Ghrelin as a fetal programming susbtance: inter and transgenerational effects on postnatal development and reproduction in mice

TORRES PJ; LUQUE EM; RAMÍREZ ND; CARLINI VP; MARTINI AC

Córdoba

Jornada; XIX Jornada de Investigación de la Facultad de Ciencias Médicas; 2021

We have previously demonstrated that ghrelin (Ghrl) participates in fetal programming since intragestational hyperghrelinemia increase pup´s growth, and the administration of a Ghrl antagonist, accelerated offspring´s sexual maturation and impaired adult reproductive physiology. In this randomized study, we analyzed if these phenotypic changes (found in F1), are also seen in F2 (intergenerational effects) and/or F3 generations (transgenerational effects).We treated Albino swiss N/NIH mice dams (F0=5-6 dams/treatment), from pregnancy Day 1 to delivery, with 4 nmol/animal/day of Ghrl or 6 nmol/animal/day of a Ghrl receptor antagonist [Ant:(D-Lys3)GHRP6]. Control females (C) received the vehicle (NaCl 0.9%) in the same regimen. When F1 female pups reached adulthood, they were paired to obtain F2, and subsequently, F2 females were paired to obtain F3. Parameters evaluated in F2 and F3 pups were: growth, physical development, neurobiological maturation, puberty onset and in adulthood, reproductive function. Data were analyzed with ANOVA or repeated-measures ANOVA.F2 and F3 Ant groups showed a significant reduction in litter size. Although no differences were detected in the weight of these pups at birth, in adulthood (pnd 75-90), Ant pups were heavier. At F3, pups from the Ant group showed advanced incisors eruption and eye opening vs C group. Furthermore at F3, male pups from the Ant group showed earlier testis descent although, in adulthood, these males exhibited reduced sperm concentration in comparison to Ghrl. No differences were detected in F2 or F3 females regarding puberty onset or reproduction.In conclusion, although subtle, the fetal programming effects of Ghrl appear also transgenerationally (F3). Since, many women in their reproductive ages suffer from conditions/diseases with reduced Ghrl levels (i.e. obesity or polycystic ovarian syndrome), these results could be relevant to human health.