ABSTRACT
Maternal exposure to glucocorticoids has been associated with adverse outcomes in offspring. However, the consequences and mechanisms of gestational exposure to prednisone on susceptibility to osteoporosis in the offspring remain unclear. Here, we found that gestational prednisone exposure enhanced susceptibility to osteoporosis in adult mouse offspring. In a further exploration of myogenic mechanisms, results showed that gestational prednisone exposure down-regulated FNDC5/irisin protein expression and activation of OPTN-dependent mitophagy in skeletal muscle of adult offspring. Additional experiments elucidated that activated mitophagy significantly inhibited the expression of FNDC5/irisin in skeletal muscle cells. Likewise, we observed delayed fetal bone development, downregulated FNDC5/irisin expression, and activated mitophagy in fetal skeletal muscle upon gestational prednisone exposure. In addition, an elevated total m6A level was observed in fetal skeletal muscle after gestational prednisone exposure. Finally, gestational supplementation with S-adenosylhomocysteine (SAH), an inhibitor of m6A activity, attenuated mitophagy and restored FNDC5/irisin expression in fetal skeletal muscle, which in turn reversed fetal bone development. Overall, these data indicate that gestational prednisone exposure increases m6A modification, activates mitophagy, and decreases FNDC5/irisin expression in skeletal muscle, thus elevating osteoporosis susceptibility in adult offspring. Our results provide a new perspective on the earlier prevention and treatment of fetal-derived osteoporosis.
Subject(s)
Fibronectins , Osteoporosis , Humans , Mice , Female , Animals , Pregnancy , Prednisone/metabolism , Fibronectins/metabolism , Maternal Exposure , Mitophagy , Muscle, Skeletal/metabolism , Transcription Factors/metabolism , Osteoporosis/chemically inducedSubject(s)
Breast Neoplasms/pathology , Carcinoma in Situ/pathology , Carcinoma, Ductal, Breast/pathology , Fibrocystic Breast Disease/pathology , Adenocarcinoma, Mucinous/pathology , Adult , Breast Neoplasms/metabolism , Breast Neoplasms/surgery , Carcinoma/pathology , Carcinoma in Situ/metabolism , Carcinoma in Situ/surgery , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/surgery , Diagnosis, Differential , Female , Fibrocystic Breast Disease/metabolism , Fibrocystic Breast Disease/surgery , Humans , Hyperplasia , Lactalbumin/metabolism , S100 Proteins/metabolismSubject(s)
Breast Neoplasms/pathology , Breast/cytology , Neoplastic Stem Cells/pathology , Stem Cells/cytology , Actins/metabolism , Breast/metabolism , Breast Neoplasms/metabolism , Cell Differentiation , Female , Humans , Keratins/metabolism , Neoplastic Stem Cells/metabolism , Signal Transduction , Stem Cells/metabolismABSTRACT
OBJECTIVE: To study the morphologic classification of mammary ductal hyperplasia, and its criteria and the significance in distinguishing atypical hyperplasia from carcinoma-in-situ. METHODS: The clinicopathologic features of 300 cases of hyperplasia of breast were reviewed. Whole-organ H&E sections were also available in 86 cases of breast carcinoma. The occurrence of atypical hyperplasia in adjacent breast tissue was assessed. RESULTS: Fibroadenomatoid changes were typically observed in the 21-30 age groups and atypical hyperplasia occurred more frequently in 40-60 age groups. Amongst the hyperplastic cases, cystic diseases of the breast were noted in only 6%. In contrast, fibroadenomatoid changes were more common (25.4%). Atypical ductal hyperplasia occurred in adjacent breast tissue of 65.1% of the carcinoma cases. The incidence was higher (74.9%) if the main lesion was ductal carcinoma-in-situ. CONCLUSIONS: There is a close association between atypical hyperplasia and breast carcinoma. It is prudent to distinguish between usual and atypical hyperplasia. Morphologic differentiation between atypical ductal hyperplasia and ductal carcinoma-in-situ may sometimes be difficult.
