Embryo number and periconceptional undernutrition in the sheep have differential effects on adrenal epigenotype, growth, and development.
Exposure to poor maternal nutrition around the time of conception results in an early prepartum activation of the fetal pituitary-adrenal axis and in increased adrenal growth and stress response after birth associated with epigenetic changes in a differentially methylated region (DMR) of adrenal IGF2/H19. We have determined the effects of maternal undernutrition during the periconceptional period (PCUN: 70% of control intake from 60 days before until 6 days after conception) and early preimplantation period (PIUN: 70% of control intake for 6 days after conception) on fetal plasma ACTH and cortisol concentrations and fetal adrenal ACTHR, StAR, 3βHSD, CYP11B, CYP17, TGFβ1, IGF1, IGF1R, IGF2, and IGF2R mRNA expression and the methylation level of sites within the DMRs of IGF2/H19 and IGF2R in the adrenal of twin and singleton fetuses at 136-138 days gestation. Being a twin resulted in a delayed prepartum increase in fetal ACTH and in a lower cortisol response to CRH in the control but not PCUN and PIUN groups. PCUN, but not PIUN, resulted in an increase in adrenal weight and CYP17 expression in singletons, a decrease in adrenal IGF2 expression in singletons, and an increase in adrenal IGF2R expression in both twins and singletons. IGF2/H19 and IGF2R DMR methylation levels and ACTHR expression were lower in the twin adrenal. Thus, exposure of the oocyte and embryo to maternal undernutrition or to the environment of a twin pregnancy have differential effects on epigenetic and other factors that regulate fetal adrenal growth and IGF2 and IGF2R expression.
Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, Australia; Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia;
Olivia
O
Williams-Wyss
Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia;
Song
S
Zhang
Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia;
Severence M
SM
MacLaughlin
South Australian Research and Development Institute, Turretfield Research Centre, Rosedale, Australia;
David
D
Kleemann
South Australian Research and Development Institute, Turretfield Research Centre, Rosedale, Australia;
Simon K
SK
Walker
Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and.
Catherine M
CM
Suter
Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and.
Jennifer E
JE
Cropley
Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia;
Janna L
JL
Morrison
Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia.
Claire T
CT
Roberts
Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia; caroline.mcmillen@newcastle.edu.au.
I Caroline
IC
McMillen
D000311:Adrenal Glands / Q000196:embryology* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D019175:DNA Methylation; D004622:Embryo, Mammalian / Q000196:embryology* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005306:Fertilization / Q000502:physiology; D005838:Genotype; D006854:Hydrocortisone / Q000097:blood; D044342:Malnutrition / Q000503:physiopathology*; D039382:Maternal Nutritional Physiological Phenomena; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011272:Pregnancy, Multiple / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012756:Sheep / Q000196:embryology* / Q000235:genetics / Q000502:physiology
D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone
adrenal; epigenetic; fetus; periconceptional; twin