Cargando…
FRI115 Sex-specific Programming Of The Late Gestational Fetal Heart With Prenatal T Excess
Disclosure: B.G. Alkhatib: None. M. Jabari: None. P. Kurup: None. S. Domke: None. J.N. Ciarelli: None. B. Pallas: None. O. Nicholas: None. V. Padmanabhan: None. A.K. Vyas: None. Excess testosterone (T) exposure from early to mid-gestation (days 30-90) leads to sexually dimorphic adverse cardiac prog...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10553643/ http://dx.doi.org/10.1210/jendso/bvad114.628 |
_version_ | 1785116220552380416 |
---|---|
author | Ghalib Alkhatib, Bashar Jabari, Mary Kurup, Prasanth Domke, Stephanie Norman Ciarelli, Joseph Pallas, Brooke Nicholas, Olivier Padmanabhan, Vasantha Kalla Vyas, Arpita |
author_facet | Ghalib Alkhatib, Bashar Jabari, Mary Kurup, Prasanth Domke, Stephanie Norman Ciarelli, Joseph Pallas, Brooke Nicholas, Olivier Padmanabhan, Vasantha Kalla Vyas, Arpita |
author_sort | Ghalib Alkhatib, Bashar |
collection | PubMed |
description | Disclosure: B.G. Alkhatib: None. M. Jabari: None. P. Kurup: None. S. Domke: None. J.N. Ciarelli: None. B. Pallas: None. O. Nicholas: None. V. Padmanabhan: None. A.K. Vyas: None. Excess testosterone (T) exposure from early to mid-gestation (days 30-90) leads to sexually dimorphic adverse cardiac programming at fetal day 90 (term 147 days). Whether this is direct effect of T or reprogramming that persists is unknown. We hypothesized that gestational T excess leads to sex specific cardiac reprogramming that persists into late gestation and neonatal period. Pregnant ewes were injected 100 T propionate in corn oil or vehicle (C), twice weekly (day 30 to 90). At day 120 ±5 gestation, fetal body weight (BW) and heart weights were recorded, and left ventricles (LV) processed for molecular analysis (Female C (FC) n=5-6, T (FT) n=7-8; Male C (MC) n=6-7, T(MT) n=6). Neonatal echocardiograms were performed in a second study (Female C n=2, T n=7, Male C n=5, T n=10). Prenatal T excess reduced BW in both sexes compared to C (male: 3.38±0.15 vs.2.68±0.14, p=0.001, Cohen’s effect size: d=1.29; female: 3.27±0.21 vs. 2.72±0.11, p=0.03, d=1.08). LV/BW ratio (3.62±0.15 vs 3.15± 0.11, p=0.04, d=0.81) was increased in MT compared to MC and not in females suggestive of sex specific programming. Prenatal T excess had no impact on insulin, estrogen or androgen receptor expression at day 120 in both sexes. However, downstream protein expression of pAKT/Total AKT protein ratio was significantly downregulated in MT compared to MC fetuses (MT-0.36±0.10 vs MC 0.47±0.11, p=0.03, d=1.34) with a non-significant moderate magnitude decrease in FT (FT-0.34±0.08 vs FC 0.50±0.14, d=0.63). A non-significant large magnitude downregulation of mTORC1 (0.86±0.05 vs 1.00±0.01, d=0.87), a non-significant moderate magnitude decrease in SERCA (0.85±0.07 vs 1.03±0.12, p=0.2, d=0.7), and a significant large magnitude decrease in Col1A1 (0.71±0.28 vs 1.02±0.09, p=0.02, d=1.48) gene expression were evident in MT compared to MC as opposed to no differences in females. A large magnitude decrease in Cytochrome C and PERK (mitochondrial metabolism genes) expression were seen in FT compared to FC (0.76±0.08 vs 1.02±0.09, p=0.07, d=1.07 and 0.81±0.10 vs 1.01±0.08, p=0.17 d=0.79 respectively) but not in males. Neonatal echocardiogram analysis demonstrated a significant increase LV area in diastole (LVAD) (5.35±0.11 vs 4.08±0.15, p=0.04, d=0.92), LV internal dimension in diastole (LVIDd) (2.54±0.02 vs 2.22±0.03, p=0.03, 0.92), and in LVID in systole (1.75±0.01 vs 1.55±0.02, p=0.04, d=0.84) in T treated offspring compared to control. In a sub analysis of only males fetuses there was a non-significant medium to large magnitude increases in LV area in diastole (LVAD) (7.6±0.36 vs 4.18±0.53, p=0.07, d=2.8), LV internal dimension in diastole (2.54±0.13 vs 2.2±0.13, p=0.14, d=0.9), and LV internal dimension in systole (1.73±0.09 vs 1.54±0.08, p=0.11, d=0.74) in MT compared to MC. Altogether, these results support persistence of sex specific adverse programming of prenatal T excess into late gestation and neonatal life. Presentation: Friday, June 16, 2023 |
format | Online Article Text |
id | pubmed-10553643 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-105536432023-10-06 FRI115 Sex-specific Programming Of The Late Gestational Fetal Heart With Prenatal T Excess Ghalib Alkhatib, Bashar Jabari, Mary Kurup, Prasanth Domke, Stephanie Norman Ciarelli, Joseph Pallas, Brooke Nicholas, Olivier Padmanabhan, Vasantha Kalla Vyas, Arpita J Endocr Soc Cardiovascular Endocrinology Disclosure: B.G. Alkhatib: None. M. Jabari: None. P. Kurup: None. S. Domke: None. J.N. Ciarelli: None. B. Pallas: None. O. Nicholas: None. V. Padmanabhan: None. A.K. Vyas: None. Excess testosterone (T) exposure from early to mid-gestation (days 30-90) leads to sexually dimorphic adverse cardiac programming at fetal day 90 (term 147 days). Whether