Circadian Rhythms in Environmental Health Sciences

Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light/dark cycle. However, nonphotic factors, such as behavioral arousal and metabolic cues, can also phase shift the master clock in the suprachiasmatic nuclei (SCNs) and/or reduce the synchronizing effects of light in nocturnal rodents. In diurnal rodents, the role of arousal or insufficient sleep in these functions is still poorly understood. In the present study, diurnal Sudanian grass rats, Arvicanthis ansorgei, were aroused at night by sleep deprivation (gentle handling) or caffeine treatment that both prevented sleep. Phase shifts of locomotor activity were analyzed in grass rats transferred from a light/dark cycle to constant darkness and aroused in early night or late night. Early night, but not late night, sleep deprivation induced a significant phase shift. Caffeine on its own induced no phase shifts. Both sleep deprivation and caffeine treatment potentiated light-induced phase delays and phase advances in response to a 30 min light pulse, respectively. Sleep deprivation in early night, but not late night, potentiated light-induced c-Fos expression in the ventral SCN. Caffeine treatment in midnight triggered c-Fos expression in dorsal SCN. Both sleep deprivation and caffeine treatment potentiated light-induced c-Fos expression in calbindin-containing cells of the ventral SCN in early and late night. These findings indicate that, in contrast to nocturnal rodents, behavioral arousal induced either by sleep deprivation or caffeine during the sleeping period potentiates light resetting of the master circadian clock in diurnal rodents, and activation of calbindin-containing suprachiasmatic cells may be involved in this effect.SIGNIFICANCE STATEMENT Arousing stimuli have the ability to regulate circadian rhythms in mammals. Behavioral arousal in the sleeping period phase shifts the master clock in the suprachiasmatic nuclei and/or slows down the photic entrainment in nocturnal animals. How these stimuli act in diurnal species remains to be established. Our study in a diurnal rodent, the Grass rat, indicates that sleep deprivation in the early rest period induces phase delays of circadian locomotor activity rhythm. Contrary to nocturnal rodents, both sleep deprivation and caffeine-induced arousal potentiate the photic entrainment in a diurnal rodent. Such enhanced light-induced circadian responses could be relevant for developing chronotherapeutic strategies.

Nitric oxide synthase inhibitor blocks light-induced phase shifts of the circadian activity rhythm, but not c- fos expression in the suprachiasmatic nucleus of the Syrian hamster

I am pleased to present “our” new strategic plan for the National Institute of Environmental Health Sciences (NIEHS 2012). I say that it’s “our” plan because the entire document reflects tremendous thought, discussion, and sharing of ideas by hundreds of scientists and community stakeholders, and it speaks to the entire field of environmental health research. This plan is about what we will strive to accomplish together as we devote ourselves to research that, in my opinion, has the greatest chance for preventing disease and for improving health throughout the world. As reflected in the new strategic plan (NIEHS 2012), the NIEHS has a fresh vision, not because our values have changed but because our research has been so successful—and many of you have made a huge contribution to that progress. New technologies and increasing knowledge bring exciting new opportunities each and every year. The NIEHS’s new strategic plan builds upon the accomplishments and vision that came before. The NIEHS has come a long way in making environmental health research responsive to the needs and concerns of the American people— to make environmental health part of the public health debate. This continues to be a source of motivation and purpose for NIEHS staff and our research partners. Environmental justice is an everlasting core value for NIEHS research. In the past few years, we at the NIEHS have made some important progress in exposure science, supporting new technologies for sensor devices and bioinformatics. We have been embracing new science such as epigenetics and exposure phenotyping, focusing on interdisciplinary research and translational research. In addition, our clinical research unit is now up and running. As the NIEHS moves forward, our overall goal is to make the institute, including the National Toxicology Program (NTP), the foremost trusted source of environmental health knowledge, leading the field in innovation and the application of research to solve health problems. Our new vision statement (NIEHS 2012) captures our collective dreams and aspirations, and reflects our strong commitment to making a real difference: The vision of the National Institute of Environmental Health Sciences is to provide global leadership for innovative research that improves public health by preventing disease and disability from our environment. What this means in practical terms is that we are pursuing some of the “big influences” that have been understudied, all of which interact with traditional environmental exposures: the microbiome, for example, and inflammation pathways, immunological pathways, nutrition, and epigenetic processes. We also want to lead the process of defining the “exposome,” which is the totality of exposure encountered by humans. We have elevated the NTP to the divisional level within the NIEHS. And we will continue to integrate our toxicology research with our excellent basic and translational science programs, not because I am a toxicologist but because the NTP is a problem-solving program—a truly translational component of the NIEHS. For example, the NTP is part of our consortium on bisphenol A, contributing to the scientific deliberations, right along with our intramural scientists and our grantees. The NTP is leading the Tox21 initiative along with the National Institute of Health’s National Center for Comparative Genomics, the U.S. Environmental Protection Agency, and the Food and Drug Administration. This high throughput testing program shows great promise not only as a new and faster method but also for moving toxicology into a predictive science. The NTP is moving beyond the traditional approaches of testing one chemical at a time and are taking on the significant challenge of evaluating mixtures. We are also looking at the effects of exposures throughout the life span, expanding our research and testing to include prenatal exposures and how they may link to adult disease. It is clear that there are multiple windows of susceptibility and that exposures early in life may have long-lasting consequences to both health and disease. Finally, the antiquated idea that the dose makes the poison is overly simplistic. The newest research clearly shows that biology is affected by low doses of chemicals, often within the range of general population exposure, and that these biological changes can be harmful, especially during periods of development. Therefore, low-dose research must go hand in hand with our life-span approach. The NIEHS’s job doesn’t stop with the publication of scientific results. We also have an obligation to help translate the nation’s research investment into public health intervention, new policy, and preventive clinical practice. To be successful, we at the NIEHS need to conduct and support the best science, whether it is led by an individual researcher or a multidisiplinary team, and this means working together with all of our partners. We thank everyone who joined us in our strategic planning process. We appreciate your commitment and support.

