Transient Exposition to Neonatal Hypothyroidism Increases Hepatic Gene Expression of Suppressors of Cytokine Signaling (SOCS) During Catch-Up Growth and in Adulthood

Abstract

Thyroid hormones (TH) are required for normal postnatal growth development in mammals. The physiological importance of TH becomes evident under the conditions of congenital-neonatal hypothyroidism (CH). If not treated immediately, CH has a profound impact on physiology and can permanently imprint neurological and endocrine systems, which, in turn, led to mental retardation, growth arrest, and metabolic disturbances. A delayed growth development or long-lasting influence of CH on liver physiology could be related with an state of Growth Hormone (GH) resistance. GH resistance has been shown in rat models of sepsis, uremia or in small rats for gestational age. In these models, GH resistance has been associated with increased expression of SOCS proteins which contribute to impair GH-JAK2-STAT5 signaling. Here, we studied expression of SOCS genes in liver from rats previously exposed to CH. Pregnant rats were given anti-thyroid drug methimazole (MMI) from Gestational Day 12 until postnatal day (PND)30 to induce CH in male offspring. Growth defects due to CH were evident as a reduction in body weight and tail length from the second week of life. Once the growth inhibiting condition (i.e., MMI) was discontinued on PND30, significant catch-up growth was evident in CH rats. On PND80, significant reduction in body mass, tail length, and circulating IGF-I remained in CH rats. Serum levels of TH, cholesterol, and triglycerides showed no significant differences. However, we observed down-regulation of female predominant (e.g., CYP2C7) together with induction of male-predominant genes (e.g., CYP2C11) which suggested that a male pattern of gene expression was enhanced in CH rat liver. Finally, we observed an impaired somatic growth followed by catch-up growth in rats previously exposed to CH that was associated with increased expression of SOCS2 and CIS. In the present study, we provide in vivo evidences that exposure to CH alters postnatal development which influences liver transcriptional program in adulthood.