Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life
Open accessAbstract
METHODS: Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG) or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains. RESULTS: Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not. CONCLUSION: Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.
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Mouse models of early life e-cigarette exposure have demonstrated altered behavior patterns in adult offspring and reduced cognitive function (18-24 mg/mL nicotine).
“Mouse models of early life e-cigarette exposure have also demonstrated altered behavior patterns in adult offspring and reduced cognitive function (18–24 mg/mL nicotine) [177, 178].”
From Prenatal nicotine exposure during pregnancy results in adverse neurodevelopmental alterations and neurobehavioral deficits (2023) · cites this paper as [178]
The Discussion reports increased activity in adult male mice exposed during late prenatal and early postnatal life to 2.4% nicotine vapor, supporting the altered-behavior claim. The Results report that all groups learned the water-maze task equally well, while the Discussion suggests a tendency toward increased—not reduced—cognitive flexibility in the nicotine-exposed mice. No page numbers are available in our copy. (LLM, conf=0.89)
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Do E‐cigarettes induce weight changes and increase cardiometabolic risk? A signal for the future
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“Furthermore, these vapours could elicit persistent behavioural changes later in adulthood.(88)”
BackgroundImpact of Nicotine Replacement and Electronic Nicotine Delivery Systems on Fetal Brain Development
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“[67] ENDS nicotine exposure during rapid brain growth period is associated with behavioral changes in adult mice.”
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“Recently, a push to provide a more translationally relevant preclinical model for examination of pharmacological mechanisms underlying inhaled substances of abuse has resulted in the development of equipment and methods that allows exposure of freely moving rodents to aerosolized psychoactive drugs (George et al., 201…”
BackgroundDelivery of nicotine aerosol to mice via a modified electronic cigarette device
Lefever, T., Lee, Y. O., Kovach, A., Silinski, M. A. R., Marusich, J., Thomas, B., & Wiley, J. (2017) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2016.12.004 · Cited by 23 · see citing works
“While many of these studies concentrated primarily on examination of the effects of inhaled nicotine on the pulmonary system or on developmental or toxicological effects (McGrathMorrow et al., 2015; Misra et al., 2014; Smith et al., 2015; Sussan et al., 2015), a few studies have investigated behavioral effects of inha…”
BackgroundImpact of E-cig aerosol vaping on fetal and neonatal respiratory development and function
Orzabal, M. R., Naik, V. D., Lee, J., Hillhouse, A., Brashear, W. A., Threadgill, D. W., & Ramadoss, J. (2022) · Translational research · doi:10.1016/j.trsl.2022.03.009 · Cited by 23 · see citing works
How bad are e‐cigarettes? What can we learn from animal exposure models?
Marczylo, T. H. (2020) · The Journal of Physiology · doi:10.1113/jp278366 · Cited by 25 · see citing works
“exposed mice from late gestation day 15 until postnatal day 16, they found no significant effects on balance, general activity, anxiety, spatial learning and cognitive flexibility in offspring (Smith et al. 2015).”
BackgroundInfluentialPrenatal Nicotine Exposure in Rodents: Why Are There So Many Variations in Behavioral Outcomes?
Polli, F. S., & Kohlmeier, K. A. (2019) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntz196 · Cited by 23 · see citing works
Early-life exposure to electronic cigarettes: cause for concern
Larcombe, A. N. (2019) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(19)30189-4 · Cited by 21 · see citing works
Effects of short-term electronic(e)-cigarette aerosol exposure in the mouse larynx
Easwaran, M., Maria, C., Martinez, J. D., Hung, B., Yu, X., Soo, J., Kimura, A., Gross, E. R., & Erickson-Direnzo, E. (2023) · The Laryngoscope · doi:10.1002/lary.31043 · Cited by 17 · see citing works
“Evidence shows animal body weight loss post e-cigarette exposure with nicotine free e-cigarettes, 29 – 31 indicating e-cigarette-induced body weight loss may not entirely be nicotine-dependent.”
