title: Effects of acrylamide exposure on serum hormones, gene expression, cell proliferation, and histopathology in male reproductive tissues of Fischer 344 rats.
abstract: Acrylamide (AA) is a reactive monomer used in many technological applications, but it is the incidental formation during cooking of common starchy foods that leads to pervasive human exposure, typically in the range of 1 μg/kg body weight (bw)/day (d). AA is carcinogenic in multiple organs from both sexes of several rodent models and a consistent body of evidence points to a genotoxic mechanism based on metabolism to a DNA-reactive epoxide, glycidamide (GA). In F344 rats, tumorigenesis occurs in several hormonally regulated tissues (thyroid, mammary gland, and peri-testicular mesothelium), which has prompted speculation about endocrine dysregulation as a possible mechanism. The present study evaluated the effects of a 14 d exposure to AA administered through the drinking water on reproductive tissues and the hypothalamic-pituitary-testes (HPG) axis in male F344 rats. The doses selected encompass a range from approximately 2.5 mg/kg bw/d, which is carcinogenic after lifetime exposure, to 50 mg/kg bw/d, a maximally tolerable dose that causes hind limb paralysis. AA caused significant changes in serum hormones, histopathology, testicular gene expression, and cell proliferation, especially at the highest dose. Despite strong evidence for activation of the HPG axis subsequent to decreases in testosterone levels, and histopathological changes associated with significant effects on Leydig and germ cells, with concomitant mRNA expression changes, the precise mechanism(s) for AA-induced testicular toxicity remains unclear; however, the absence of evidence for increased proliferation of the peri-testicular mesothelium (Ki-67 immunoreactivity) does not support hormonal dysregulation as a contributing factor to the predisposition of this tissue to the carcinogenic effects of AA.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
authors.forename: L
authors.initials: L
authors.lastname: Camacho
authors.forename: J R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: L
authors.initials: L
authors.lastname: Muskhelishvili
authors.forename: R
authors.initials: R
authors.lastname: Patton
authors.forename: J F
authors.initials: JF
authors.lastname: Bowyer
authors.forename: M
authors.initials: M
authors.lastname: Thomas
authors.forename: D R
authors.initials: DR
authors.lastname: Doerge
mesh_terms: D020106:Acrylamide / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D004958:Estradiol / Q000097:blood; D005640:Follicle Stimulating Hormone / Q000097:blood; D020869:Gene Expression Profiling; D006728:Hormones / Q000097:blood*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D007985:Leydig Cells / Q000187:drug effects; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D013737:Testis / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000097:blood
chemical_list: D006728:Hormones; D020106:Acrylamide; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone