Varas S M, Muñoz E M, Hapon M B, Aguilera Merlo C I, Giménez M S, Jahn G A
Laboratorio de Bioquímica Molecular, Departamento de Bioquímica y Ciencias Biológicas, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, 5700 San Luis, Argentina.
Reproduction. 2002 Nov;124(5):691-702.
This study investigated the influence of chronic hyperthyroidism on mammary function in lactating rats and the effects on their pups. Thyroxine-treated (10 microg per 100 g body weight per day; hyperthyroid (HT)) or vehicle-treated rats were mated 2 weeks after the start of treatment and killed with their litters on days 7, 14 and 21 of lactation. Serum concentrations of triiodothyronine (T(3)) and tetraiodothyronine (T(4)) increased in thyroxine-treated rats. In HT mothers, serum prolactin decreased on day 7 and day 14 of lactation, whereas insulin-like growth factor I (IGF-I) and progesterone concentrations decreased, and corticosterone increased on day 7 of lactation. In HT pups, T(4) concentration increased on day 7 and day 14 of lactation, whereas T(3) increased only on day 14 of lactation, and growth hormone increased on day 7 of lactation. Mammary prolactin binding sites did not vary, but there was an increase in the binding sites in the liver on day 14 of lactation in thyroxine-treated rats. In an acute suckling experiment, thyroxine-treated rats released less oxytocin, growth hormone and prolactin and excreted less milk than did control rats. Mammary casein, lactose and total lipid concentrations in thyroxine-treated rats were similar to those of control rats on day 14 of lactation. Histological studies of the mammary glands showed an increased proportion of alveoli showing reduced or no lumina and cells with condensed nuclei on day 14 and day 21 of lactation; the TdT-mediated dUTP nick-end labelling (TUNEL) test revealed an increase in apoptosis in alveolar cells on day 21 of lactation in thyroxine-treated rats. Expression of SGP-2, a gene expressed during mammary involution, increased in thyroxine-treated rats on day 14 and day 21 of lactation, whereas expression of insulin-like growth factor binding protein 5, a proapoptotic signal, was unchanged. Bcl-2, which promotes survival of mammary gland epithelial cells was unchanged, whereas expression of IGF-I, which also promotes survival of mammary gland epithelial cells, increased on day 21 of lactation in thyroxine-treated rats. These results indicate that thyroxine treatment produces some milk stasis as a result of impairments in suckling induced release of oxytocin that may initiate the first stage of mammary involution, increasing apoptosis in a gland that is otherwise actively producing and secreting milk.
本研究调查了慢性甲状腺功能亢进对哺乳期大鼠乳腺功能及其幼崽的影响。在治疗开始2周后，用甲状腺素处理（每天每100克体重10微克；甲状腺功能亢进（HT））或用赋形剂处理的大鼠进行交配，并在哺乳期第7、14和21天与其幼崽一同处死。甲状腺素处理的大鼠血清三碘甲状腺原氨酸（T(3)）和四碘甲状腺原氨酸（T(4)）浓度升高。在HT组母鼠中，哺乳期第7天和第14天血清催乳素降低，而胰岛素样生长因子I（IGF-I）和孕酮浓度降低，哺乳期第7天皮质酮升高。在HT组幼崽中，哺乳期第7天和第14天T(4)浓度升高，而T(3)仅在哺乳期第14天升高，哺乳期第7天生长激素升高。乳腺催乳素结合位点没有变化，但甲状腺素处理的大鼠在哺乳期第14天肝脏中的结合位点增加。在急性哺乳实验中，甲状腺素处理的大鼠释放的催产素、生长激素和催乳素较少，分泌的乳汁也比对照大鼠少。甲状腺素处理的大鼠在哺乳期第14天乳腺酪蛋白、乳糖和总脂质浓度与对照大鼠相似。乳腺组织学研究显示，在哺乳期第14天和第21天，显示管腔减少或无管腔的肺泡比例增加，细胞核浓缩的细胞增多；TdT介导的dUTP缺口末端标记（TUNEL）试验显示，甲状腺素处理的大鼠在哺乳期第21天肺泡细胞凋亡增加。在哺乳期第14天和第21天，甲状腺素处理的大鼠中在乳腺退化过程中表达的SGP-2基因表达增加，而促凋亡信号胰岛素样生长因子结合蛋白5的表达未改变。促进乳腺上皮细胞存活的Bcl-2未改变，而在哺乳期第21天甲状腺素处理大鼠中同样促进乳腺上皮细胞存活的IGF-I表达增加。这些结果表明，甲状腺素处理由于哺乳诱导的催产素释放受损而产生一些乳汁淤积，这可能启动乳腺退化的第一阶段，增加在其他方面积极产奶和分泌乳汁的腺体中的细胞凋亡。
