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Life-long impairment of glucose homeostasis upon prenatal exposure to psychostimulants.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-11-21 , DOI: 10.15252/embj.2018100882 Solomiia Korchynska 1 , Maria Krassnitzer 1 , Katarzyna Malenczyk 1 , Rashmi B Prasad 2 , Evgenii O Tretiakov 1 , Sabah Rehman 1 , Valentina Cinquina 1 , Victoria Gernedl 3 , Matthias Farlik 3 , Julian Petersen 1 , Sophia Hannes 1 , Julia Schachenhofer 1 , Sonali N Reisinger 4 , Alice Zambon 4 , Olof Asplund 2 , Isabella Artner 5, 6 , Erik Keimpema 1 , Gert Lubec 7 , Jan Mulder 8 , Christoph Bock 3 , Daniela D Pollak 4 , Roman A Romanov 1 , Christian Pifl 1 , Leif Groop 2, 9 , Tomas Gm Hökfelt 10 , Tibor Harkany 1, 10
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-11-21 , DOI: 10.15252/embj.2018100882 Solomiia Korchynska 1 , Maria Krassnitzer 1 , Katarzyna Malenczyk 1 , Rashmi B Prasad 2 , Evgenii O Tretiakov 1 , Sabah Rehman 1 , Valentina Cinquina 1 , Victoria Gernedl 3 , Matthias Farlik 3 , Julian Petersen 1 , Sophia Hannes 1 , Julia Schachenhofer 1 , Sonali N Reisinger 4 , Alice Zambon 4 , Olof Asplund 2 , Isabella Artner 5, 6 , Erik Keimpema 1 , Gert Lubec 7 , Jan Mulder 8 , Christoph Bock 3 , Daniela D Pollak 4 , Roman A Romanov 1 , Christian Pifl 1 , Leif Groop 2, 9 , Tomas Gm Hökfelt 10 , Tibor Harkany 1, 10
Affiliation
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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.
中文翻译：
产前接触精神兴奋剂会导致葡萄糖稳态终生受损。
母亲在怀孕期间滥用药物是一个迅速升级的社会问题。精神兴奋剂，包括安非他明、可卡因和甲基安非他明，是孕妇最常消费的非法药物之一。神经药理学概念认为，精神兴奋剂通过与神经递质再摄取和囊泡转运蛋白的亲和力影响神经系统中的单胺信号传导，从而提高细胞外神经递质的可用性。多巴胺信号传导的加剧被特别认为是精神兴奋剂作用的关键决定因素。关于这些药物对周围器官可能产生的不良影响以及如果在子宫内暴露会引起终生病变，人们知之甚少。在这里，我们通过将人类 RNA-seq 数据与神经内分泌发育的细胞和小鼠模型相结合来解决这个问题。我们发现，母亲在怀孕期间偶尔接触精神兴奋剂，与胰腺β细胞的宫内规范一致，会永久损害其产生胰岛素的能力，导致成年女性而非男性后代出现葡萄糖不耐受。我们将精神刺激作用与血清素信号传导联系起来，并暗示转录因子 Pet1/Fev 上游血清素相关基因调控网络的性别特异性表观遗传重编程是胰岛素产生减少的决定因素。
更新日期：2020-01-02
中文翻译：
产前接触精神兴奋剂会导致葡萄糖稳态终生受损。
母亲在怀孕期间滥用药物是一个迅速升级的社会问题。精神兴奋剂，包括安非他明、可卡因和甲基安非他明，是孕妇最常消费的非法药物之一。神经药理学概念认为，精神兴奋剂通过与神经递质再摄取和囊泡转运蛋白的亲和力影响神经系统中的单胺信号传导，从而提高细胞外神经递质的可用性。多巴胺信号传导的加剧被特别认为是精神兴奋剂作用的关键决定因素。关于这些药物对周围器官可能产生的不良影响以及如果在子宫内暴露会引起终生病变，人们知之甚少。在这里，我们通过将人类 RNA-seq 数据与神经内分泌发育的细胞和小鼠模型相结合来解决这个问题。我们发现，母亲在怀孕期间偶尔接触精神兴奋剂，与胰腺β细胞的宫内规范一致，会永久损害其产生胰岛素的能力，导致成年女性而非男性后代出现葡萄糖不耐受。我们将精神刺激作用与血清素信号传导联系起来，并暗示转录因子 Pet1/Fev 上游血清素相关基因调控网络的性别特异性表观遗传重编程是胰岛素产生减少的决定因素。
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