposed to light before their performance tests. And, if future research were to experiment with variable lighting as well, for instance comparing bright (BL& 4.420 lx) with dim light (DL& 230 lx) effects (Kantermann et al., 2012), answers to the following

Melatonin, Sleep, and Prostate Cancer in Elderly Men: Study, Hypothesis Development, and Icelandic Options

In this month’s issue of European Urology, Sigurdardottir and colleagues [2] present their case-cohort study examining urinary 6-sulfatoxymelatonin (aMT6s) levels and incident prostate cancer (PCa) risk among 928 Icelandic men. An extension of an earlier Icelandic study [3] embedded within the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort with 2425males aged 67–96 yr, the authors of the present study observed 111 incident PCa cases (mean age of diagnosis: 77.9 yr) fulfilling the eligibility criteria, of which 24 represented advanced disease. The two key results were as follows: those men with reported sleep problems at baseline had lower morning aMT6s levels compared with those who did not report sleep problems; those men with ‘‘low’’ aMT6s levels were four times as likely to be diagnosedwith advanced PCa disease compared to men with ‘‘high’’ aMT6s levels (hazard ratio: 4.04; 95% confidence interval, 1.26–12.98).

Everybody's plastic: so what?

Rochester’s timely review leaves no doubt that there are mportant areas of investigation both for basic research and for pidemiology in regards to bisphenol A [BPA] and human health 1]. While unambiguous proof of causal relationships between BPA nd disease remains elusive, the toxicological question throughout ochester’s review ‘can there be doses which make the poison?’ s not. Disconcertingly, if endocrine and/or epigenetic disruptions ere involved, very small internal doses of BPA may suffice to co-)determine disease. Moreover, across food webs, ubiquitous ynthetic monomers and additives to plastics with expected ‘halfives’ of centuries accumulate in wildlife and humans to possibly ecome a critical burden [2,3]. The scope should be broadened to plastics, though, i.e., beyond PA as one increasingly studied plastic monomer. Indeed, “The lastics puzzle” [4] evolved since the middle of the 19th century hen organic polymers were developed and John Hyatt patented lastic-based alternatives to expensive ivory billiard balls. Groundork that plastic ingredients may have oestrogenic effects dates ack to the early 1900s [5,6]. Inasmuch as numerous untested lastic compounds “are really all around us” [4], the quote in he heading attributed to Andy Warhol is becoming increasingly rue. Overall, therefore, we clearly need research as outlined by ochester towards a sustainable use of bisphenol A [7], in particular, nd of plastics, in general [8].

Computing sleep deficiency

Sleep deficiency is a major public health concern. Since epidemiological studies play an important role in public health evaluations, this theoretical paper pursues answers to the question: ‘How can we compute sleep deficiency as informative measures of exposures or doses in observational research?’ Starting from the social jetlag concept and based on the chronodisruption rationale, we illustrate and discuss five approaches (one established and four untested, each with unique strengths and limitations) to quantify sleep deficiency by focusing on the timing and duration of sleep. Hitherto, social jetlag and chronodisruption rationale were neither explicitly proposed nor developed as assessments of sleep deficiency but, as we suggest, could potentially be utilized to this end. This first foray into computing sleep deficiency in epidemiological studies makes clear that laboratory, field and epidemiological collaboration is pre‐requisite to elucidating potential (co‐)causal roles of sleep deficiency in disease endpoints.

Shift work that involves circadian disruption and breast cancer: a first application of chronobiological theory and the consequent challenges

Objectives In 2007, the International Agency for Research on Cancer classified shift work involving circadian disruption (CD) as probably carcinogenic to humans. Circadian disruption could be conceptualised as the overlap of activity, such as work, with an individual’s biological night. The latter can be approximated from a worker’s chronotype (or morning/evening preference). Few previous studies have taken chronotype into account when assessing CD caused by shift work. Our objective was to test the hypothesis that women working during their biological night would be at increased risk of breast cancer. Methods We used data from our case–control study of breast cancer to investigate associations between shift work involving CD and breast cancer risks. Previously, we had assumed that everyone working in jobs which involved work for two or more shifts between midnight and 05:00 hours was equally exposed to CD. In the present analyses, we reclassified as unexposed those who had a late chronotype in which their preferred bedtime was 2 hours after the end of their shift. Results Only 30 of 1385 night jobs changed classification and the overall finding (OR 1.17, 95% CI 0.98 to 1.41) was not different to the original finding when chronotype was not considered. Conclusions We found virtually no difference between our new and old classifications of exposure. However, we were not able to calculate the total number of chronodisrupted shifts over a lifetime in order to assess dose and nor were we able to determine how many women were exposed to CD when doing shifts which began before midnight. Our first practical application highlights challenges for future chronobiology-based research.

