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

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 beta 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.Peer reviewe

The effect of prenatal methamphetamine exposure on glucose homeostasis in offspring

Die korrekte Sekretion von Insulin als Reaktion auf eine erhöhte Glukose Konzentration im Blut ist wichtig um das Glukose Gleichgewicht aufrecht zu erhalten. Insulin wird in den β-Zellen der Langerhans’schen Inseln produziert und sezerniert. Die Dopamin Rezeptoren DRD1 und DRD2, der Dopamintransporter (DAT), der Vesikuläre Monoaminetransporter (VMAT2), L-3,4-dihydroxyphenylalanin (L-Dopa) und Dopamin wurden in den β-Zellen von Nagetieren nachgewiesen. Es wurde beobachtet, dass der Dopamin Signalweg durch Methamphetamin beeinflußt wird. Wir nehmen an, dass die Verabreichung von Methamphetamin zu einem bestimmten Zeitpunkt in der embryonalen Entwicklung Einfluß auf die Entwicklung des endokrinen Pankreas und der Langerhans’schen Insel hat und damit die adequate Insulinsekretion beeinflußt. Wir zeigen, dass die Anzahl der β-Zellen von Tieren welchen prenatal Methamphetamin verabreicht wurde, signifikant sinkt. Die Nachkommen der Methamphetamin behandelten Muttertiere zeigen ein erhöhtes Glukose Level im Blut zu Beginn und während des gesamten GTT. Weiters können wir zeigen, dass in der mit Methamphetamine behandelten INS-1E Zellen die Genexpression von DRD1 signifikant sinkt. In den 6 Wochen alten Nachkommen Methamphetamin behandelter Tiere nimmt die Anzahl der Insulin-positiven β-Zellen ab und wir untersuchten, ob dies durch Apoptosis hervorgerufen wird. Die Cleaved Caspase3 (Casp3) Immunofärbung zeigte, dass die Anzahl apoptotischer INS-1E Zellen durch eine Methamphetamin Exposition signifikant erhöht ist. Diese Resultate zeigen, dass Methamphetamin die Architektur der Langerhans’schen Inseln und die Genexpression von DRD1 beeinflußt und eine nicht angemessene Reaktion auf eine erhöhte Glukosekonzentrationen im Blut zur Folge hat.For glucose homeostasis the adequate secretion of insulin in a response to elevated glucose concentration in blood is necessary. Insulin is produced by and secreted from β-cells in the islets of Langerhans. It has been previously suggested that dopamine receptor 1 (DRD1) and dopamine receptor 2 (DRD2), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), as well as dopamine itself are present in the β-cells of rodents. It was observed that dopamine signaling is affected by methamphetamine. We hypothesized that the treatment with methamphetamine at a specific time-point in embryonic development can affect the dopaminergic signaling pathway in endocrine pancreas and thus interfere with islet development and an adequate insulin secretion. We showed that the number of β-cells in 6 week old animals prenatally exposed to methamphetamine is significantly decreased. Moreover glucose tolerance test (GTT) showed that the level of glucose in the blood is elevated at baseline and throughout GTT in offspring prenatally exposed to methamphetamine. We further demonstrate that in methamphetamine treated INS-1E cells gene expression of DRD1 is significantly decreased. Because the number of insulin positive β-cells is decreased in 6 week old animals prenatally exposed to methamphetamine we examined if it is due to apoptosis. Cleaved Caspase3 (Casp3) immunostaining showed that the number of apoptotic INS-1E-cells is significantly increased upon methamphetamine exposure. These findings reveal that methamphetamine affects the architecture of islets and gene expression of DRD1 resulting in a non-adequate response to elevated blood glucose concentrations