title: Hypothyroidism advances mammary involution in lactating rats through inhibition of PRL signaling and induction of LIF/STAT3 mRNAs.
abstract: 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, β-casein and α-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 β-Actin, α-Tubulin and Lamin B were increased, indicating the activation of apoptotic pathways and tissue remodelation. HypoT also increased PRA (mRNA and protein) and erβ and decreased erα mRNAs, and increased strongly TRα1, TRβ1, PRA and ERα 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.
authors.affiliation: Laboratorio de Reproducción y Lactancia, Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CONICET, 5500 Mendoza, Argentina. Electronic address: farbocco@mendoza-conicet.gov.ar.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Campo Verde Arboccó
authors.affiliation: Laboratorio de Hormonas y Biología del Cancer, IMBECU, Argentina.
authors.forename: Corina V
authors.initials: CV
authors.lastname: Sasso
authors.affiliation: Laboratorio de Reproducción y Lactancia, Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CONICET, 5500 Mendoza, Argentina.
authors.forename: Esteban A
authors.initials: EA
authors.lastname: Actis
authors.affiliation: Laboratorio de Hormonas y Biología del Cancer, IMBECU, Argentina.
authors.forename: Rubén W
authors.initials: RW
authors.lastname: Carón
authors.affiliation: Laboratorio de Reproducción y Lactancia, Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CONICET, 5500 Mendoza, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo, Mendoza, Argentina.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Hapon
authors.affiliation: Laboratorio de Reproducción y Lactancia, Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), CONICET, 5500 Mendoza, Argentina. Electronic address: gjahn@mendoza-conicet.gov.ar.
authors.forename: Graciela A
authors.initials: GA
authors.lastname: Jahn
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007037:Hypothyroidism / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D007774:Lactation / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism*; D011441:Propylthiouracil / Q000008:administration & dosage / Q000009:adverse effects; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008894:Milk Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D011441:Propylthiouracil; D011388:Prolactin
keywords: Caspases; LIF; Nuclear receptors; PRL signaling pathway; STAT3; Tissue remodeling