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Your Environment. Your Health.

DEVELOPMENTAL PBDE EXPOSURE, GUT MICROBIOME, AND DIABETES

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Principal Investigator: Cui, Yue
Institute Receiving Award University Of Washington
Location Seattle, WA
Grant Number R01ES030197
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Jan 2019 to 31 Dec 2023
DESCRIPTION (provided by applicant): PROJECT SUMMARY     Diabetes  is  a  pandemic,  causing  grave  social  and  economic  burdens.  This  complex  disease  is  caused  by  an  interaction among genetic, metabolic, behavioral, and environmental factors.  Epidemiology studies and animal  experiments  demonstrate  that  developmental  exposure  to  the  persistent  environmental  toxicants  polybrominated  diphenyl  ethers  (PBDEs)  is  associated  with  increased  diabetes  prevalence  and  persistent  diabetic  phenotype  in  adulthood.  However,  mechanisms  governing  early  life  PDBE  exposure  and  the  diabetogenic  phenotype  remain  unknown.  Current  literature  supports  the  mechanistic  link  between  gut  microbiome  and  metabolic  syndrome  in humans  and  animal  models.  We  showed that  oral  exposure  to PBDEs  in  adult  mice  results  in  dysbiosis  with  profound  changes  in bacteria  known  to be  associated  with  inflammation  and  obesity, as  well  as  reduced  tryptophan  microbial  metabolites  including  indoles,  which  are novel  activators  of  the  host  pregane  X  receptor  (PXR)  which  is  known  to  contribute  to  obesity  and  diabetes.    Building  on  our  findings  that  there  is  a  gene-­environment  interaction  between  PXR  and  PBDEs  through  gut  microbiome  and  indole  metabolites,  we  seek  to  establish  a  causal  relationship  between  developmental  PBDE  exposure,  a  change  in the  gut  microbiome, and  diabetes  later  in  life using humanized PXR  transgenic  (hPXR-­TG)  mice  in  conventional  (CV)  and  germ-­free  (GF)  background.  We  hypothesize  that  developmental  PBDE  exposure  causes  acute  and  persistent  dysbiosis,  which  contributes  to  diabetes  through  suppression  of  microbial  tryptophan  metabolism  and  selective  PXR  modulation  (sPXRm)  in  early  life  and  beyond.  To  test  our  hypothesis,  in  Aim  1  we  will  determine  if  developmental  PBDE  exposure  perturbs  the  gut  microbiome  and  microbial  metabolism  of  tryptophan,  leading  to  sPXRm  in  early  life  and  beyond.  In  Aim  2  we  will  determine  whether  microbial  metabolites,  mainly  including  indoles  and  indole-­derivatives,  can  reduce  inflammation and  rescue  the  diabetic  phenotype  following  developmental  PBDE  exposure.  In  Aim  3  we  will  determine  that  reprogramming  the gut  microbiome  using  fecal transplant  mechanistically  contributes  to developmental PBDE  exposure  mediated  disruption  of  PXR  signaling  and  delayed  onset  of  diabetes.  The  expected  outcome  of  the  proposed  research  is  a  new  research  paradigm  demonstrating  that  dysbiosis  of  the  gut  microbiome  mechanistically  contributes to  early  life PBDE exposure-­induced diabetes  and  metabolic  syndrome  later  in  life,  and  more  importantly,  enables  a  toxico-­metagenomics  approach  targeting  metabolic  disorders  resulted  from  exposure to PBDEs and potentially other persistent organic pollutants.        
Science Code(s)/Area of Science(s) Primary: 68 - Microbiome
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Anika Dzierlenga
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