Life‐long impairment of glucose homeostasis upon prenatal exposure to psychostimulants. (21st November 2019) - Korchynska, Solomiia
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. 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. 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.