Carbon monoxide (CO), generated in neurons by the enzyme heme oxygenase-2 (HO2), is postulated to be a gaseous signaling molecule in the mammalian brain. Because of the recent evidence suggesting an important role of another endogenously produced gas, nitric oxide (NO), in entrainment of circadian rhythms in mammals, we hypothesized that CO may also be involved in regulating these rhythms. Consistent with this idea, others have found a circadian rhythm of heme turnover and CO synthesis can be induced by bright light. Furthermore, HO2 is co-localized with guanylyl cyclase, the putative target of CO, throughout the brain, with high amounts of staining in the suprachiasmatic nucleus (SCN) of the hypothalamus. The goal of the present study was to evaluate the role of CO in photic entrainment in wild-type and HO2 deficient mice. HO2–/– mice did not display any abnormalities in circadian rhythmicity. Entrainment to a light–dark cycle, the ability to phase delay locomotor activity after a four hour phase shift in photoperiod, and the period of the free running rhythm (t) were similar between HO2–/– and wild-type mice. Taken together, these data suggest that CO does not play a major role in regulating circadian activity rhythms in mice.

The relationship between nutrition and circadian rhythms in mammals

Chapter 1 The biological clock: it's all in the genes

At the New Mexico Center for Environmental Health Sciences (NMCEHS), community concerns and relationships are as much at the center’s foundation as the latest research techniques. According to center director Scott Burchiel, the unique populations of New Mexico—including a high number of Hispanics and Native American tribes, pueblos, and sovereign nations—steer the center’s course. “One of the things we have tried to do is to determine what these populations’ concerns are for environmental health, because we want our center to be focused on environmental public health, and we want to work on basic research projects that address issues that people in this region are particularly interested in,” he says. Based in Albuquerque as a partnership of The University of New Mexico Health Sciences Center and the Lovelace Respiratory Research Institute (LRRI), the NIEHS-funded center comprises major research cores in environmental cancer and oxidative stress, cardiovascular toxicology, environmental lung disease, and population health and epidemiology. The center also includes world-class facility cores (particularly for inhalation toxicology), a pilot project program to provide funding for small innovative research studies, and an unusually strong community outreach and education program (COEP). Community input is essential, as is trust. “We have investigators who may have certain interests for certain kinds of projects and want to work with communities,” says Burchiel. “But when we go to the community, we find out that [the community has] a different agenda, different interests. We’ve been learning how to work with communities since we’ve had this environmental health center.” It’s a process that involves a lot of development of community relationships and trust relationships. Burchiel says that investigating environmental health problems such as asthma requires a broad definition of environment. He says, “In our center, we define the environment quite broadly. It includes nutritional, social, behavioral, economic, and built environment components. . . . We have not only environmental epidemiologists [but] also social epidemiologists who help us look at social factors in assessing economic and poverty factors.”

