Intestinal lymphangiectasis and lipidosis in rats following subchronic exposure to indole-3-carbinol via oral gavage.
To investigate the toxicity and carcinogenic potential of indole-3-carbinol (I3C), the National Toxicology Program has conducted 13-week subchronic studies in Fisher 344 rats and B6C3F1 mice, and chronic 2-year bioassays in Sprague-Dawley rats and B6C3F1 mice. While the chronic study results are not yet available, subchronic study results and short-term special evaluations of interim sacrifices in the 2-year rat bioassay are presented. F344 rats were orally gavaged ≤300 mg I3C/kg body weight 5 days a week for 13 weeks. Rats treated with ≥150 mg/kg demonstrated a dose-related dilation of lymphatics (lymphangiectasis) of the duodenum, jejunum, and mesenteric lymph nodes. Material within dilated lacteals stained positively for Oil Red O and Sudan Black, consistent with lipid. Electron microscopic evaluation confirmed extracellular lipid accumulation within the villar lamina propria, lacteals, and within villar macrophages. Analyses of hepatic and pulmonary CYP1A enzymes demonstrated dose-dependent I3C induction of CYP1A1 and 1A2. B6C3F1 mice orally gavaged ≤250 mg I3C/kg body weight did not demonstrate histopathological changes; however, hepatic CYP induction was similar to that in rats. The histopathologic changes of intestinal lymphangiectasis and lipidosis in this study share similarities with intestinal lymphangiectasia as observed in humans and dogs. However, the resultant clinical spectrum of protein-losing enteropathy was not present.
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Michael C
MC
Boyle
Torrie A
TA
Crabbs
Michael E
ME
Wyde
J Todd
JT
Painter
Georgette D
GD
Hill
David E
DE
Malarkey
Warren G
WG
Lieuallen
Abraham
A
Nyska
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D005260:Female; D006651:Histocytochemistry; D007211:Indoles / Q000008:administration & dosage / Q000633:toxicity*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008064:Lipidoses / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008201:Lymphangiectasis, Intestinal / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D036401:Toxicity Tests, Chronic; D059550:Toxicity Tests, Subchronic
D007211:Indoles; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2