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

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.

Does Prenatal Exposure to CNS Stimulants Increase the Risk of Cardiovascular Disease in Adult Offspring?

“…In addition to direct effects on the heart, methamphetamine exposure during gestation may promote the development of cardiovascular risk factors such as diabetes, hypertension, and obesity. A recent study by Korchynska et al ( 13 ) reported hypermethylation and decreased expression of multiple genes required for insulin production by pancreatic β cells in adult mice that were prenatally exposed to methamphetamine, amphetamine, or cocaine. This resulted in permanent impairment of insulin production and lifelong dysregulation of glucose homeostasis.…”

“…This hypothesis is speculative as we are unaware of any studies that have compared the expression levels of DAT, the norepinephrine transporter (NET), or adrenergic and dopaminergic receptors in the developing male and female fetus. Understanding the mechanism by which prenatal exposure to methamphetamine or cocaine induces sex-dependent effects in the adult heart is complicated by the fact that some methamphetamine induced effects are found exclusively in males ( 52 ) and other effects occur exclusively in females ( 13 , 27 ). Similarly, prenatal cocaine produces some effects in only in male offspring ( 26 , 28 ) and other effects that occur exclusively in female offspring ( 13 , 26 ).…”

“…Understanding the mechanism by which prenatal exposure to methamphetamine or cocaine induces sex-dependent effects in the adult heart is complicated by the fact that some methamphetamine induced effects are found exclusively in males ( 52 ) and other effects occur exclusively in females ( 13 , 27 ). Similarly, prenatal cocaine produces some effects in only in male offspring ( 26 , 28 ) and other effects that occur exclusively in female offspring ( 13 , 26 ). Further work is needed to understand the mechanism by which these effects occur in a sex-dependent manner.…”

“…It is well-established that substance use during pregnancy can negatively impact cognition ( 2 , 3 ), the stress response ( 4 ), anxiety ( 5 , 6 ), and susceptibility to drug addiction ( 7 , 8 ) in the adult offspring. These transgenerational effects involve epigenetic mechanisms (DNA methylation, histone acetylation, micro RNA) ( 9 – 11 ) as well as drug-induced changes in endocrine function ( 12 , 13 ), receptor expression ( 14 – 16 ), and structural changes within the brain ( 17 , 18 ) that can have pathological consequences extending into adulthood.…”

“…Most studies exploring the impact of prenatal exposure to CNS stimulants have focused on behavioral and neurological outcomes. However, recent studies indicate that prenatal exposure to CNS stimulants such as methamphetamine, cocaine, nicotine, and caffeine, can lead to diabetes ( 13 , 20 ), obesity ( 20 ), alterations in lipid metabolism ( 21 – 23 ), vascular dysfunction ( 24 – 26 ), and increased susceptibility to cardiac ischemic injury ( 27 , 28 ) in adult offspring. The purpose of this review is to summarize our current understanding of the impact of prenatal exposure to CNS stimulants on adult cardiovascular function.…”