Elsevier

Molecular Metabolism

Volume 6, Issue 10, October 2017, Pages 1126-1136
Molecular Metabolism

Original Article
Dwarfism and insulin resistance in male offspring caused by α1-adrenergic antagonism during pregnancy

https://doi.org/10.1016/j.molmet.2017.06.016Get rights and content
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open access

Highlights

  • α1-adrenergic antagonism during pregnancy leads to dwarfism in male mouse offspring.

  • Maternal α1-adrenergic antagonism leads to insulin resistance in male mouse offspring.

  • The growth hormone receptor gene is a target for fetal programming.

  • The promotor of the growth hormone receptor can be differentially methylated.

  • Epigenetic repression of hepatic growth hormone receptor can cause reduced IGF1.

Abstract

Objective

Maternal and environmental factors control the epigenetic fetal programming of the embryo, thereby defining the susceptibility for metabolic or endocrine disorders in the offspring. Pharmacological interventions required as a consequence of gestational problems, e.g. hypertension, can potentially interfere with correct fetal programming. As epigenetic alterations are usually only revealed later in life and not detected in studies focusing on early perinatal outcomes, little is known about the long-term epigenetic effects of gestational drug treatments. We sought to test the consequences of maternal α1-adrenergic antagonism during pregnancy, which can occur e.g. during hypertension treatment, for the endocrine and metabolic phenotype of the offspring.

Methods

We treated C57BL/6NCrl female mice with the α1-adrenergic antagonist prazosin during pregnancy and analyzed the male and female offspring for endocrine and metabolic abnormalities.

Results

Our data revealed that maternal α1-adrenergic blockade caused dwarfism, elevated body temperature, and insulin resistance in male offspring, accompanied by reduced IGF-1 serum concentrations as the result of reduced hepatic growth hormone receptor (Ghr) expression. We subsequently identified increased CpG DNA methylation at the transcriptional start site of the alternative Ghr promotor caused by the maternal treatment, which showed a strong inverse correlation to hepatic Ghr expression.

Conclusions

Our results demonstrate that maternal α1-adrenergic blockade can constitute an epigenetic cause for dwarfism and insulin resistance. The findings are of immediate clinical relevance as combined α/β-adrenergic blockers are first-line treatment of maternal hypertension.

Keywords

Brown fat
Pregnancy
Thermogenesis
Fever
Insulin resistance
IGF-1

Abbreviations

iBAT
interscapular brown adipose tissue
Cyclo
cyclophilin D
DNP
2,4-dinitrophenol
GH
growth hormone
GHR
growth hormone receptor
HPRT
hypoxanthine-guanine phosphoribosyltransferase
IGF-1
insulin-like growth factor 1
IUGR
intrauterine growth restriction
iWAT
inguinal white adipose tissue
gWAT
gonadal white adipose tissue
UCP1
uncoupling protein 1

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