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

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.
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.