Endocrine programming of the pituitary-thyroid-adrenal axis: Sex-Specific effects of maternal malnutrition in rats

The Developmental Origins of Health and Disease (DOHaD) concept highlights that early-life development can be influenced by environmental factors, leading to long-term metabolic programming in the offspring. Maternal Protein Restriction (MPR) is a well-established model within this framework, inducing cellular stress and hormonal imbalances that disrupt basal metabolic regulation in descendants. We aim to investigate the consequences of MPR (6 %) on the metabolism and the pituitary-thyroid-adrenal axis of male and female postweaning rats. Systemically, there was a decrease in hormones T3 and T4 in the males and a decrease in T4 in the females. In the pituitary, we observed an increase in the Ppar a, Ppar g, and Neurod1 gene expression and a decrease in the Prl gene in the males of the GLLP group, while females exhibited a decrease in the Pomc and Ir gene expression. In the thyroid, male rats showed an increase in the Tshr and Ar gene expression. In gene expression of adrenal glands, we observed an increase in the expression of the Sts gene in males and a decrease in Cyp21a2 and Mao in females. In silico analyses demonstrated the potential sex-specific disturbance of MPR, mainly on developmental biology, endocrine response, endoplasmic reticulum, and endocytic pathways, indicating a risk scenario for endocrine diseases. Therefore, we conclude that MPR directly affects the early functioning of the pituitary-thyroid-adrenal axis in a sex-specific manner, highlighting its role in metabolic programming and the developmental origins of endocrine disorders.