Comment on “diversity outbred: A new generation of mouse model”

A news article by Charles Schmidt propagates the Diversity Outbred mouse model to facilitate the extrapolation of toxicology findings to humans. In this regard, we would like to highlight two sources of animal diversity that could be relevant: 1) the differential—and genetically codetermined—circadian propensity for activity and rest with which the mice are born, and 2) the differential stability of circadian rhythms in later life stages of mice, to which perinatal photoperiods may contribute. Regarding 1), humans come in different chronotypes corresponding to variations in how physiology, endocrinology, metabolism, and behavior are organized and timed over the individual’s biological day and night. Inasmuch as the extent of genetic variability among model mice should be similar to genetic variations in humans, how do new-generation mouse models capture differential chronobiological propensity? Laboratory mice, like humans, come in various chronotypes, and different strains come in different ones (Wicht et al. 2014); therefore, different time windows of biological nights and days should significantly impact when and what we observe or measure, be it parameters of toxicology, behavior, physiology, or anatomy. With evidence that responses to DNA damage are regulated by the circadian clock in mice (Kang et al. 2010), chronotype-dependent lows and highs of DNA repair within a 24-hour period must be considered when extrapolating mouse-based toxicological data to humans. Regarding 2), although inbred mice may be genetically identical, perinatal photoperiods may nevertheless—by imprinting the circadian clock—lead to a differential stability of circadian rhythms. Perinatal exposures to summer versus winter light conditions (i.e., with a light:dark ratio of 16:8 versus 8:16) can determine the susceptibility of a mouse’s circadian rhythm to dysfunction or disruption throughout the animal’s life (Ciarleglio et al. 2011). Furthermore, the integrity of circadian clocks and rest–activity circadian rhythms plays a major role for tumor suppression by controlling cell proliferation and other cellular functions (Fu and Lee 2003). Taken together, if the perinatal photoperiod may codetermine the very robustness of mice to fight off severe circadian dysfunction (Filipski et al. 2002) and the development of tumors, then a fortiori we would have to understand, and possibly control, circadian diversity. Overall, the biological activity of circadian clocks must be taken into account when experimenting with mice. Taking note of 1) and 2), we should consider possible chronotypes in new-generation mice and standards for the light:dark conditions under which laboratory mice are bred and raised. Moreover, the efficacy, toxicity, and carcinogenicity of chemicals or drugs should be tested at different times within a 24-hour period. Given evidence for links between aging clocks and progressive declines of the circadian control of crucial biological processes (Belancio et al. 2014), age should also be factored in when using mice for testing.

Do Perinatal Photoperiods Imprint Human Chronobiology? Suggestion for a study into the possible signature of light in the Northern and Southern Hemispheres

