title: Impact of Acrylamide on Calcium Signaling and Cytoskeletal Filaments in Testes From F344 Rat.
abstract: Acrylamide (AA) at high exposure levels is neurotoxic, induces testicular toxicity, and increases dominant lethal mutations in rats. RNA-sequencing in testes was used to identify differentially expressed genes (DEG), explore AA-induced pathway perturbations that could contribute to AA-induced testicular toxicity and then used to derive a benchmark dose (BMD). Male F344/DuCrl rats were administered 0.0, 0.5, 1.5, 3.0, 6.0, or 12.0 mg AA/kg bw/d in drinking water for 5, 15, or 31 days. The experimental design used exposure levels that spanned and exceeded the exposure levels used in the rat dominant lethal, 2-generation reproductive toxicology, and cancer bioassays. The time of sample collection was based on previous studies that developed gene expression-based BMD. At 12.0 mg/kg, there were 38, 33, and 65 DEG ( P value <.005; fold change >1.5) in the testes after 5, 15, or 31 days of exposure, respectively. At 31 days, there was a dose-dependent increase in the number of DEG, and at 12.0 mg/kg/d the top three functional clusters affected by AA exposure were actin filament organization, response to calcium ion, and regulation of cell proliferation. The BMD lower 95% confidence limit using DEG ranged from 1.8 to 6.8 mg/kg compared to a no-observed-adverse-effect-level of 2.0 mg/kg/d for male reproductive toxicity. These results are consistent with the known effects of AA on calcium signaling and cytoskeletal actin filaments leading to neurotoxicity and suggest that AA can cause rat dominant lethal mutations by these same mechanisms leading to impaired chromosome segregation during cell division.
authors.affiliation: 1 Integrated Laboratory Systems Inc, Research Triangle Park, NC, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Recio
authors.affiliation: 2 SNF SAS, rue Adrienne Bolland, ZAC de Milieux, Andrézieux, Rhône-Alpes, France.
authors.forename: Marvin
authors.initials: M
authors.lastname: Friedman
authors.affiliation: 2 SNF SAS, rue Adrienne Bolland, ZAC de Milieux, Andrézieux, Rhône-Alpes, France.
authors.forename: Dennis
authors.initials: D
authors.lastname: Marroni
authors.affiliation: 1 Integrated Laboratory Systems Inc, Research Triangle Park, NC, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Maynor
authors.affiliation: 3 Chepelev Consulting, Ottawa, Ontario, Canada.
authors.forename: Nikolai L
authors.initials: NL
authors.lastname: Chepelev
mesh_terms: D020106:Acrylamide / Q000633:toxicity*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D003599:Cytoskeleton / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D011916:Rats, Inbred F344; D013737:Testis / Q000187:drug effects* / Q000378:metabolism
chemical_list: D020106:Acrylamide
keywords: acrylamide; gene expression