this is direct effect of T or reprogramming that persists is unknown. We hypothesized that gestational T excess leads to sex specific cardiac reprogramming that persists into late gestation and neonatal period. Pregnant ewes were injected 100 T propionate in corn oil or vehicle (C), twice weekly (day 30 to 90). At day 120 ±5 gestation, fetal body weight (BW) and heart weights were recorded, and left ventricles (LV) processed for molecular analysis (Female C (FC) n=5-6, T (FT) n=7-8; Male C (MC) n=6-7, T(MT) n=6). Neonatal echocardiograms were performed in a second study (Female C n=2, T n=7, Male C n=5, T n=10). Prenatal T excess reduced BW in both sexes compared to C (male: 3.38±0.15 vs.2.68±0.14, p=0.001, Cohen’s effect size: d=1.29; female: 3.27±0.21 vs. 2.72±0.11, p=0.03, d=1.08). LV/BW ratio (3.62±0.15 vs 3.15± 0.11, p=0.04, d=0.81) was increased in MT compared to MC and not in females suggestive of sex specific programming. Prenatal T excess had no impact on insulin, estrogen or androgen receptor expression at day 120 in both sexes. However, downstream protein expression of pAKT/Total AKT protein ratio was significantly downregulated in MT compared to MC fetuses (MT-0.36±0.10 vs MC 0.47±0.11, p=0.03, d=1.34) with a non-significant moderate magnitude decrease in FT (FT-0.34±0.08 vs FC 0.50±0.14, d=0.63). A non-significant large magnitude downregulation of mTORC1 (0.86±0.05 vs 1.00±0.01, d=0.87), a non-significant moderate magnitude decrease in SERCA (0.85±0.07 vs 1.03±0.12, p=0.2, d=0.7), and a significant large magnitude decrease in Col1A1 (0.71±0.28 vs 1.02±0.09, p=0.02, d=1.48) gene expression were evident in MT compared to MC as opposed to no differences in females. A large magnitude decrease in Cytochrome C and PERK (mitochondrial metabolism genes) expression were seen in FT compared to FC (0.76±0.08 vs 1.02±0.09, p=0.07, d=1.07 and 0.81±0.10 vs 1.01±0.08, p=0.17 d=0.79 respectively) but not in males. Neonatal echocardiogram analysis demonstrated a significant increase LV area in diastole (LVAD) (5.35±0.11 vs 4.08±0.15, p=0.04, d=0.92), LV internal dimension in diastole (LVIDd) (2.54±0.02 vs 2.22±0.03, p=0.03, 0.92), and in LVID in systole (1.75±0.01 vs 1.55±0.02, p=0.04, d=0.84) in T treated offspring compared to control. In a sub analysis of only males fetuses there was a non-significant medium to large magnitude increases in LV area in diastole (LVAD) (7.6±0.36 vs 4.18±0.53, p=0.07, d=2.8), LV internal dimension in diastole (2.54±0.13 vs 2.2±0.13, p=0.14, d=0.9), and LV internal dimension in systole (1.73±0.09 vs 1.54±0.08, p=0.11, d=0.74) in MT compared to MC. Altogether, these results support persistence of sex specific adverse programming of prenatal T excess into late gestation and neonatal life. Presentation: Friday, June 16, 2023 Oxford University Press 2023-10-05 /pmc/articles/PMC10553643/ http://dx.doi.org/10.1210/jendso/bvad114.628 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Cardiovascular Endocrinology Ghalib Alkhatib, Bashar Jabari, Mary Kurup, Prasanth Domke, Stephanie Norman Ciarelli, Joseph Pallas, Brooke Nicholas, Olivier Padmanabhan, Vasantha Kalla Vyas, Arpita FRI115 Sex-specific Programming Of The Late Gestational Fetal Heart With Prenatal T Excess |
title | FRI115 Sex-specific Programming Of The Late Gestational Fetal Heart With Prenatal T Excess |
title_full | FRI115 Sex-specific Programming Of The Late Gestational Fetal Heart With Prenatal T Excess |
title_fullStr | FRI115 Sex-specific Programming Of The Late Gestational Fetal Heart With Prenatal T Excess |
title_full_unstemmed | FRI115 Sex-specific Programming Of The Late Gestational Fetal Heart With Prenatal T Excess |
title_short | FRI115 Sex-specific Programming Of The Late Gestational Fetal Heart With Prenatal T Excess |
title_sort | fri115 sex-specific programming of the late gestational fetal heart with prenatal t excess |
topic | Cardiovascular Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10553643/ http://dx.doi.org/10.1210/jendso/bvad114.628 |
work_keys_str_mv | AT ghalibalkhatibbashar fri115sexspecificprogrammingofthelategestationalfetalheartwithprenataltexcess AT jabarimary fri115sexspecificprogrammingofthelategestationalfetalheartwithprenataltexcess AT kurupprasanth fri115sexspecificprogrammingofthelategestationalfetalheartwithprenataltexcess AT domkestephanie fri115sexspecificprogrammingofthelategestationalfetalheartwithprenataltexcess AT normanciarellijoseph fri115sexspecificprogrammingofthelategestationalfetalheartwithprenataltexcess AT pallasbrooke fri115sexspecificprogrammingofthelategestationalfetalheartwithprenataltexcess AT nicholasolivier fri115sexspecificprogrammingofthelategestationalfetalheartwithprenataltexcess AT padmanabhanvasantha fri115sexspecificprogrammingofthelategestationalfetalheartwithprenataltexcess AT kallavyasarpita fri115sexspecificprogrammingofthelategestationalfetalheartwithprenataltexcess |