Fœtal impact of glucocorticoids in the programming of the disease

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  • SFE Lyon 2014 / Annales dEndocrinologie 75 (2014) 250251 251

    mieux dfinir lHMBS. Outre les connaissances en physiopathologie la descrip-tion de ces causes gntiques ouvre des perspectives de dpistage prcoce decette maladie.

    Dclaration dintrts Lauteur na pas transmis de dclaration de conflitsdintrts.

    http://dx.doi.org/10.1016/j.ando.2014.07.007

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    Ftal impact of glucocorticoids in theprogramming of the diseaseJ. Seckl (Pr)The Queens Medical Research Institute, University Edinburgh, 47 LittleFrance Crescent, Edinburgh EH16 4TJ, UKE-mail address: j.seckl@ed.ac.uk

    Epidemiological and experimental evidence suggests that an adverse fetal envi-ronment permanently programmes physiology leading to increased risks ofcardiometabolic and neuropsychiatric disorders in later life. We originally hypo-thesised that fetal glucocorticoid overexposure might underpin this link. Ingenetically identical rodents, prenatal stress, glucocorticoid overexposure orinhibition/knockout of 11-hydroxysteroid dehydrogenase type 2 (11-HSD2),the feto-placental barrier to maternal glucocorticoids, reduces birth weightand causes permanent hypertension, hyperglycaemia, increased hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviours in adultoffspring. The phenotype persists into a second generation and transmits viamale and female lines. This implies epigenetic mediation, a mechanism emer-ging for HPA axis and metabolic programming. However, whilst first and secondgeneration phenotypes are similar, the molecular mechanisms and epigeneticmarkers differ in each generation, implying strong selection on phenotype butweighing against neo-Lamarckian notions of epigenetic inheritance.Glucocorticoid programming appears of clinical relevance. In humans, placen-tal 11-HSD2 activity correlates directly with birth weight and inversely withinfant blood pressure. Moreover, low birth weight babies have higher plasmacortisol levels throughout adult life, indicating HPA programming. Indeed,maternal glucocorticoid therapy or ingestion of liquorice (which inhibits 11-HSD) alters offspring cognition, behaviour and HPA axis function. Stress hassimilar effects since the offspring of women pregnant during and directly expo-sed to the 9.11.2001 atrocity and who developed PTSD exhibit neuroendocrinechanges but only if exposure was in the third trimester. Furthermore, expo-sure to the Nazi Holocaust exerted permanent effects upon glucocorticoid levelsand steroid metabolism, effects dependent upon the age at exposure. The second(unexposed) generation also shows altered cortisol levels and metabolism, againwith discordance in detail between generations. Overall, the data suggest thatdevelopmental exposure to excess glucocorticoids/stress programmes peripheraland CNS functions in adult life, predisposing to affective and other pathology,

    and these effects may impact on a subsequent generation. Any core mechanis-tic role for epigenetic processes in such early environment-induced effects isattractive but remains to be unequivocally established.

    Disclosure of interest The author has not supplied his declaration of conflictof interest.

    http://dx.doi.org/10.1016/j.ando.2014.07.008

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    La sdentarit, un facteur de risque partentire : de lcologie la preuvephysiopathologiqueC. Simon (Pr) a,, E. Lefai ba CarMEN INSERM U1060, Universit de Lyon, CRNH Rhne-Alpes, Lyon,Franceb CarMEN INSERM U1060, Universit de Lyon, Lyon, France Auteur correspondant.Adresse e-mail : chantal.simon@univ-lyon1.fr (C. Simon)

    Lvolution des modes de vie et les changements socitaux ont entran unediminution majeure des activits physiques de la vie quotidienne (AVQ),qui reprsentent aujourdhui peine 65 % de celle de lhomme de lge depierre, et une augmentation des occupations sdentaires. Il est admis que,de ce fait, lactivit physique est aujourdhui en dessous du niveau pourlequel notre biologie a t programme au cours de lvolution et que cecicontribue laugmentation rcente des maladies mtaboliques et cardiovas-culaires ou de certains cancers. De facon surprenante, par opposition lamasse de connaissances accumules sur les effets de lexercice (sous-tendantles recommandations actuelles), nous navons que peu de donnes sur lesrponses molculaires, physiologiques et cliniques associes une diminu-tion des AVQ ou une station assise prolonge. Des tudes pidmiologiquesrcentes indiquent pourtant que le temps pass assis et un faible niveau dAVQ,mme peu intenses, sont des facteurs de risque de maladie chronique et demortalit prcoce, indpendamment de la pratique rgulire dun exercice.Dun autre ct quelques travaux suggrent que les effets des AVQ et de lastation assise ne sont pas expliqus par leur seul impact sur la dpense ner-gtique et impliquent des mcanismes diffrents de ceux de lexercice. Mmesi ces mcanismes et les dterminants de ces deux facettes du comportementsdentaire restent explorer, ce nouveau paradigme de sdentarit a des cons-quences importantes en termes de sant publique et ouvre de nouvelles voiesthrapeutiques.

    Dclaration dintrts Les auteurs nont pas transmis de dclaration deconflits dintrts.

    http://dx.doi.org/10.1016/j.ando.2014.07.009

    dx.doi.org/10.1016/j.ando.2014.07.007http://crossmark.crossref.org/dialog/?doi=10.1016/j.ando.2014.07.008&domain=pdfmailto:j.seckl@ed.ac.ukdx.doi.org/10.1016/j.ando.2014.07.008http://crossmark.crossref.org/dialog/?doi=10.1016/j.ando.2014.07.009&domain=pdfmailto:chantal.simon@univ-lyon1.frdx.doi.org/10.1016/j.ando.2014.07.009

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