BackgroundMorris, M., Shaw, A., Lambert, M., Perry, H., Lowenstein, E., Valenzuela, D., & Velazquez-Ulloa, N. (2018) · BMC Developmental Biology · doi:10.1186/s12861-018-0172-6 · Cited by 17 · see citing works
“There is little evidence that e-cigarettes are effective for smoking cessation and it has been shown that e-cigarette exposure during development leads to behavioral changes in rodents [17, 18].”
Route of Administration Effects on Nicotine Discrimination in Female and Male Mice
Lefever, T., Thomas, B., Kovach, A., Snyder, R. W., & Wiley, J. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.06.007 · Cited by 16 · see citing works
“Because inhalation is the most common route of administration of nicotine-containing tobacco products in humans, a recent push to provide more translationally relevant preclinical models has concentrated on development of equipment and methods that allow exposure of freely moving rodents to aerosolized nicotine (Georg…”
BackgroundPassive exposure to electronic cigarette aerosol in pregnancy: A case study of a family.
Ballbè, M., Fu, M., Masana, G., Pérez-Ortuño, R., Gual, A., Fernando, G., Olmedo, P., García-Algar, Ó., Antonio, P. V. J., & Fernández, E. (2022) · Environmental Research · doi:10.1016/j.envres.2022.114490 · Cited by 15 · see citing works
Nicotine and the developing brain: Insights from preclinical models
McCarthy, D. M., Zhang, L., Wilkes, B. J., Vaillancourt, D., Biederman, J., & Bhide, P. (2022) · Pharmacology, Biochemistry and Behavior · doi:10.1016/j.pbb.2022.173355 · Cited by 15 · see citing works
Flores, R. J., Alshbool, F. Z., Giner, P., O’Dell, L. E., & Mendez, I. A. (2021) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntab141 · Cited by 16 · see citing works
E-Cigarette Advice to Patients From Physicians and Dentists in the United States
Drouin, O., McMillen, R. C., Klein, J., & Winickoff, J. (2018) · American Journal of Health Promotion · doi:10.1177/0890117117710876 · Cited by 15 · see citing works
Self-citationNeurobehavioral effects of 1,2-propanediol in zebrafish (Danio rerio)
Massarsky, A., Abdel, A., Glazer, L., Levin, E., & Giulio, R. D. (2018) · Neurotoxicology · doi:10.1016/j.neuro.2018.02.007 · Cited by 15
Kondo, M., Fukudome, D., Smith, D. R., Gallagher, M., Kamiya, A., & Sawa, A. (2016) · Neuroscience Research · doi:10.1016/j.neures.2016.01.006 · Cited by 18 · see citing works
Self-citationEffect of Electronic Cigarettes on the Gastrointestinal System
Debnath, M., Debnath, D., Singh, P., Wert, Y., & Nookala, V. (2022) · Cureus · doi:10.7759/cureus.27210 · Cited by 14
“In various animal studies, EC exposure has also shown a negative prenatal and postnatal effect on lung growth [9,10].”
BackgroundGarrett, P. I., Honeycutt, S. C., Marston, C., Allen, N., Barraza, A. G., Dewey, M., Turner, B., Peterson, A. M., & Hillhouse, T. M. (2021) · Pharmacology, Biochemistry and Behavior · doi:10.1016/j.pbb.2021.173207 · Cited by 14 · see citing works
Mills, A., Nassabeh, S., Hurley, A., Shouldis, L., Chantler, P. D., Dakhlallah, D. A., & Olfert, I. M. (2024) · The Journal of Physiology · doi:10.1113/jp286493 · Cited by 15 · see citing works
“Our findings, like others (Archie et al., 2023; Church et al., 2020; Nguyen et al., 2018; Sifat et al., 2020; Smith et al., 2015), observed an increase in locomotor activity in offspring.”
