Comparison of Toxicity and Recovery in the Duodenum of B6C3F1 Mice Following Treatment with Intestinal Carcinogens Captan, Folpet, and Hexavalent Chromium

Abstract

High concentrations of hexavalent chromium (Cr(VI)), captan, and folpet induce duodenal tumors in mice. Using standardized tissue collection procedures and diagnostic criteria, we compared the duodenal histopathology in B6C3F1 mice following exposure to these 3 carcinogens to determine whether they share similar histopathological characteristics. B6C3F1 mice (n = 20 per group) were exposed to 180 ppm Cr(VI) in drinking water, 12,000 ppm captan in feed, or 16,000 ppm folpet in feed for 28 days. After 28 days of exposure, villous enterocyte hypertrophy and mild crypt epithelial hyperplasia were observed in all exposed mice. In a subset of mice allowed to recover for 28 days, duodenal samples were generally indistinguishable from those of unexposed mice. Changes in the villi and lack of observable damage to the crypt compartment suggest that toxicity was mediated in the villi, which is consistent with earlier studies on each chemical. These findings indicate that structurally diverse agents can induce similar (and reversible) phenotypic changes in the duodenum. These intestinal carcinogens likely converge on common pathways involving irritation and wounding of the villi leading to crypt regenerative hyperplasia that, under protracted high-dose exposure scenarios, increases the risk of spontaneous mutation and tumorigenesis.

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

“…The in-life study details are described elsewhere. 6 In brief, the study was conducted at Charles River (Spencerville, Ohio) following Good Laboratory Practice standards. Exposed mice were treated with Cr(VI) in the form of sodium dichromate dihydrate (99.95% pure; CAS 7789-12-0; Sigma-Aldrich Inc, Milwaukee, Wisconsin), captan (98.3% purity; CAS 133-060-2; AK Scientific, Inc, Union City, California), and folpet (98% purity; CAS 133-07-3; Santa Cruz Biotechnology, Inc., Santa Cruz, California).…”

“…The rationale for dose selection was provided previously 6 ; 180 ppm Cr(VI) and 16 000 ppm captan represent the highest concentration employed in their respective cancer bioassays. 3,2 Because evidence indicates that these carcinogens require long-term exposure to induce tumors, the highest carcinogenic concentrations were used for these short-term studies.…”

“…6 Despite the obvious structural differences between Cr(VI) and the 2 fungicides, the histopathological effects in the duodenum were quite similar, involving villus cytotoxicity and crypt hyperplasia. 6…”

“…The purpose of this study was to extend the histopathological analyses in Thompson et al (2017) 6 to assess the transcriptomic responses to the 3 intestinal carcinogens. To this end, we extracted RNA from formalin-fixed intestinal tissue sections from the aforementioned study.…”

Exposure to the Fungicide Captan Induces DNA Base Alterations and Replicative Stress in Mammalian Cells

“…Under in vivo conditions, the presence of thiol‐rich environment such as cysteine or glutathione found in blood or liver, could explain the absence of genotoxicity by the rapid elimination of the reactive and volatile breakdown product of captan, the thiophosgene (Swenberg et al ; Moriya et al ; Gordon ). Thus, the increased tumor risk observed in mice might be due to chronic mucosal wounding and regenerative hyperplasia (Arce et al ; Thompson et al ), leading to non‐genotoxic effects inducing duodenal carcinogenesis. Nevertheless, Mac Cauley and colleagues have described a significant positive association between DNA damage in oral human leukocytes using alkaline comet assay and urinary concentration of the captan metabolite tetrahydrophthalimide (McCauley et al ).…”