title: Effects of cigarette smoke, cessation and switching to a candidate modified risk tobacco product on the liver in Apoe -/- mice--a systems toxicology analysis.
abstract: The liver is one of the most important organs involved in elimination of xenobiotic and potentially toxic substances. Cigarette smoke (CS) contains more than 7000 chemicals, including those that exert biological effects and cause smoking-related diseases. Though CS is not directly hepatotoxic, a growing body of evidence suggests that it may exacerbate pre-existing chronic liver disease. In this study, we integrated toxicological endpoints with molecular measurements and computational analyses to investigate effects of exposures on the livers of Apoe(-/- )mice. Mice were exposed to 3R4F reference CS, to an aerosol from the Tobacco Heating System (THS) 2.2, a candidate modified risk tobacco product (MRTP) or to filtered air (Sham) for up to 8 months. THS2.2 takes advantage of a "heat-not-burn" technology that, by heating tobacco, avoids pyrogenesis and pyrosynthesis. After CS exposure for 2 months, some groups were either switched to the MRTP or filtered air. While no group showed clear signs of hepatotoxicity, integrative analysis of proteomics and transcriptomics data showed a CS-dependent impairment of specific biological networks. These networks included lipid and xenobiotic metabolism and iron homeostasis that likely contributed synergistically to exacerbating oxidative stress. In contrast, most proteomic and transcriptomic changes were lower in mice exposed to THS2.2 and in the cessation and switching groups compared to the CS group. Our findings elucidate the complex biological responses of the liver to CS exposure. Furthermore, they provide evidence that THS2.2 aerosol has reduced biological effects, as compared with CS, on the livers of Apoe(-/- )mice.
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lo Sasso
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Bjoern
authors.initials: B
authors.lastname: Titz
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Catherine
authors.initials: C
authors.lastname: Nury
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boué
authors.affiliation: b Philip Morris International Research Laboratories , Singapore , Singapore , and.
authors.forename: Blaine
authors.initials: B
authors.lastname: Phillips
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Belcastro
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Thomas
authors.initials: T
authors.lastname: Schneider
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Sophie
authors.initials: S
authors.lastname: Dijon
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Karine
authors.initials: K
authors.lastname: Baumer
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Daruisz
authors.initials: D
authors.lastname: Peric
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Remi
authors.initials: R
authors.lastname: Dulize
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Ashraf
authors.initials: A
authors.lastname: Elamin
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.affiliation: c Histovia GmbH , Overath , Germany.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Buettner
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Patrice
authors.initials: P
authors.lastname: Leroy
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Samuel
authors.initials: S
authors.lastname: Kleinhans
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Gregory
authors.initials: G
authors.lastname: Vuillaume
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Emilija
authors.initials: E
authors.lastname: Veljkovic
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanscheeuwijck
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.affiliation: a Philip Morris International Research and Development , Neuchatel , Switzerland .
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D005260:Female; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D018345:Mice, Knockout; D040901:Proteomics; D012306:Risk; D012906:Smoke; D016540:Smoking Cessation; D062789:Tobacco Products / Q000633:toxicity*
chemical_list: D001057:Apolipoproteins E; D012906:Smoke
keywords: Data integration; inhalation toxicology; lipidomics; modified risk tobacco product; quantitative proteomics; reduced risk product; systems toxicology; transcriptomics