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. 2023 Feb 2:14:1122432.
doi: 10.3389/fendo.2023.1122432. eCollection 2023.

Effect of maternal periconceptional undernutrition in sheep on cortisol regulation in offspring from mid-late gestation, through to adulthood

Mark H Oliver  1 , Anne L Jaquiery  1 , Kristin L Connor  2 , Hui Hui Phua  1 , Jane E Harding  1 , Eric B Thorstensen  1 , Frank H Bloomfield  1
Affiliations

Effect of maternal periconceptional undernutrition in sheep on cortisol regulation in offspring from mid-late gestation, through to adulthood

Mark H Oliver et al. Front Endocrinol (Lausanne). .

Abstract

Introduction: Maternal periconceptional undernutrition (PCUN) alters fetal hypothalamic-pituitary-adrenal axis (HPAA) function and placental glucocorticoid metabolism in sheep. The effects of PCUN on HPAA function in adult life are not known. We investigated the effects of PCUN on fetal adrenal development across gestation and on cortisol regulation in adult offspring.

Methods: Ewes were undernourished from 61 days before to 30 days after conception ('PCUN') or fed ad libitum ('N'). mRNA expression in the fetal adrenal gland of ACTH receptor (ACTHR), steroidogenic acute regulatory protein (STAR), cytochrome P450 17A1 (CYP17A1), 11beta-hydroxysteroid-dehydrogenase type 2 (11βHSD2), insulin-like growth factor-2 (IGF2), and in the fetal hippocampus of 11βHSD1, 11βHSD2, mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) was determined at 50 (adrenal only), 85, 120 and 131 days of gestation (term=148 days). In adult offspring (≥ 3 years, N; 10 female, 5 male, PCUN; 10 female, 10 male) a combined arginine vasopressin (AVP, 0.1 μg/kg) and corticotropin-releasing hormone (CRH, 0.5 μg/kg) challenge and a metyrapone (40 mg/kg) challenge were undertaken. mRNA expression of ACTHR, STAR and CYP17A1 were determined in adult adrenals.

Results: Fetal adrenal STAR, CYP17A1 and IGF2 mRNA expression were not different between groups in early gestation but were higher in PCUN than N at 131 days' gestation (all p<0.01). PCUN reduced fetal hippocampal MR and GR mRNA expression by 50% at 85 day, but not in later gestation. Adult offspring plasma cortisol responses to AVP+CRH or metyrapone were not different between groups. Plasma ACTH response to AVP+CRH was lower in PCUN males but ACTH response to metyrapone was not different between groups. Adult adrenal ACTHR, STAR, and CYP17A1 mRNA expression were not affected by PCUN.

Conclusions: We conclude that the effects of PCUN on fetal HPAA function that became apparent in late gestation, are not reflected in adrenal cortisol secretion in mid-adulthood.

Keywords: adrenal; cortisol; long-term; outcomes; programming.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the various studies using this cohort of animals during fetal (A) and postnatal life (B). ‘adr’, mRNA expression in adrenals. ‘hip’, mRNA expression in hippocampus. ‘epi1’, fetal epigenetic studies (28). ‘epi2, epigenetic studies in adult (29). ‘‘AVP+CRH’, corticotropin stimulation tests in previous (13) and the current study. ‘met’, metyrapone blockade.
Figure 2
Figure 2
Fetal hippocampal mRNA expression. Log2 fold change of 11βHSD1, 11βHSD2, GR and MR mRNA expression levels in PCUN (symbol in red) in comparison to N (symbol in blue) based on real-time PCR analysis in the fetal hippocampus. Data are shown as mean ± 95% confidence interval. Symbols represent individual animals. Student’s t-tests were used to assess statistical difference, with significance defined as p < 0.05.
Figure 3
Figure 3
Fetal adrenal mRNA expression. Log2 fold change of ACTHR, STAR, CYP17A1, 11βHSD2, and IGF2 mRNA expression levels in PCUN (symbol in red) in comparison to N (symbol in blue) based on real-time PCR analysis in the fetal adrenal. Data are shown as mean ± 95% confidence interval. Symbols represent individual animals. Student’s t-tests were used to assess statistical difference, with significance defined as p < 0.05.
Figure 4
Figure 4
Adult plasma ACTH and cortisol responses to equimolar challenge of intravenous AVP+CRH (0.1 and 0.5 μg/kg respectively) given at time ‘0’. a treatment x time interaction in males. b sex effect (p < 0.0001). Values are mean ± SEM.
Figure 5
Figure 5
Adult plasma cortisol, 11-Deoxycortisol and ACTH responses to cortisol synthesis blockade with intravenous metyrapone (40 mg/kg) given at time ‘0’. b sex effect (p < 0.0001). c treatment x sex interaction (p < 0.05). d treatment effect in females (p < 0.05). Values are mean ± SEM.
Figure 6
Figure 6
Adult adrenal mRNA expression. Log2 fold change of ACTHR, STAR, and CYP17A1 mRNA expression levels in PCUN (symbol in red) in comparison to N (symbol in blue) in female (A) and in male (B). Data are mean ± 95% confidence interval. Symbols represent individual animals. Student’s t-tests were used to assess statistical difference, with significance defined as p < 0.05.
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