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Title: Synchrotron-based imaging of chromium and  γ-H2AX immunostaining in the duodenum following repeated exposure to Cr(VI) in drinking water

Current drinking water standards for chromium are for the combined total of both hexavalent and trivalent chromium (Cr(VI) and Cr(III)). However, recent studies have shown that Cr(III) is not carcinogenic to rodents, whereas mice chronically exposed to high levels of Cr(VI) developed duodenal tumors. These findings may suggest the need for environmental standards specific for Cr(VI). Whether the intestinal tumors arose through a mutagenic or non-mutagenic mode of action (MOA) greatly impacts how drinking water standards for Cr(VI) are derived. Herein, X-ray fluorescence (spectro)microscopy (µ-XRF) was used to image the Cr content in the villus and crypt regions of duodena from B6C3F1 mice exposed to 180 mg/l Cr(VI) in drinking water for 13 weeks. DNA damage was also assessed by γ-H2AX immunostaining. Exposure to Cr(VI) induced villus blunting and crypt hyperplasia in the duodenum—the latter evidenced by lengthening of the crypt compartment by ~2-fold with a concomitant 1.5-fold increase in the number of crypt enterocytes. γ-H2AX immunostaining was elevated in villi, but not in the crypt compartment. µ-XRF maps revealed mean Cr levels >30 times higher in duodenal villi than crypt regions; mean Cr levels in crypt regions were only slightly above background signal. Despite the presence of Cr andmore » elevated γ-H2AX immunoreactivity in villi, no aberrant foci indicative of transformation were evident. Lastly, these findings do not support a MOA for intestinal carcinogenesis involving direct Cr-DNA interaction in intestinal stem cells, but rather support a non-mutagenic MOA involving chronic wounding of intestinal villi and crypt cell hyperplasia.« less
Authors:
 [1] ;  [2] ;  [2] ;  [3] ;  [4] ;  [4] ;  [5] ;  [6] ;  [7] ;  [1] ;  [8] ;  [9] ;  [1]
  1. ToxStrategies, Inc., Katy, TX (United States)
  2. U.S. Army Engineer Research and Development Center, Vicksburg, MS (United States)
  3. Brookhaven National Lab. (BNL), Upton, NY (United States). Photon Sciences Dept.
  4. ToxStrategies, Inc., Mission Viejo, CA (United States)
  5. Experimental Pathology Lab., Sterling, VA (United States)
  6. ToxStrategies, Inc., Austin, TX (United States)
  7. Environmental Standards, Inc., Valley Forge, PA (United States)
  8. Summit Toxicology, LLP, Orange Village, OH (United States)
  9. Summit Toxicology, LLP, Allenspark, CO (United States)
Publication Date:
OSTI Identifier:
1229430
Report Number(s):
BNL--111506-2015-JA
Journal ID: ISSN 1096-6080
Grant/Contract Number:
SC00112704; FG02-92ER14244
Type:
Accepted Manuscript
Journal Name:
Toxicological Sciences
Additional Journal Information:
Journal Volume: 143; Journal Issue: 1; Journal ID: ISSN 1096-6080
Publisher:
Oxford University Press
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
47 OTHER INSTRUMENTATION; 59 BASIC BIOLOGICAL SCIENCES H2AX; carcinogenesis; duodenum; synchrotron; Cr(VI); hexavalent chromium; mode of action