Drs. Natale and Di Milia conclude from their recent study (Natale & DiMilia, 2011) that the observed distribution of evening or morning types in humans could depend on whether individuals were born during seasons with longer or shorter photoperiods, respectively, thus providing indirect support for “an imprinting-like phenomenon played by the photoperiod at birth”. Importantly, this empirical study could offer circumstantial evidence for the possibility that perinatal photoperiods may imprint facets of circadian rhythmicity in humans. And yet, to really do so, based on the background that we provide here, the current study would need to be extended. By comparing an individual’s morning or evening orientation to the individual’s season of birth with reference toNorthernor Southern-hemisphere photoperiods, the authors employed a unique approach to test epidemiologically in humans what has recently been suggested following experiments with rodents (Ciarleglio et al., 2011): Mice developed and raised under “winter light (L)-dark (D) ratios” (8L:16D) versus “summer light-dark ratios” (16L:8D) not only evidenced differential circadian stability, but did so for an extended period of time, implying a conceivable imprinting effect of the perinatal photoperiod on a rodent’s chronobiology. Intriguingly, in addition to these observations supporting imprinting, an earlier study (Ohta et al., 2006), albeit with an extreme light-dark ratio of 24L:0D applied postnatally, may be interpreted as a demonstration of imprinting of circadian stability via perinatal cues stemming from environmental photoperiods. In the latter study, the postnatal constantlight environment was employed to mimic the light conditions newborns are regularly exposed to in neonatal intensive care units. In the rodents studied, unstable circadian organization was observed in later life stages; the overall results suggested a disrupted temporal order as a consequence of postnatal photoperiod imprinting. Drs. Natale and Di Milia refer to the Ciarleglio et al. (2011) experiments like a scientific blueprint for what they interpreted from their unique epidemiological approach. And yet, almost en passant, the authors refer to a key element of the experiments in Nature Neuroscience. In fact, when Drs. Natale and Di Milia suggest that perinatal photoperiods may have imprinted facets of circadian rhythmicity such as “morningness” and “eveningness”, it is actually not crucial that their assessments were based on the study of individuals in Bologna, at latitude 41°N, and in Rockhampton, at latitude 22°S. But when and where the study individuals were born and had spent, say their first 3 mo of life, is pertinent information, which would be highly relevant and indispensable with regard to any conclusion regarding an “imprinting-like phenomenon played by the photoperiod at birth” (emphasis added). Clearly, the assumption that the students spent their perinatal period under similar photoperiods compared with those where the study was conducted is not a safe one. In particular, with regard to the critical ‘exposure’ data, the authors state: “Finally, we did not collect information on whether participants were actually born in the cities where they were studied”. The fact that this information was not gathered could be ‘remedied’ in an a posteriori way, as it should be feasible to collect and use the missing ‘exposure’ information in followup analyses. We strongly encourage the pursuit of the specified information as a conditio sine qua non for any inference regarding the perinatal imprinting of facets of human chronobiology. We need empirical information about such possible imprinting, because, as already commented, if such imprinting of human chronobiology via perinatal light-darkness exposures were to work in humans, circadian instability caused by detrimental L:

Shift work and cancer: more research needed from low and middle income countries

In 2007, the International Agency for Research on Cancer classified shift work that involves circadian disruption as probably carcinogenic to humans. However, until today the question ‘ Are there causal relationships between shift work, circadian disruption and cancer?’ is open. Therefore, studies such as the one by Wendeu-Foyet et al 1 are important to investigate this presumed association with potential high relevance for occupational medicine and public health. We agree with the authors that conflicting results in different studies could result from different definitions of shift work. More generally, though, we ask: Are epidemiological studies designed appropriately to identify associations between shift work and circadian disruption and cancer in diverse …

Comparing different approaches to assess individual chronotypes in epidemiological studies (SEVERUS-Cohort)

ABSTRACT Assessing individual chronotypes can become relevant for epidemiological studies, for instance when investigating the impact of night-shift work on human’s health. The objective of this study was to explore and compare three different approaches (Self-rating, Munich Chronotype Questionnaire (MCTQ), Perfect Day (PD)) of assessing the chronotype in a group of 48 police officers. We compared the categorical classification of self-rated chronotypes with Mid Sleep Times (MST) on free days from the MCTQ and MST on PDs. Chronotype categories derived from self-rating were only weakly associated with the MST derived from free days (Spearman’s rho = 0.33, p = 0.078) and PDs (rho = 0.26, p = 0.073). We found a positive correlation between the MSTs assessed via MCTQ and PD (Pearson’s r = 0.67, p < 0.001). There were differences in the MST on free days and on PDs between individuals who did and did not use an alarm clock. All three approaches to assess chronotype information have to be used with caution. Concerns of selection and misclassification bias are raised when assessing chronotypes through the MST on free days for those who do not use alarm clocks. Further research is needed to develop sound strategies to assess chronotypes in epidemiological studies.