title: Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity.
abstract: Numerous studies support the fact that a genetically diverse mouse population may be useful as an animal model to understand and predict toxicity in humans. We hypothesized that cultures of hepatocytes obtained from a large panel of inbred mouse strains can produce data indicative of inter-individual differences in in vivo responses to hepato-toxicants. In order to test this hypothesis and establish whether in vitro studies using cultured hepatocytes from genetically distinct mouse strains are feasible, we aimed to determine whether viable cells may be isolated from different mouse inbred strains, evaluate the reproducibility of cell yield, viability and functionality over subsequent isolations, and assess the utility of the model for toxicity screening. Hepatocytes were isolated from 15 strains of mice (A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, BALB/cByJ, AKR/J, MRL/MpJ, NOD/LtJ, NZW/LacJ, PWD/PhJ and WSB/EiJ males) and cultured for up to 7 days in traditional 2-dimensional culture. Cells from B6C3F1, C57BL/6J, and NOD/LtJ strains were treated with acetaminophen, WY-14,643 or rifampin and concentration-response effects on viability and function were established. Our data suggest that high yield and viability can be achieved across a panel of strains. Cell function and expression of key liver-specific genes of hepatocytes isolated from different strains and cultured under standardized conditions are comparable. Strain-specific responses to toxicant exposure have been observed in cultured hepatocytes and these experiments open new opportunities for further developments of in vitro models of hepatotoxicity in a genetically diverse population.
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Martinez
authors.forename: Blair U
authors.initials: BU
authors.lastname: Bradford
authors.forename: Valerie Y
authors.initials: VY
authors.lastname: Soldatow
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.forename: Amelia
authors.initials: A
authors.lastname: Sandot
authors.forename: Rafal
authors.initials: R
authors.lastname: Witek
authors.forename: Robert
authors.initials: R
authors.lastname: Kaiser
authors.forename: Todd
authors.initials: T
authors.lastname: Stewart
authors.forename: Kirsten
authors.initials: K
authors.lastname: Amaral
authors.forename: Kimberly
authors.initials: K
authors.lastname: Freeman
authors.forename: Chris
authors.initials: C
authors.lastname: Black
authors.forename: Edward L
authors.initials: EL
authors.lastname: LeCluyse
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Ferguson
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D023421:Models, Animal; D011743:Pyrimidines / Q000633:toxicity; D012293:Rifampin / Q000633:toxicity; D018675:Toxicity Tests
chemical_list: D018712:Analgesics, Non-Narcotic; D000904:Antibiotics, Antitubercular; D011743:Pyrimidines; D000082:Acetaminophen; C006253:pirinixic acid; D012293:Rifampin