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

• Published in: The EMBO journal Vol. 39; no. 1; pp. e100882 - n/a
• Main Authors: Korchynska, Solomiia, Krassnitzer, Maria, Malenczyk, Katarzyna, Prasad, Rashmi B, Tretiakov, Evgenii O, Rehman, Sabah, Cinquina, Valentina, Gernedl, Victoria, Farlik, Matthias, Petersen, Julian, Hannes, Sophia, Schachenhofer, Julia, Reisinger, Sonali N, Zambon, Alice, Asplund, Olof, Artner, Isabella, Keimpema, Erik, Lubec, Gert, Mulder, Jan, Bock, Christoph, Pollak, Daniela D, Romanov, Roman A, Pifl, Christian, Groop, Leif, Hökfelt, Tomas GM, Harkany, Tibor
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-01-2020; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Amphetamines; Animal models; Animals; Beta cells; Cell culture; Central Nervous System Stimulants - toxicity; Clinical Medicine; Cocaine; Deoxyribonucleic acid; Deregulation; diabetes; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; DNA; DNA Methylation; Dopamine; Dopamine transporter; Drug abuse; Drug tolerance; EMBO27; Endocrinology and Diabetes; Endokrinologi och diabetes; Epigenetics; Exposure; Female; Females; Fetuses; gender; Gene Expression Profiling; Gene Expression Regulation; Glucose; Glucose - metabolism; Glucose Intolerance - etiology; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; Glucose Intolerance - pathology; Glucose tolerance; Homeostasis; Homeostasis - drug effects; Humans; Insulin; Intolerance; Intrauterine exposure; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Klinisk medicin; Male; Maternal Exposure - adverse effects; Medical and Health Sciences; Medicin och hälsovetenskap; Methamphetamine; Methamphetamine - toxicity; Mice; Narcotics; Nervous system; Neurotransmitters; Offspring; Organs; Pancreas; Pregnancy; Prenatal experience; Prenatal exposure; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - genetics; Prenatal Exposure Delayed Effects - metabolism; Prenatal Exposure Delayed Effects - pathology; Ribonucleic acid; RNA; Serotonin; Sex; Sex differences; Signaling; Social problems; susceptibility; Target recognition; Transcription factors; β cell; β cell; serotonin; susceptibility; gender; diabetes
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2018100882

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.
Synopsis
The abuse of illicit drugs is a major societal problem, including their continued use during pregnancy. Even though harmful effects of commonly used psychostimulants to the unborn fetus have been postulated, if and how maternal exposure to illicit psychostimulants during pregnancy could reprogram the fetal pancreas and limit glucose metabolism and tolerance for life in affected offspring remain unknown. Here, we combine human and mouse data to outline the sex‐specific epigenetic deregulation of serotonin signaling‐related gene regulatory networks, which leads to reduced insulin production postnatally.
As little as episodic intrauterine psychostimulant exposure is sufficient to permanently limit β cell function in postnatal female rather than mouse male offspring.
The serotonin transporter, rather than the dopamine transporter, is identified as a molecular target of psychostimulants in fetal β cells and in β cell‐like cellular models.
Psychostimulants adversely affect protein serotonylation in β cell models.
Altered DNA methylation and accessibility link the life‐long deregulation of transcription factors and genes shaping serotonin signaling with reduced functionality in β cells.
Graphical Abstract
Use of drugs like amphetamine affects pancreatic beta‐cell function and insulin production of unborn mouse offspring via deregulation of serotonin‐related gene networks.