Circadian rhythmicity in mammals, is controlled by the suprachiasmatic nuclei (SCN) of the hypothalamus. We previously described a discrete subnucleus in the core of the hamster SCN containing calbindin-D28k-positive cells which are fos-positive in response to a light pulse. Ablation of this subnucleus results in loss of circadian locomotor rhythmicity even when other parts of the SCN are spared. Here we show that Tau mutant hamsters have significantly more calbindin-D28k in the SCN than do wild type hamsters, and that SCN calbindin-immunoreactivity in the SCN increases in the dark. This is correlated with changes in magnitude of light mediated phase shifts in locomotion. The data are consistent with a role for calbindin cells in light mediated entrainment and phase shifting.

The circadian rhythm is generally existed in mammalian behavior and metabolic processes, which results from the self-sustained circadian clocks. The mammalian circadian clocks are composed of a master clock located in the hypothalamic suprachiasmatic nucleus (SCN), and of many peripheral clocks in tissues and extra-SCN brain regions. It is indicated that feeding could take over part of the SCN signaling, and affect internal synchrony between the master clock and the peripheral clocks. Thus, recent studies focus more on the relationship between the nutrients and circadian rhythms. Various nutrient components (glucose, amino acid, alcohol) are found to be able to directly affect the circadian rhythm of clock genes. Moreover, the feeding schedule of nutrients is as important as the nutrient components in maintaining a healthy circadian rhythm. Therefore, the circadian homeostasis needs not only balanced nutrient components but also regular timed nutrients.

Environmental health research and the COVID-19 pandemic: A turning point towards sustainability

Protein interaction networks of the mammalian core clock proteins.

Non-peptide oxytocin receptor ligands and hamster circadian wheel running rhythms

Circadian Clocks (Handbook of Behavioral Neurobiology, Vol. 12) Takahashi, Joseph S., Turek, Fred W. and Moore, Robert Y. (eds) Kluwer Academic/Plenum Publishers 2001 , $175 , 794 pages, ISBN 0-306-46504-3 Most organisms have been forced to adapt to the once-daily rotation of our planet on its axis. The geophysical day–night cycle is not only reflected as circadian (Latin: circa = about, dies = day) rhythms of physiology and behavior, but is also actually incorporated within organisms as a genetically determined temporal program. This endogenous, temperature-compensated timekeeping mechanism recognizes local time, measures its passage, and contributes to the regulation of homeostasis, seasonal behavior, and migration. Evidence for its existence was still being debated as late as 1960, but by 1981 the field had advanced to such a stage that it was reviewed in Volume 4 of the new Handbook of Behavioral Neurobiology. At that time, single gene mutants affecting rhythms in flies and fungi had been isolated, and the suprachiasmatic nucleus (SCN) was being proposed as a candidate circadian clock in mammals, but the terms ‘genetics’, ‘neurotransmitter’, and ‘shift work’ were not yet listed in the index. In the editor's preface, Jürgen Aschoff wrote, ‘The study of the physiological mechanisms underlying circarhythms is a rapidly developing field, and the question of how discrete is the clock from the rest of the body…may soon be answered in the circadian case…’. Twenty years have now passed and our progress has been almost unimaginable. Among other advances, the body of evidence that has identified the SCN as a master circadian pacemaker is so compelling and multidisciplinary that the strength of this functional localization is unsurpassed by that of any other structure in the vertebrate brain. We have discovered intracellular regulatory molecules and biochemical processes that are likely to constitute the actual oscillatory mechanism of the clock. The practical application of our new knowledge has been recognized, and chronobiologists now advise astronauts. Volume 12 of the Handbook, Circadian Clocks, summarizes how extraordinarily far we have come. It is a comprehensive and authoritative reference work of 26 chapters in 6 parts. Included are chapters on entrainment theory and the ecology and evolution of circadian rhythmicity; on the organization of circadian systems, from unicells to invertebrates and non-mammalian and mammalian vertebrates; on the regulation of mammalian rhythmicity, including photic and non-photic entrainment, development and aging, sleep and wakefulness, and seasonality; on cellular and molecular mechanisms in Synechococcus, Gonyaulax, Neurospora, Drosophila, opisthobranch mollusks, and rodents; and on the human circadian system and its role in sleep, performance, aging, affective disorders, endocrine secretion, and photoperiodic responses. The book is handsomely produced and certain to become a manual for molecular biologists, neuroscientists, physiologists, and physicians working on circadian rhythms. While no existing book matches the scope of Circadian Clocks, a few topics are missing even from this volume. Not considered are the clocks of higher plants, or the role of clocks in tidal rhythms and sun compass orientation. There is little, if any, coverage of how circadian rhythms might impact medical practice, i.e. by influencing the timing of pharmacotherapy or the manifestations of disease. Finally, some chapters on molecular mechanisms were apparently written five years ago and are a bit outdated, although the field is moving so fast anyway that it would be impossible for any book to be completely up to date. So, some remarkable new stories – the mutant clock genes responsible for advanced sleep phase syndrome, the role of peripheral oscillators in body rhythmicity, and the identification of candidate circadian photoreceptors and molecules – will need to wait for the next volume. Circadian Clocks clearly shows why the circadian timekeeping system has become such a unique and powerful model for studying genes, brain and behavior. There are remarkable opportunities to begin to understand a biological system at multiple levels of organization, ranging from the regulation of gene expression, to intercellular networks and multisynaptic pathways, and finally to integrated patterns of physiology and performance. Clock investigators include geneticists cloning clock genes, zoologists examining rhythmic behaviors in the wild, neurophysiologists recording spike trains in the hypothalamus, and psychiatrists treating patients with seasonal affective disorder (to name just a few). By enhancing the dialogue between these researchers and their disciplines, Circadian Clocks should serve as a very valuable resource. William J. Schwartz Department of Neurology University of Massachusetts Medical School 55 Lake Ave. North Worcester MA 01655, USA

