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

Abstract

ObjectiveMaternal 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.MethodsWe 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.ResultsOur 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.ConclusionsOur 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.

Effects of sildenafil treatment on thermogenesis and glucose homeostasis in diet-induced obese mice

“…RNA isolation and quantitative real-time PCR of liver, iBAT, iWAT, and epididymal WAT (eWAT) were performed as described previously 11 .…”

An improved method for the precise unravelment of non-shivering brown fat thermokinetics

“…Here, the animals need to be anaesthetised and are exposed to potentially harmful radiation during these measurements, which makes it difficult, if not impossible, to conduct longitudinal studies. Infrared thermography has been successfully used in many rodent studies to directly measure BAT thermogenesis 5 , 8 – 10 , however there is an ongoing debate on whether to anesthetize the animals and/or remove their fur during the measurements to gain more reproducible results 6 , 11 – 14 . These procedures not only increase the burden for the animals but in case of anaesthetised animals lead to an underestimation of the maximum BAT temperature, which reduces the quality of scientific outcomes.…”

Anti-hypertensive treatment in pregnancy impacts offspring growth and metabolism: Q&A

“…In this issue of Molecular Metabolism , Oelkrug et al. [1] describe that anti-hypertensive treatment in pregnancy generates long-lasting metabolic phenotypes in offspring. This work belongs to a bigger group of studies aiming to highlight acquired and heritable phenotypes, and to uncover molecular mechanisms for DOHaD and TEI in mammals.…”

“…Therefore, in the case of parental inheritance including in utero effects, such as in Oelkrug et al. [1] , the parents are the EU. That said, a proper study design is critical to determine the size of the experimental groups needed to identify epigenetic phenotypes, which, in many cases, are subtle or partially penetrant [3] .…”

“…To conclude, Oelkrug et al. [1] present a new model of acquired inheritance and highlight that toxicology has to keep an open eye on drug effects within and across generations. Though presenting interesting and far reaching findings, some aspects of the study need further investigation.…”