Ashley S Meakin1, Zarqa Saif1, Astrud R Tuck2, Vicki L Clifton3. 1. Pregnancy and Development, Mater Medical Research Institute-University of Queensland, Brisbane, Australia. 2. Robinson Research Institute, University of Adelaide, Adelaide, Australia. 3. Pregnancy and Development, Mater Medical Research Institute-University of Queensland, Brisbane, Australia. Electronic address: vicki.clifton@mater.uq.edu.au.
Abstract
INTRODUCTION: Numerous studies show that males have increased intrauterine growth compared to females, and that pregnancy complications may further these growth differences, but the regulatory mechanisms underlying these differences remain unknown. We propose that these growth outcomes may be due to sex-specific differences in androgen sensitivity - giving rise to altered growth signalling pathways - mediated by the differential expression of placental androgen receptor (AR) variants. METHODS: Placental protein and mRNA were used to identify AR protein variant levels and AR-downstream target gene expression, and were then analysed against neonatal measurements. Dihydrotestosterone (DHT)-induced AR protein variant expression and downstream growth factors were examined in vitro. RESULTS: Four known AR variants (AR-FL, AR-V1, AR-V7, and AR-45), and three unknown proteins (120, 90 and 55 kDa) immunoreactive to the anti-AR antibody were identified in human placentae. Male placentae from controlled asthmatic pregnancies had increased AR-45 and decreased AR-V1 and AR-V7 nuclear expression. Increased nuclear AR-45 expression was associated with increased insulin-like growth factor 1 (IGF-1), IGF-1 receptor (IGF-1R), and IGF-binding protein 5 (IGFBP-5) mRNA expression and normal male growth. AR-45 mRNA and protein did not change in the presence of uncontrolled maternal asthma and associated with an increase in small for gestational (SGA) male fetuses. In vitro DHT stimulation increased AR-45 protein and IGF-1R and IGFBP-5 mRNA expression. CONCLUSIONS: Collectively, our data shows altered AR protein expression and downstream signalling targets may contribute to sex-specific fetal growth outcomes in response to an adverse environment, and that AR-45 appears central in mediating these changes.
INTRODUCTION: Numerous studies show that males have increased intrauterine growth compared to females, and that pregnancy complications may further these growth differences, but the regulatory mechanisms underlying these differences remain unknown. We propose that these growth outcomes may be due to sex-specific differences in androgen sensitivity - giving rise to altered growth signalling pathways - mediated by the differential expression of placental androgen receptor (AR) variants. METHODS: Placental protein and mRNA were used to identify AR protein variant levels and AR-downstream target gene expression, and were then analysed against neonatal measurements. Dihydrotestosterone (DHT)-induced AR protein variant expression and downstream growth factors were examined in vitro. RESULTS: Four known AR variants (AR-FL, AR-V1, AR-V7, and AR-45), and three unknown proteins (120, 90 and 55 kDa) immunoreactive to the anti-AR antibody were identified in human placentae. Male placentae from controlled asthmatic pregnancies had increased AR-45 and decreased AR-V1 and AR-V7 nuclear expression. Increased nuclear AR-45 expression was associated with increased insulin-like growth factor 1 (IGF-1), IGF-1 receptor (IGF-1R), and IGF-binding protein 5 (IGFBP-5) mRNA expression and normal male growth. AR-45 mRNA and protein did not change in the presence of uncontrolled maternal asthma and associated with an increase in small for gestational (SGA) male fetuses. In vitro DHT stimulation increased AR-45 protein and IGF-1R and IGFBP-5 mRNA expression. CONCLUSIONS: Collectively, our data shows altered AR protein expression and downstream signalling targets may contribute to sex-specific fetal growth outcomes in response to an adverse environment, and that AR-45 appears central in mediating these changes.
Authors: S L Young; Z Saif; A S Meakin; E S McMaster; N Hayes; L A Gallo; N Reid; K M Moritz; V L Clifton Journal: Reprod Sci Date: 2021-01-06 Impact factor: 3.060
Authors: Elisabeth A Messner; Thomas M Steele; Maria Malvina Tsamouri; Nazila Hejazi; Allen C Gao; Maria Mudryj; Paramita M Ghosh Journal: Biomedicines Date: 2020-10-15
Authors: Tianyanxin Sun; Tania L Gonzalez; Nan Deng; Rosemarie DiPentino; Ekaterina L Clark; Bora Lee; Jie Tang; Yizhou Wang; Barry R Stripp; Changfu Yao; Hsian-Rong Tseng; S Ananth Karumanchi; Alexander F Koeppel; Stephen D Turner; Charles R Farber; Stephen S Rich; Erica T Wang; John Williams; Margareta D Pisarska Journal: J Clin Endocrinol Metab Date: 2020-12-01 Impact factor: 5.958
Authors: Ashley S Meakin; James S M Cuffe; Jack R T Darby; Janna L Morrison; Vicki L Clifton Journal: Int J Mol Sci Date: 2021-06-15 Impact factor: 5.923