The effects of subchronic acrylamide exposure on gene expression, neurochemistry, hormones, and histopathology in the hypothalamus-pituitary-thyroid axis of male Fischer 344 rats
- U.S. Food and Drug Administration, National Center for Toxicological Research, Division of Neurotoxicology, 3900 NCTR Road, Jefferson, AR 72079 (United States)
- U.S. Food and Drug Administration, National Center for Toxicological Research, Division of Toxicologic Pathology Associates, 3900 NCTR Road, Jefferson, AR 72079 (United States)
- Department of Epidemiology, University of Arkansas for Medical Sciences, College of Public Health, 4301 W Markham Street, 820, Little Rock, AR 72205 (United States)
- U.S. Food and Drug Administration, National Center for Toxicological Research, Division of Personalized Nutrition and Medicine, 3900 NCTR Road, Jefferson, AR 72079 (United States)
- U.S. Food and Drug Administration, National Center for Toxicological Research, Division of Genetic and Reproductive Toxicology, 3900 NCTR Road, Jefferson, AR 72079 (United States)
Acrylamide (AA) is an important industrial chemical that is neurotoxic in rodents and humans and carcinogenic in rodents. The observation of cancer in endocrine-responsive tissues in Fischer 344 rats has prompted hypotheses of hormonal dysregulation, as opposed to DNA damage, as the mechanism for tumor induction by AA. The current investigation examines possible evidence for disruption of the hypothalamic-pituitary-thyroid axis from 14 days of repeated exposure of male Fischer 344 rats to doses of AA that range from one that is carcinogenic after lifetime exposure (2.5 mg/kg/d), an intermediate dose (10 mg/kg/d), and a high dose (50 mg/kg/d) that is neurotoxic for this exposure time. The endpoints selected include: serum levels of thyroid and pituitary hormones; target tissue expression of genes involved in hormone synthesis, release, and receptors; neurotransmitters in the CNS that affect hormone homeostasis; and histopathological evaluation of target tissues. These studies showed virtually no evidence for systematic alteration of the hypothalamic-pituitary-thyroid axis and do not support hormone dysregulation as a plausible mechanism for AA-induced thyroid cancer in the Fischer 344 rat. Specifically, there were no significant changes in: 1) mRNA levels in hypothalamus or pituitary for TRH, TSH, thyroid hormone receptor {alpha} and {beta}, as well 10 other hormones or releasing factors; 2) mRNA levels in thyroid for thyroglobulin, thyroid peroxidase, sodium iodide symporter, or type I deiodinases; 3) serum TSH or T3 levels (T4 was decreased at high dose only); 4) dopaminergic tone in the hypothalamus and pituitary or importantly 5) increased cell proliferation (Mki67 mRNA and Ki-67 protein levels were not increased) in thyroid or pituitary. These negative findings are consistent with a genotoxic mechanism of AA carcinogenicity based on metabolism to glycidamide and DNA adduct formation. Clarification of this mechanistic dichotomy may be useful in human cancer risk assessments for AA.
- OSTI ID:
- 21140895
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 230, Issue 2; Other Information: DOI: 10.1016/j.taap.2008.02.028; PII: S0041-008X(08)00098-7; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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