Assessment of Inflammatory Responses and Novel Systemic Signals as Potential Screening Targets of Shift-Work Related Disruption.

ABSTRACT
Shift workers represent nearly 30 % of the US workforce, and this occupational hazard conveys increased risk
for multiple pathologies. Still, the specific mechanisms behind this increased risk of illness by shift workers as
well as investigation of screening targets to identify susceptible individuals are scarcely known.
Our preclinical research and initial translational studies provide insight into the basis of shift-work disease and
show that markers of systemic inflammation appear to increase as a function of exposure-duration to shift work.
However, when samples are challenged with bacterial endotoxin, we find that low-grade systemic inflammation
does no warrant a heightened ex-vivo endotoxin response. As shift work exposure increases, the relationship
between systemic inflammation and endotoxin responses weakens, suggesting a mismatch between discrete pro-
and anti-inflammatory pathways during endotoxin challenge. Novel systemic signals in plasma samples from
shift workers identify a potential mediator of shift-work related disruption of inflammation. These preliminary
results illustrate how shift work impacts the complex interaction of events needed to initiate and control an
efficient response to an inflammatory challenge and support the hypothesis that chronic dysregulation of
inflammation is behind the increased risk of diabetes, cancer and cardiovascular disease in shift workers.
In this application, we propose to conduct a cross-sectional prospective study of day workers and career shift
workers exposed to temporally changing occupational environments. We will further develop and improve a
profile of shift-work risk assessment which includes individual metrics of systemic inflammation, cardiovascular
disease, stress, sleep/activity, diet composition, and circadian disruption. This assessment aims to quantify the
state of low-grade systemic inflammation characteristic of shift work exposure as a potential predictor of the
response of the immune system to a controlled, ex-vivo and in-vitro, endotoxin challenge. We aim to assess the
potential mechanisms by which increased inflammation determine dysregulated activation and test the central
hypothesis that the degree of low-grade systemic inflammation worsens with increased shift work exposure.
Our primary goal is to understand how shift work exposure duration leads to the development of uncontrolled
inflammation in career shift workers increasing disease risk. This work is of paramount importance because it
could lead to early diagnostic tools that can help mitigate shift-work disease. On the long term, we seek to uncover
the mechanistic links between shift work exposure and disease.

Grant Number: 5SC1GM144022-04
NIH Institute/Center: NIH
Principal Investigator: Oscar Castanon-Cervantes