Os efeitos da nicotina são transmitidos através das gerações de ratos: Lamarck redivivus???

sexta-feira, novembro 30, 2018

Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants

Deirdre M. McCarthy, Thomas J. Morgan Jr., Sarah E. Lowe, Matthew J. Williamson, Thomas J. Spencer, Joseph Biederman, Pradeep G. Bhide 


Source/Fonte: The Scientist

Abstract

Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 μg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.

Author summary

Use of tobacco products is a major public health concern throughout the world. Cigarette smoking by pregnant women receives significant attention by scientific, public health, and public policy experts because it poses health risks for the mother and her children. Although more men smoke cigarettes than women, the health consequences of paternal smoking for their descendants are much less explored. Using a mouse model, we show that the offspring of nicotine-exposed males have hyperactivity, attention deficit, and cognitive inflexibility. These behavioral phenotypes are associated with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder in humans. Cognitive inflexibility persists into the third (F2) generation. The neurotransmitters dopamine and noradrenaline and their receptors, critically implicated in neurodevelopmental disorders, are also altered in the offspring’s brains. The nicotine-exposed males show significant alterations in spermatozoal DNA methylation patterns, especially at dopamine receptor gene promoter regions, implicating epigenetic modification of germ cell DNA as a mechanism for the transgenerational transmission of the behavioral and neurotransmitter phenotypes. The impact of nicotine on germ cells and the neurobehavioral impairments in multiple subsequent generations call for renewed focus of research and public policy on tobacco use by men and its consequences for their descendants.

Citation: McCarthy DM, Morgan TJ Jr, Lowe SE, Williamson MJ, Spencer TJ, Biederman J, et al. (2018) Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants. PLoS Biol 16(10): e2006497. https://doi.org/10.1371/journal.pbio.2006497

Academic Editor: Eric Nestler, Icahn School of Medicine at Mount Sinai, United States of America

Received: April 27, 2018; Accepted: September 13, 2018; Published: October 16, 2018

Copyright: © 2018 McCarthy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: Jim and Betty Anne Rodgers Chair Fund at Florida State University (grant number F00662). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Escher Fund for Autism http://www.germlineexposures.org (grant number). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Institute on Drug Abuse https://www.drugabuse.gov/ (grant number R15 DA043848). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: I have read the journal's policy and the authors of this manuscript have the following potential competing interests. Pradeep Bhide: Dr. Bhide is a co-founder and consultant to Avekshan LLC, Tallahassee, FL, a pharmaceutical enterprise engaged in the development of novel therapies for attention deficit hyperactivity disorder (ADHD). Dr. Bhide is an inventor in following patents or patent applications relevant to ADHD therapy: US Patent, “Class of non-stimulant treatment and ADHD and related disorders” (#US9623023 B2), and US patent application, “Methods and compositions to prevent addiction (#US20130289061 A1). Deirdre McCarthy: Ms. McCarthy is a co-founder and consultant to Avekshan LLC, Tallahassee, FL, a pharmaceutical enterprise engaged in the development of novel therapies for attention deficit hyperactivity disorder (ADHD). Thomas Spencer: Dr. Spencer received research support or was a consultant from the following sources: Alcobra, Avekshan, Ironshore, Lundbeck, Shire Laboratories Inc, Sunovion, the FDA, and the Department of Defense. Consultant fees are paid to the Clinical Trials Network at the Massachusetts General Hospital (MGH) and not directly to Dr. Spencer. Dr. Spencer has been on an advisory board for the following pharmaceutical companies: Alcobra. Dr. Spencer received research support from Royalties and Licensing fees on copyrighted ADHD scales through MGH Corporate Sponsored Research and Licensing. Through MGH corporate licensing, Dr. Spencer is an inventor on a US Patent, “Class of non-stimulant treatment and ADHD and related disorders” (#US9623023 B2), and US patent application, “Methods and compositions to prevent addiction" (#US20130289061 A1). Joseph Biederman: Dr. Biederman is currently receiving research support from the following sources: AACAP, The Department of Defense, Food & Drug Administration, Headspace, Lundbeck, Neurocentria Inc., NIDA, PamLab, Pfizer, Shire Pharmaceuticals Inc., Sunovion, and NIH. Dr. Biederman has a financial interest in Avekshan LLC, a company that develops treatments for attention deficit hyperactivity disorder (ADHD). His interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. Dr. Biederman’s program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. In 2017, Dr. Biederman is a consultant for Aevi Genomics, Akili, Guidepoint, Ironshore, Medgenics, and Piper Jaffray. He is on the scientific advisory board for Alcobra and Shire. He received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses. Through MGH corporate licensing, he is an inventor on US Patent, “Class of non-stimulant treatment and ADHD and related disorders” (#US9623023 B2), and US patent application, “Methods and compositions to prevent addiction (#US20130289061 A1). In 2016, Dr. Biederman received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses, and from Alcobra and APSARD. He was on the scientific advisory board for Arbor Pharmaceuticals. He was a consultant for Akili and Medgenics. He received research support from Merck and SPRITES. Thomas Morgan, Sara Lowe, and Matthew Williamson have no competing interests to declare.

Abbreviations: 3-MT, 3-methoxytyramine; ADHD, attention deficit hyperactivity disorder; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; MeDIP, methylated DNA immunoprecipitation; miRNA, microRNA; NE, norepinephrine; P0, postnatal day 0; qPCR, quantitative PCR

FREE PDF GRATIS: PLoS Biology