Release and toxicity of adipose tissue-stored TCDD: Direct evidence from a xenografted fat model

Nolwenn Joffin (1, 2, 3) , Philippe Noirez (4, 1, 2, 5, 6, 3, 7, 8) , Jean-Philippe Antignac (9) , Min-Ji Kim (1, 7) , Philippe Marchand (9) , Marion Falabrègue (2, 5, 4, 3) , Bruno Le Bizec (9) , Claude Forest (1, 2, 3) , Claude Emond (10, 6, 11) , Robert Barouki (1, 2, 3) , Xavier Coumoul (1, 2, 3)

1 T3S - UMR_S 1124 - Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire
2 UPD5 - Université Paris Descartes - Paris 5
3 USPC - Université Sorbonne Paris Cité
4 INSEP - Institut national du sport, de l'expertise et de la performance
5 IRMES - EA 7329 - Institut de recherche biomédicale et d’épidémiologie du sport
6 UQAM - Université du Québec à Montréal = University of Québec in Montréal
7 UP13 - Université Paris 13
8 PSMS - Performance, Santé, Métrologie, Société - EA 7507
9 LABERCA - Laboratoire d'étude des Résidus et Contaminants dans les Aliments
10 BioSimulation Consulting Inc.
11 UdeM - Université de Montréal

Background Persistent organic pollutants (POPs) are known to accumulate in adipose tissues (AT). This storage may be beneficial by diverting POPs from other sensitive tissues or detrimental because of chronic release of pollutants as indirectly suggested during weight loss. The aim is to study the biological and/or toxic effects that chronic POP release from previously contaminated grafted AT could exert in a naïve mouse. Methods C57BL/6J male mice were exposed intraperitoneally to 2,3,7,8-tetrachlorodibenzo-p-doxin (TCDD); their epididymal fat pads were collected and grafted on the back skin of uncontaminated recipient mice whose brain, liver, and epididymal ATs were analyzed (TCDD concentration, relevant gene expression). Kinetics of release and redistribution were modeled using Physiologically Based PharmacoKinetics (PBPK). Results The grafts released TCDD over a period of 10 weeks with different kinetics of distribution in the three organs studied. A PBPK model was used to simulate the AT releasing process and the incorporation of TCDD into the major organs. At three weeks post-graft, we observed significant changes in gene expression in the liver and the host AT with signatures reminiscent of inflammation, gluconeogenesis and fibrosis as compared to the control. Conclusions This study confirms that AT-stored TCDD can be released and distributed to the organs of the recipient hence leading to distinct changes in gene expression. This original model provides direct evidence of the potential toxic-relevant effects when endogenous sources of contamination are present.

Mots clés: TCDD; PBPK; Dioxin; Internal release; Adipose tissue; Graft; Fibrosis

Domaines: Santé; Toxicologie; Sciences de l'environnement

Nolwenn Joffin, Philippe Noirez, Jean-Philippe Antignac, Min-Ji Kim, Philippe Marchand, et al.. Release and toxicity of adipose tissue-stored TCDD: Direct evidence from a xenografted fat model. Environment International, 2018, 121, pp.1113-1120. ⟨10.1016/j.envint.2018.10.027⟩. ⟨hal-01922515⟩