Health Consequences of Circadian Disruption in Humans and Animal Models - Progress in Molecular Biology and Translational Science - page 302

or backward-rotating (advancing) direction. Rotation speed and shift dura-
tion also vary by industry and work site. Studies in animal models have dem-
onstrated the negative impact of shift sizes of 6 h, 77,111,353 8h, 109 and
12 h, 75,402 but the relative consequences of different schedules such as those
used in industry represents an area for further investigation. The few studies
that have addressed these types of questions suggest that health effects of cir-
cadian disruption are significantly modulated by schedule characteristics
such as shift direction and exposure duration. 77,353,373-379 Additional
research in both animal models and people comparing the effects of various
schedules on specific health measures would aid in shift work scheduling. Of
primary value would be additional research examining the role of exposure
duration across schedule types, the persistence of health consequences, and
individual susceptibility factors.
Also of interest remains the role of central versus local clock function in
the effects of circadian disruption. In humans, clock gene polymorphisms
would be expected to affect the function of all cells and most of the genetic
models employed to date likewise have ubiquitous effects on cells in
both central and peripheral clocks. Over the last few years, several
reports have described health consequences of tissue-specific genetic
manipulations, 205,211-214 supporting a role for local clock function in deter-
mining health outcomes. SCN-specific gene targeting strategies have yet to
be developed, but environmental models that disrupt SCN function and
system-level control provide useful models and may be highly representative
of the specific conditions commonly producing circadian disruption in
humans. With environmental lighting manipulations, it remains unclear
the degree to which health consequences arise due to changes in central
or peripheral function (i.e., loss of synchronization within or among periph-
eral clocks). Cancer research represents one area where these questions have
begun to be addressed, using tissue-specific profiling during disease states 427
and independent manipulation of implanted cell and host genomes during
tumor progression. 428 Recent advances in cell-specific in vivo expression
technologies can facilitate research into the relative consequences of losing
normal circadian timing in central versus peripheral sites.
One final area in need of additional insight is the role of a broken versus
misaligned clock in disease genesis. Both environmental and nonarrhythmic
genetic models provide excellent tools here as well; however, work thus far
has failed at times to adequately describe the rhythmic state of the model at
the gross (e.g., behavioral and hormonal) and fine (cellular) levels of analysis.
For example, experiments using constant

light should document the