Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 419, Issue C, Pages 18-28Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2015.09.023
Keywords
PRL signaling pathway; Nuclear receptors; STAT3; LIF; Caspases; Tissue remodeling
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Funding
- CONICET (Consejo Nacional de Investigaciones Cientificas y Tecnicas, Argentina) [PIP 2298/09, 0863/12]
- Universidad Nacional de Cuyo. Argentina [SeCTyP 06/M070]
- CONICET
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Thyroid diseases have deleterious effects on lactation, litter growth and survival, and hinder the suckling induced hormone release, leading in the case of hyperthyroidism, to premature mammary involution. To determine the effects of hypothyroidism (HypoT) on late lactation, we analyzed the effect of chronic 6-propyl-2-thiouracil (PTU)-induced HypoT on mammary histology and the expression of members of the JAK/STAT/SOCS signaling pathway, milk proteins, prolactin (PRLR), estrogen (ER), progesterone (PR) and thyroid hormone (TR) receptors, markers of involution (such as stat3, lif, bcl2, BAX and PARP) on lactation (L) day 21. HypoT mothers showed increased histological markers of involution compared with control rats, such as adipose/epithelial ratio, inactive alveoli, picnotic nuclei and numerous detached apoptotic cells within the alveolar lumina. We also found decreased PRLR, 13-casein and alpha-lactoalbumin mRNAs, but increased SOCS1, SOCS3, STAT3 and LIF mRNAs, suggesting a decrease in PRL signaling and induction of involution markers. Furthermore, Caspase-3 and 8 and PARP labeled cells and the expression of structural proteins such as beta-Actin, alpha-Tubulin and Lamin B were increased, indicating the activation of apoptotic pathways and tissue remodelation. HypoT also increased PRA (mRNA and protein) and er,6 and decreased era mRNAs, and increased strongly TR alpha 1, TR beta 1, PRA and ER alpha protein levels. These results show that lactating HypoT rats have premature mammary involution, most probably induced by the inhibition of prolactin signaling along with the activation of the LIF-STAT3 pathway. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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