title: Genotoxic risk of ethyl-paraben could be related to telomere shortening.
abstract: The ability of parabens to promote the appearance of multiple cancer hallmarks in breast epithelium cells provides grounds for regulatory review of the implication of the presence of parabens in human breast tissue. It is well documented that telomere dysfunction plays a significant role in the initiation of genomic instability during carcinogenesis in human breast cancer. In the present study, we evaluated the genotoxic effect of ethyl 4-hydroxybenzoate (ethyl-paraben), with and without metabolic activation (S9), in studies following OECD guidelines. We observed a significant increase in genotoxic damage using the Mouse Lymphoma Assay and in vitro micronucleus (MN) tests in the L5178Y cell line in the presence of S9 only after a short exposure. A high frequency of MN was observed in the TK6 cells after a short exposure (3 h) in the presence of S9 and a long exposure (26 h) without S9. We found significant increases in the MN frequency and induced chromosomal aberrations in the lymphocytes of only one donor after ethyl-paraben exposure in the presence of S9 after a short exposure. Cytogenetic characterization of the paraben-treated cells demonstrated telomere shortening associated with telomere loss and telomere deletions in L5178Y and TK6 cells and lymphocytes of the paraben sensitive-donor. In a control cohort of 68 human lymphocytes, telomere length and telomere aberrations were age-dependent and showed high inter-individual variation. This study is the first to link telomere shortening and the genotoxic effect of ethyl paraben in the presence of S9 and raises the possibility that telomere shortening may be a proxy for underlying inter-individual sensitivity to ethyl-paraben. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Covance Laboratory, 78440, Porcheville, France.|Cell Environment, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Finot
authors.affiliation: Cell Environment, Paris, France.|Tunis El Manar University, School of Medicine, Tunis, Tunisia.
authors.forename: A
authors.initials: A
authors.lastname: Kaddour
authors.affiliation: Radiology and Oncology Laboratory, IRCM, DSV, Commissariat à l'energie atomique (CEA), Fontenay-aux Roses, France.
authors.forename: L
authors.initials: L
authors.lastname: Morat
authors.affiliation: Covance Laboratory, 78440, Porcheville, France.|Cell Environment, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Mouche
authors.affiliation: Radiology and Oncology Laboratory, IRCM, DSV, Commissariat à l'energie atomique (CEA), Fontenay-aux Roses, France.
authors.forename: N
authors.initials: N
authors.lastname: Zaguia
authors.affiliation: Radiology and Oncology Laboratory, IRCM, DSV, Commissariat à l'energie atomique (CEA), Fontenay-aux Roses, France.
authors.forename: C
authors.initials: C
authors.lastname: Cuceu
authors.affiliation: Covance Laboratory, 78440, Porcheville, France.
authors.forename: D
authors.initials: D
authors.lastname: Souverville
authors.affiliation: Covance Laboratory, 78440, Porcheville, France.
authors.forename: S
authors.initials: S
authors.lastname: Négrault
authors.affiliation: Covance Laboratory, 78440, Porcheville, France.
authors.forename: O
authors.initials: O
authors.lastname: Cariou
authors.affiliation: Covance Laboratory, 78440, Porcheville, France.
authors.forename: A
authors.initials: A
authors.lastname: Essahli
authors.affiliation: Covance Laboratory, 78440, Porcheville, France.
authors.forename: N
authors.initials: N
authors.lastname: Prigent
authors.affiliation: Covance Laboratories, Yorkshire, HG3 1PY, UK.
authors.forename: J
authors.initials: J
authors.lastname: Saul
authors.affiliation: Covance Laboratory, 78440, Porcheville, France.
authors.forename: F
authors.initials: F
authors.lastname: Paillard
authors.affiliation: MetaSystems GmbH, Robert-Bosch-Str. 6, 68804, Altlussheim, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Heidingsfelder
authors.affiliation: Covance Laboratory, 78440, Porcheville, France.
authors.forename: P
authors.initials: P
authors.lastname: Lafouge
authors.affiliation: Cell Environment, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Al Jawhari
authors.affiliation: Radiology and Oncology Laboratory, IRCM, DSV, Commissariat à l'energie atomique (CEA), Fontenay-aux Roses, France.
authors.forename: W M
authors.initials: WM
authors.lastname: Hempel
authors.affiliation: Tunis El Manar University, School of Medicine, Tunis, Tunisia.
authors.forename: M
authors.initials: M
authors.lastname: El May
authors.affiliation: Laboratoire MIPS - Groupe IMTI Université de Haute-Alsace, F-68093, Mulhouse, France.
authors.forename: B
authors.initials: B
authors.lastname: Colicchio
authors.affiliation: Laboratoire MIPS - Groupe IMTI Université de Haute-Alsace, F-68093, Mulhouse, France.
authors.forename: A
authors.initials: A
authors.lastname: Dieterlen
authors.affiliation: Service de génétique Groupe Hospitalier de la Région de Mulhouse et Sud Alsace, 68070, Mulhouse, France.
authors.forename: E
authors.initials: E
authors.lastname: Jeandidier
authors.affiliation: Radiology and Oncology Laboratory, IRCM, DSV, Commissariat à l'energie atomique (CEA), Fontenay-aux Roses, France.
authors.forename: L
authors.initials: L
authors.lastname: Sabatier
authors.affiliation: Covance Laboratories, Yorkshire, HG3 1PY, UK.
authors.forename: J
authors.initials: J
authors.lastname: Clements
authors.affiliation: Cell Environment, Paris, France.|Radiology and Oncology Laboratory, IRCM, DSV, Commissariat à l'energie atomique (CEA), Fontenay-aux Roses, France.
authors.forename: R
authors.initials: R
authors.lastname: M'Kacher
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced* / Q000706:statistics & numerical data; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000633:toxicity*; D010226:Parabens / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D059506:Telomere Shortening / Q000187:drug effects*
chemical_list: D009153:Mutagens; D010226:Parabens; C012313:ethyl-p-hydroxybenzoate
keywords: chromosomal aberrations; ethyl-paraben; metabolic activation; micronucleus; telomere shortening