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

• Solomiia Korchynska ^[1] ; Maria Krassnitzer ^[1] ; Katarzyna Malenczyk ^[1] ; Rashmi B Prasad ^[3] ; Evgenii O Tretiakov ^[1] ; Sabah Rehman ^[1] ; Valentina Cinquina ^[1] ; Victoria Gernedl ^[4] ; Matthias Farlik ^[4] ; Julian Petersen ^[1] ; Sophia Hannes ^[1] ; Julia Schachenhofer ^[1] ; Sonali N Reisinger ^[1] ; Alice Zambon ^[1] ; Olof Asplund ^[3] ; Isabella Artner ^[2] ; Erik Keimpema ^[1] ; Gert Lubec ^[5] ; Jan Mulder ^[6] ; Christoph Bock ^[4] ; Daniela D Pollak ^[1] ; Roman A Romanov ^[1] ; Christian Pifl ^[1] ; Leif Groop ^[7] ; Tomas GM Hökfelt ^[8] ; Tibor Harkany ^[1]
  1. [1] Medical University of Vienna

     Medical University of Vienna

     Innere Stadt, Austria

     
  2. [2] Lund University

     Lund University

     Suecia

     
  3. [3] 2 Department of Clinical Sciences, Diabetes and Endocrinology CRC Skåne University Hospital Malmö Malmö Sweden
  4. [4] 3 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria
  5. [5] 7 Paracelsus Medical University Salzburg Austria
  6. [6] 8 Science for Life Laboratory Karolinska Institutet Solna Sweden
  7. [7] 2 Department of Clinical Sciences, Diabetes and Endocrinology CRC Skåne University Hospital Malmö Malmö Sweden; 9 Institute for Molecular Medicine Finland (FIMM) Helsinki University Helsinki Finland
  8. [8] 10 Department of Neuroscience Karolinska Institutet Solna Sweden

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 39, Nº. 1, 2020
• Idioma: inglés
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  • 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.