Life-long impairment of glucose homeostasis upon prenatal exposure to psychostimulants

Research output: Contribution to journalArticle

Abstract

Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, including amphetamine, cocaine, and methamphetamine, are amongst the illicit drugs most commonly consumed by pregnant women. Neuropharmacology concepts posit that psychostimulants affect monoamine signaling in the nervous system by their affinities to neurotransmitter reuptake and vesicular transporters to heighten neurotransmitter availability extracellularly. Exacerbated dopamine signaling is particularly considered as a key determinant of psychostimulant action. Much less is known about possible adverse effects of these drugs on peripheral organs, and if in utero exposure induces lifelong pathologies. Here, we addressed this question by combining human RNA-seq data with cellular and mouse models of neuroendocrine development. We show that episodic maternal exposure to psychostimulants during pregnancy coincident with the intrauterine specification of pancreatic β cells permanently impairs their ability of insulin production, leading to glucose intolerance in adult female but not male offspring. We link psychostimulant action specifically to serotonin signaling and implicate the sex-specific epigenetic reprogramming of serotonin-related gene regulatory networks upstream from the transcription factor Pet1/Fev as determinants of reduced insulin production.

Details

Authors
  • Solomiia Korchynska
  • Maria Krassnitzer
  • Katarzyna Malenczyk
  • Evgenii O Tretiakov
  • Sabah Rehman
  • Valentina Cinquina
  • Victoria Gernedl
  • Matthias Farlik
  • Julian Petersen
  • Sophia Hannes
  • Julia Schachenhofer
  • Sonali N Reisinger
  • Alice Zambon
  • Erik Keimpema
  • Gert Lubec
  • Jan Mulder
  • Christoph Bock
  • Daniela D Pollak
  • Roman A Romanov
  • Christian Pifl
  • Tomas Gm Hökfelt
  • Tibor Harkany
Organisations
External organisations
  • Paracelsus Private Medical University of Salzburg
  • Karolinska Institutet
  • Medical University of Vienna
  • Skåne University Hospital
  • CeMM Research Center for Molecular Medicine
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Article numbere100882
JournalEMBO Journal
Volume39
Issue number1
Early online date2019 Nov 21
Publication statusPublished - 2020 Jan 2
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

©2019 The Authors. Published under the terms of the CC BY 4.0 license.