Hilpert, M., Ilievski, V., Coady, M., Andrade-Gutierrez, M., Yan, B., Chillrud, S., Navas-Acien, A., & Kleiman, N. (2019) · Inhalation Toxicology · doi:10.1080/08958378.2019.1698678 · Cited by 12 · see citing works
“Most commonly, tubing is attached to the mouthpiece and aerosol is sucked away via a vacuum pump, mimicking the action of an e-cig user who applies a vacuum to his/her mouthpiece (McGrath-Morrow et al. 2015; Smith et al. 2015; Sussan et al. 2015; Sleiman et al. 2016; Laube et al. 2017).”
BackgroundMethodInfluentialBunney, P. E., Hansen, M., & Lesage, M. (2017) · Pharmacology, Biochemistry and Behavior · doi:10.1016/j.pbb.2017.11.004 · Cited by 12 · see citing works
“While some studies have shown that e-cigarette vapor produces increases in physical activity and delayed weight gain (Russo et al., 2015; Smith et al., 2015), others have shown that e-cigarette vapor has no effect on weight gain or food intake (Golli El et al.”
Is There a Critical Period for the Developmental Neurotoxicity of Low-Level Tobacco Smoke Exposure?
Slotkin, T. A., Stadler, A., Skavicus, S., Card, J., Ruff, J., Levin, E. D., & Seidler, F. J. (2016) · Toxicological Sciences · doi:10.1093/toxsci/kfw180 · Cited by 14 · see citing works
“, 2015) and this is also seen with nicotine-containing e-cigarette vapor (Smith et al., 2015).”
BackgroundThe respiratory epithelium in the era of vaping: insights from in vitro, in vivo and human studies
Gandhi, A., Lee, C. E., Beaumont, A., Ozeki, S., Parambil, C. J., Bowler, R., & Rezaee, F. (2025) · European Respiratory Review · doi:10.1183/16000617.0256-2024 · Cited by 10
“Growth deficits have also been reported with nicotine-free exposures, implicating other aerosol constituents, such as PG, VG or flavourings [72].”
Electronic cigarettes—A review of the physiological health effects
Zucchet, A., & Schmaltz, G. (2017) · FACETS · doi:10.1139/facets-2017-0014 · Cited by 13 · see citing works
Lechasseur, A., & Morissette, M. C. (2020) · European Respiratory Review · doi:10.1183/16000617.0268-2020 · Cited by 9
Effects of Prenatal Electronic Cigarette Exposure On Foetal Development: a Review of the Literature
Römer, P., Putzer, A. G., Kemmerich, R., & Mathes, B. (2021) · Geburtshilfe und Frauenheilkunde · doi:10.1055/a-1524-5155 · Cited by 11 · see citing works
“The same effect was also noted in adolescent mice [51].”
Schilling, L., Schneider, S., Maul, H., & Spallek, J. (2020) · Geburtshilfe und Frauenheilkunde · doi:10.1055/a-1061-7288 · Cited by 7 · see citing works
“…covered perceptions about absolute harms as well as about the specific potential health risks to the mother and the unborn child [6,9, 10,12 – 14,40,41], overall perceived threats/worries about po-▶ Table 1 Information about identified threads in online discussion forums (qualitative section of…”
Bellés, M., Heredia, L., Serra, N., Domingo, J., & Linares, V. (2016) · Food and Chemical Toxicology · doi:10.1016/j.fct.2016.08.032 · Cited by 7 · see citing works
Effect of chronic vapor nicotine exposure on affective and cognitive behavior in male mice
Murdaugh, L., Miliano, C., Chen, I., Faunce, C. L., Natividad, L. A., Gregus, A. M., & Buczynski, M. W. (2024) · Scientific Reports · doi:10.1038/s41598-024-56766-z · Cited by 6 · see citing works
Bakker, C., Chivers, E. K., Chia, X. L., Quintrell, E., Wyrwoll, C., & Larcombe, A. N. (2023) · Physiology and Behavior · doi:10.1016/j.physbeh.2023.114118 · Cited by 6 · see citing works
Enduring effects of perinatal nicotine exposure on murine sleep in adulthood.
