Gene Dysregulation in the Adult Rat Paraventricular Nucleus and Amygdala by Prenatal Exposure to Dexamethasone

Abstract

Fetal programming is the concept that maternal stressors during critical periods of fetal development can alter offspring phenotypes postnatally. Excess glucocorticoids can interact with the fetus to effect genetic and epigenetic changes implicated in adverse developmental outcomes. The present study investigates how chronic exposure to the synthetic glucocorticoid dexamethasone during late gestation alters the expression of genes related to behavior in brain areas relevant to the regulation and function of the hypothalamic–pituitary–adrenal axis. Pregnant Wistar Kyoto rats received subcutaneous injections of dexamethasone (100 μg/kg) daily from gestational day 15–21 or vehicle only as sham controls. The amygdala and paraventricular nucleus (PVN) were micro-punched to extract mRNA for reverse transcription and quantitative polymerase chain reaction for the analysis of the expression of specific genes. In the PVN, the expression of the glucocorticoid receptor NR3C1 was downregulated in female rats in response to programming. The expression of CACNA1C encoding the Cav1.2 pore subunit of L-type voltage-gated calcium channels was downregulated in male and female rats prenatally exposed to dexamethasone. Collectively, the results suggest that prenatal exposure to elevated levels of glucocorticoids plays a role in the dysregulation of the hypothalamic–pituitary–adrenal axis and potentially learning and memory by altering the expression of specific genes within the amygdala and PVN.

Case Report: A novel KNCH2 variant-induced fetal heart block and the advantages of fetal genomic sequencing in prenatal long-term dexamethasone exposure

“…Recently, the long-term adverse effects of prenatal DEX exposure have been noted by researchers ( Pal et al, 2022 ; Shinwell et al, 2022 ; Wang et al, 2022 ). In experimental animals, pulmonary fibrosis, osteoporosis, long bone growth impairment, and neonatal hypoglycemia were identified following prenatal DEX exposure ( Rivet et al, 2022 ; Wu et al, 2022 ; Xie et al, 2022 ; Zhang et al, 2022 ). Mechanistically, circadian rhythms, insulin-like growth factor 1 signaling, angiotensin II signaling, histone modifications, and dysregulation of miRNAs were responsible for long-term adverse presentations following DEX exposure ( Han et al, 2022 ; Liu et al, 2022 ; Madhavpeddi et al, 2022 ; Murray et al, 2022 ; Qiu et al, 2022 ).…”

Segmenting hypothalamic subunits in human newborn magnetic resonance imaging data

“…As recently argued (Rasmussen et al, 2021 ), this supports the importance of characterizing the structure and function of the hypothalamus at birth, a developmental period that reflects the cumulative sum of influences by in utero exposures during fetal brain development, yet precedes influence by the postnatal environment under which the hypothalamus further adapts. However, despite the abundant preclinical evidence supporting the role of the hypothalamus in the intergenerational transfer of disease risk (Balsevich et al, 2016 ; Bouret, 2009 ; Dearden & Ozanne, 2015 ; Rivet et al, 2022 ), very little in vivo newborn human hypothalamus data are currently available. One key hurdle in this respect is the relative paucity of methods available for the automatic segmentation of the newborn hypothalamus in modalities capable of in vivo characterization (e.g., MRI).…”

Maternal immune activation with toll‐like receptor 7 agonist during mid‐gestation alters juvenile and adult developmental milestones and behavior

“…A common output of such maternal stressors is fetal overexposure to elevated maternal stress hormones (e.g., epinephrine or glucocorticoids) that may alter immune function by changing the secretory profiles of multiple cytokines. 1,9,10 When these abnormalities in the maternal stress-immune system occur during middle to late gestation, the development of brain circuits [9][10][11][12] and vasculature 13,14 can be highly impacted in sex-biased ways. Important brain circuitries include those that regulate stress response, mood, autonomic function, and metabolism.…”