skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Journal Article · · Toxicological Sciences
 [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)
+ Show Author Affiliations

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 and 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.

Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
SC00112704; FG02-92ER14244
OSTI ID:
1229430
Report Number(s):
BNL-111506-2015-JA
Journal Information:
Toxicological Sciences, Vol. 143, Issue 1; ISSN 1096-6080
Publisher:
Oxford University PressCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 30 works
Citation information provided by
Web of Science

References (32)

Hexavalent chromium reduction kinetics in rodent stomach contents journal October 2012
Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans journal February 2013
Crypt stem cells as the cells-of-origin of intestinal cancer journal December 2008
Captan: Transition from ‘B2’ to ‘not likely’. How pesticide registrants affected the EPA Cancer Classification Update journal January 2007
An evaluation of the mode of action framework for mutagenic carcinogens case study II: Chromium (VI) journal January 2009
γH2AX and cancer journal November 2008
Metabolic deactivation of mutagens in the Salmonella-microsome test journal February 1978
Stem Cells, Self-Renewal, and Differentiation in the Intestinal Epithelium journal March 2009
Mutation and Cancer: A Model for Human Carcinogenesis2 journal June 1981
Carcinogenic mode of action of folpet in mice and evaluation of its relevance to humans journal February 2010
Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia following 7 and 90days of exposure to hexavalent chromium in drinking water journal February 2012
Genesis of hexavalent chromium from natural sources in soil and groundwater journal April 2007
Chronic toxicity and carcinogenicity studies of chromium picolinate monohydrate administered in feed to F344/N rats and B6C3F1 mice for 2 years journal April 2009
Physiologically based pharmacokinetic model for humans orally exposed to chromium journal June 2013
Assessment of K-Ras mutant frequency and micronucleus incidence in the mouse duodenum following 90-days of exposure to Cr(VI) in drinking water journal June 2013
Chromium in Drinking Water: Sources, Metabolism, and Cancer Risks journal October 2011
Chromium genotoxicity: A double-edged sword journal November 2010
Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium journal October 2012
Complexities of chromium carcinogenesis: role of cellular response, repair and recovery mechanisms journal December 2003
Investigation of the Mode of Action Underlying the Tumorigenic Response Induced in B6C3F1 Mice Exposed Orally to Hexavalent Chromium journal June 2011
Assessment of Cr(VI)-Induced Cytotoxicity and Genotoxicity Using High Content Analysis journal August 2012
Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties journal January 2013
 -H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin journal August 2008
Comparison of the Effects of Hexavalent Chromium in the Alimentary Canal of F344 Rats and B6C3F1 Mice Following Exposure in Drinking Water: Implications for Carcinogenic Modes of Action journal October 2011
Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins: Corrigendum journal June 2012
Hexavalent Chromium Is Carcinogenic to F344/N Rats and B6C3F1 Mice after Chronic Oral Exposure journal May 2009
Estimates of the chromium(VI) reducing capacity in human body compartments as a mechanism for attenuating its potential toxicity and carcinogenicity journal March 1997
Gut stem cells in tissue renewal and disease: methods, markers, and myths: Gut stem cells journal May 2012
A general probabilistic model of carcinogenesis: analysis of experimental urinary bladder cancer journal January 1984
Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats journal March 2001
Chromium Isotopes and the Fate of Hexavalent Chromium in the Environment journal March 2002
Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt journal December 1990

Cited By (10)

Comparison of Gene Expression Responses in the Small Intestine of Mice Following Exposure to 3 Carcinogens Using the S1500+ Gene Set Informs a Potential Common Adverse Outcome Pathway journal July 2019
Oral Chromium Exposure and Toxicity journal June 2015
Comparison of Toxicity and Recovery in the Duodenum of B6C3F1 Mice Following Treatment with Intestinal Carcinogens Captan, Folpet, and Hexavalent Chromium journal November 2017
Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water journal November 2015
Chromium disrupts chromatin organization and CTCF access to its cognate sites in promoters of differentially expressed genes text January 2018
Influence of Chronic Toxicity, Lipid Metabolism, Learning and Memory Ability, and Related Enzyme in Sprague-Dawley Rats by Long-Term Chromium Malate Supplementation journal May 2018
Chromium disrupts chromatin organization and CTCF access to its cognate sites in promoters of differentially expressed genes journal April 2018
High-Throughput Screening Data Interpretation in the Context of In Vivo Transcriptomic Responses to Oral Cr(VI) Exposure journal May 2017
Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin-of-exposure values for hexavalent chromium journal October 2017
Myricetin induces apoptosis via endoplasmic reticulum stress and DNA double-strand breaks in human ovarian cancer cells journal January 2016

Similar Records

Duodenal crypt health following exposure to Cr(VI): Micronucleus scoring, γ-H2AX immunostaining, and synchrotron X-ray fluorescence microscopy
Journal Article · Sat Aug 01 00:00:00 EDT 2015 · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · OSTI ID:1229430
+9 more
Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia following 7 and 90 days of exposure to hexavalent chromium in drinking water
Journal Article · Wed Feb 15 00:00:00 EST 2012 · Toxicology and Applied Pharmacology · OSTI ID:1229430
+4 more
Comparative toxicogenomic analysis of oral Cr(VI) exposure effects in rat and mouse small intestinal epithelia
Journal Article · Sun Jul 15 00:00:00 EDT 2012 · Toxicology and Applied Pharmacology · OSTI ID:1229430
+1 more

Related Subjects

47 OTHER INSTRUMENTATION
59 BASIC BIOLOGICAL SCIENCES
H2AX
carcinogenesis
duodenum
synchrotron
Cr(VI)
hexavalent chromium
mode of action