Inhibition of mTOR, PPARgamma and PPARdelta during early organogenesis induces decidua and feto-placental alterations

ROBERTI S, SATO H, HIGA ROMINA, JAWERBAUM A

Mar del Plata

Congreso; LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC), Buenos Aires, Noviembre de 2017; 2017

SAIC

Our previous studies have shown that mTOR inhibition induces changes in PPARgamma and PPARdelta levels in the decidua during early organogenesis, a period in which it serves for embryo development and histotrophic nutrition. Fatty acid binding protein 4 (FABP4, involved in decidualization and lipid transport) and perilipin2 (PLIN2, involved in lipid accumulation) are PPAR targets. Objective: To evaluate FABP4 and PLIN2 levels in the decidua (day 9 of pregnancy) and measure morphological parameters (day 14 of pregnancy) in rats treated or not with rapamycin (mTOR inhibitor), T0070907 (PPARgamma inhibitor) and GSK0660 (PPARdelta inhibitor) from days 7 to 9 of pregnancy. Methods: Female rats were mated and received sc injections of rapamycin, T0070907, GSK0660 or vehicle during days 7, 8 and 9 of pregnancy. On day 9 of pregnancy, the decidua was explanted, PLIN2 levels were evaluated by Western blot and FABP4 levels by immunohistochemistry. On day 14 of pregnancy, resorption rate, placental weigh and fetal size were evaluated. Results: Administration of the mTOR inhibitor rapamycin reduced FABP4 levels (22%, p <0.05) and increased PLIN2 levels (24%, p<0,01). Administration of the PPARgamma inhibitor T0070907 reduced the levels of FABP4 (40%, p<0,001) and PLIN2 (51%, p<0,001). Administration of the PPARdelta inhibitor GSK0660 did not change FABP4 levels but reduced PLIN2 levels (37%, p<0,01). On day 14 of pregnancy increased reabsorptions rate (control 6%, rapamycin 92%, p<0,001) were observed in rapamycin-treated rats and reduced feto-placental growth was observed in the rats treated with the three inhibitors. Conclusion: The early postimplantation stage is crucial in the determination of fetal growth, as inhibition of mTOR, PPARgamma and PPARdelta in this short period affects feto-placental growth, an alteration possibly related to impairments in decidual function as suggested by the impaired levels of FABP4 and PLIN2 proteins.