What do tiny black-and-white-striped zebrafish have in common with human beings? As it turns out, quite a lot. The zebrafish and other aquatic model organisms are helping researchers to better understand complex biomedical questions including how humans develop and are affected by toxic exposures. This work is the focus of the and Freshwater Biomedical Sciences Center (MFBSC) at the University of Wisconsin (UW) –Milwaukee, an NIEHS environmental health sciences center. “Most investigators who work with living systems use mammalian species as model systems,” says director David Petering, a professor of chemistry at UW–Milwaukee. “So, up until recently, general toxicologists wondered what in the world aquatic organisms could contribute to the study of environmental health and toxicology. It turns out that, historically, aquatic organisms have been enormously important in the development of biomedical research.” Petering notes, for example, that most of the basic understanding of how nerve impulses are conducted arose from studies of the large nerve axon of the squid. The MFBSC is one of four aquatic research centers funded by the NIEHS. It is located in the Wisconsin Aquatic Technology and Environmental Research (WATER) Institute at UW–Milwaukee. (In addition to UW–Milwaukee faculty, the center draws researchers from several other Wisconsin institutions, including Marquette University, the Medical College of Wisconsin, and UW–Madison.) The center’s genesis dates to the late 1970s, when former NIEHS director David Rall promoted the use of aquatic systems to study human and environmental health issues. The Milwaukee center was the first MFBSC to form. It has since evolved into an advanced aquatic animal facility with laboratories supporting four core research areas: signal transduction and endocrine disruption, metals toxicology and neurotoxicology, the use of zebrafish as a model organism for developmental toxicology, and behavioral toxicology. Additionally, the MFSBC supports a pilot project program, which offers researchers an opportunity to explore the utility of aquatic models in environmental health research and to further develop methods that are already in use.

Background:Environmental health (EH) professionals, one of the largest segments of the public health workforce, are responsible for delivery of essential environmental public health services. The challenges facing these professionals and research needs to improve EH practice are not fully understood, but 26% of EH professionals working in health departments of the United States plan to retire in 5 y, while only 6% of public health students are currently pursuing EH concentrations.Objectives:A groundbreaking initiative was recently launched to understand EH practice in health departments of the United States. This commentary article aims to identify priority EH practice challenges and related research needs for health departments.Methods:A horizon scanning approach was conducted in which challenges facing EH professionals were provided by 1,736 respondents working at health departments who responded to a web-based survey fielded in November 2017. Thematic analyses of the responses and determining the frequency at which respondents reported specific issues and opportunities identified primary EH topic areas. These topic areas and related issues informed focus group discussions at an in-person workshop held in Anaheim, California. The purpose of the in-person workshop was to engage each of the topic areas and issues, through facilitated focus groups, leading to the formation of four to five related problem statements for each EH topic.Discussion:EH professionals are strategically positioned to diagnose, intervene, and prevent public health threats. Focus group engagement resulted in 29 priority problem statements partitioned among 6 EH topic areas: a) drinking water quality, b) wastewater management, c) healthy homes, d) food safety, e) vectors and public health pests, and f) emerging issues. This commentary article identifies priority challenges and related research needs to catalyze effective delivery of essential environmental public health services for common EH program areas in health departments. An unprecedented initiative to revitalize EH practice with timely and strategic recommendations for student and professional training, nontraditional partnerships, and basic and translational research activities is recommended. https://doi.org/10.1289/EHP5161