Borniger, J. C., Don, R. F., Zhang, N., Boyd, R., & Nelson, R. (2017) · American Journal of Physiology. Regulatory Integrative and Comparative Physiology · doi:10.1152/ajpregu.00156.2017 · Cited by 6 · see citing works
Mazza, D., McGrath-Morrow, S., & Collaco, J. (2017) · Pediatric Allergy, Immunology, and Pulmonology · doi:10.1089/ped.2017.0771 · Cited by 6 · see citing works
“12 13–16 To this end, environmental exposure to e-cigarette emissions could pose a health risk for the child with BPD since these infants and children are already at increased risk for behavioral issues and rely on catch-up lung growth to achieve adequate lung function.”
Self-citationThe Impact of Traditional Cigarettes and E-Cigarettes on the Brain
Wawryk-Gawda, E., Lis-Sochocka, M., Chylińska-Wrzos, P., Budzyńska, B., & Jodłowska-Jędrych, B. (2019) · Neuroscience of Nicotine · doi:10.1016/b978-0-12-813035-3.00004-6 · Cited by 6 · see citing works
Tsiapakidou, S., Mahmood, T., & Savona‐Ventura, C. (2023) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2023.08.384 · Cited by 6 · see citing works
“There are currently no studies on the reproductive outcome of pregnant women who vaped; however, animal studies have demonstrated the potential harm of vaping ’ s nicotine exposure to birth defects and altered birth weight [5,6].”
BackgroundPassive Electronic Cigarette Vapor Exposure in Children: A Systematic Review
Rodriguez, J., Silverstein, D. R., Mutic, A. D., Liang, D.-H., Peterson, S. R., & Yang, I. (2025) · Biological Research for Nursing · doi:10.1177/10998004251357832 · Cited by 4 · see citing works
“Body weight was signi fi cantly associated with secondhand e-cigarette vapor exposure (McGrath-Morrow et al., 2015; Smith et al., 2015), but not thirdhand e-cigarette vapor exposure in young mice (Chen et al., 2020).”
InfluentialAlharthi, A., Alasmari, F., Alsharari, S. D., Alrasheed, N., Alshammari, M. A., & Alshammari, T. K. (2023) · Brain Science · doi:10.3390/brainsci13101417 · Cited by 4 · see citing works
Developmental Effects of Electronic Cigarette Use
Collaco, J., & McGrath-Morrow, S. (2022) · Comprehensive Physiology · doi:10.1002/j.2040-4603.2022.tb00214.x · Cited by 4 · see citing works
Self-citationSmoking and pregnancy: The era of electronic nicotine delivery systems
Desai, N. S. (2020) · Obstetric Medicine · doi:10.1177/1753495x19893224 · Cited by 4 · see citing works
“Similar models have also demonstrated dysregulation in frontal cortex gene expression as well as a decrease in hippocampal gene expression.(20,21) Small studies have shown evidence of short-term memory deficits, reduced anxiety, and hyperactivity in mice.”
ResultElectronic Cigarettes: Exposure and Use Among Pediatric Populations.
Collaco, J., & McGrath-Morrow, S. (2017) · Journal of Aerosol Medicine · doi:10.1089/jamp.2017.1418 · Cited by 4 · see citing works
“Nevertheless, data from neonatal mice suggest that both alveolar lung and overall growth are impaired with exposure to e-cigarette emissions,((49)) and exposure during early life may lead to persistent behavioral changes in adult mice.((50)) Thirdhand exposure from conventional cigarettes and/or e-cigarettes is define…”
BackgroundSelf-citationAnimal models of developmental toxicity induced by early life electronic-cigarettes exposure
Huang, L., Gao, L., Chen, D., & Sun, Q. (2025) · Critical Reviews in Toxicology · doi:10.1080/10408444.2025.2497754 · Cited by 2 · see citing works
“…al. 2020; Archie et al. 2023), while another study revealed that solely the offspring exposed to E-cig vapor with 24 mg/mL nicotine, as opposed to nicotine-free vapor (Smith et al. 2015), thereby implying a significant role of nicotine in inducing hyperactivity among the offspring of E-cig users.”
