The liver-testis axis: from physiology to xenobiotic-induced pathologies – Liten

Environmental contaminants contribute to the increased incidence of non-alcoholic fatty liver disease and reproductive disorders. The links between hepatic and reproductive disorders suggest etiological mechanisms that would involve the disruption of a bidirectional dialogue between liver and testis. Modulation of the nuclear receptor CAR (Constitutive Androstane Receptor) signalling pathways represents a mechanism for altering liver and testicular functions and/or the reciprocal regulatory systems of these functions. This may contribute to the endocrine and metabolic disrupting effects of CAR modulators including alkyl perfluorinated compounds (PFCs) which are of concern due to the high level of human exposure.
We will analyse the implications of CAR and PFCs in the regulation of energy homeostasis and reproduction and on the reciprocal impacts of hepatic and testicular perturbations in the genesis of metabolic and/or fertility disorders. Mice invalidated for CAR specifically in the liver or testis (Leydig or germ cells) will be exposed in utero and during lactation to a mixture of four PFCs (PFOA, PFNA, PFHxS and PFOS) at doses reproducing human exposure. The effects of CAR deletion and exposure to PFCs will be assessed to evaluate the kinetics of the incidence of liver and testicular disorders. Correlation analyses between hepatic and testicular markers and potential mediators of the liver-testis dialogue will determine the involvement of this dialogue in the observed phenotypes.
The integrated approach of the interrelations between hepatic and testicular functions in a context of environmental exposure will define the mechanisms that link reproductive and metabolic functions and their implication in the effects of endocrine and metabolic disruptors of major interest in public health.