title: The effects of subchronic acrylamide exposure on gene expression, neurochemistry, hormones, and histopathology in the hypothalamus-pituitary-thyroid axis of male Fischer 344 rats.
abstract: 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.
authors.affiliation: U.S. Food and Drug Administration, National Center for Toxicological Research, Division of Neurotoxicology, 3900 NCTR Road, Jefferson, AR 72079, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Bowyer
authors.forename: J R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: R R
authors.initials: RR
authors.lastname: Delongchamp
authors.forename: L
authors.initials: L
authors.lastname: Muskhelishvili
authors.forename: A R
authors.initials: AR
authors.lastname: Warbritton
authors.forename: M
authors.initials: M
authors.lastname: Thomas
authors.forename: E
authors.initials: E
authors.lastname: Tareke
authors.forename: L P
authors.initials: LP
authors.lastname: McDaniel
authors.forename: D R
authors.initials: DR
authors.lastname: Doerge
mesh_terms: D000178:Acrylamides / Q000633:toxicity*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006728:Hormones / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D011916:Rats, Inbred F344; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000178:Acrylamides; D015306:Biogenic Monoamines; D018076:DNA, Complementary; D006728:Hormones; D017981:Receptors, Neurotransmitter; D012313:RNA