InfluentialArticle Review: Effect of Electronic Cigarette on Fertility in Male
Abud, H. N. (2024) · Journal for Research in Applied Sciences and Biotechnology · doi:10.55544/jrasb.3.1.33 · Cited by 2 · see citing works
Adolescents and Electronic Vapor Product Use: A Dangerous Unknown
Yale, S. C., McFadden, V., & Mikhailov, T. A. (2023) · Adolescents · doi:10.3390/adolescents3040047 · Cited by 2 · see citing works
“In addition to the above-listed neurologic concerns, the role of EVP-induced oxidative stress can be linked to sleep concerns [63], increased levels of psychological distress [64], depression [65,66], and suicide [56,65,67].”
BackgroundParnell, A. A., McCarthy, D. M., Trupiano, M. X., Schatschneider, C. W., & Bhide, P. G. (2025) · Scientific Reports · doi:10.1038/s41598-025-19504-7 · Cited by 2 · see citing works
Effect of chronic vapor nicotine exposure on affective and cognitive behavior in male mice
Murdaugh, L., Miliano, C., Chen, I., Faunce, C. L., Natividad, L. A., Gregus, A. M., & Buczynski, M. W. (2024) · Research Square · doi:10.21203/rs.3.rs-3892315/v1
Exposure to nicotine vapor causes short-term increases in impulsive choice in ratsPreprint
Flores, R. J., Alshbool, F. Z., Giner, P., O'Dell, L., & Mendez, I. A. (2019) · bioRxiv · doi:10.1101/842005
“13 available 0 mg/mL nicotine solutions also reported similarly low amounts of serum cotinine (under 10 ng/mL) and concluded that nicotine contamination had occurred in the 0 mg/mL solution that they used (Smith et al., 2015).”
InfluentialDevelopmental effects of nicotine on cognitive, motivated, and executive behaviors
Kohlmeier, K., & Polli, F. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-817988-8.00015-4
Health Effects of E-Cigarettes and Other Vaping Devices on Non-users
Collaco, J., & McGrath-Morrow, S. (2021) · Electronic Cigarettes and Vape Devices · doi:10.1007/978-3-030-78672-4_5
Self-citation
- Authors
- Smith, D., Aherrera, A., Lopez, A., Neptune, E., Winickoff, J. P., Klein, J. D., Chen, G., Lazarus, P., Collaco, J. M., & McGrath-Morrow, S. A.
- Affiliations
- Johns Hopkins University (US)
- American Academy of Pediatrics (US)
- Washington State University (US)
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-09-15
- Volume
- 10
- Issue
- 9
- Pages
- e0137953
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4570802
- OpenAlex
- W2118238343
- Cited by
- 103
- References
- 30
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 10 · 2023: 11 · 2022: 8 · 2021: 8 · 2020: 12 · 2019: 17 · 2018: 7 · 2017: 13 · 2016: 10 · 2013: 1
- FWCI
- 9.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Flight Attendant Medical Research Institute (NIH RHL114800A)
- National Institutes of Health
- U.S. Public Health Service (RHL114800A)
- National Heart, Lung, and Blood Institute (R01HL114800)
- National Institute of Environmental Health Sciences (R01ES025460)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- prenatal nicotine exposure, sensorimotor behavior, emotional behavior, cognitive function, rearing behavior, propylene glycol, C57BL/6J mice, developmental neurotoxicity
- MeSH terms
- Animals, Behavior, Animal, Body Weight, Cognition, Cotinine, Female, Male, Mice, Inbred C57BL, Motor Activity, Nicotine, Pregnancy, Prenatal Exposure Delayed Effects, Sensation, Volatilization, Maternal Exposure, Mice, Electronic Nicotine Delivery Systems
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