title: Teratogenic, bioenergetic, and behavioral effects of exposure to total particulate matter on early development of zebrafish (Danio rerio) are not mimicked by nicotine.
abstract: Cigarette smoke has been associated with a number of pathologies; however, the mechanisms leading to developmental effects are yet to be fully understood. The zebrafish embryo is regarded as a 'bridge model'; however, not many studies examined its applicability to cigarette smoke toxicity. This study examined the effects of total particulate matter (TPM) from 3R4F reference cigarettes on the early development of zebrafish (Danio rerio). Zebrafish embryos were exposed to two concentrations of TPM (0.4 and 1.4 μg/mL equi-nicotine units) or nicotine at equivalent doses. The exposures began at 2h post-fertilization (hpf) and lasted until 96 hpf. Several physiological parameters were assessed during or after the exposure. We show that TPM increased mortality, delayed hatching, and increased the incidence of deformities in zebrafish. TPM exposure also increased the incidence of hemorrhage and disrupted the angiogenesis of the major vessels in the brain. Moreover, TPM exposure reduced the larval body length, decreased the heart rate, and reduced the metabolic rate. Biomarkers of xenobiotic metabolism and oxidative stress were also affected. TPM-exposed zebrafish also differed behaviorally: at 24 hpf the embryos had a higher frequency of spontaneous contractions and at 144 hpf the larvae displayed swimming hyperactivity. This study demonstrates that TPM disrupts several aspects of early development in zebrafish. The effects reported for TPM were not attributable to nicotine, since embryos treated with nicotine alone did not differ significantly from the control group. Collectively, our work illustrates the utility of zebrafish as an alternative model to evaluate the toxic effects of cigarette smoke constituents.
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, NC 27708, USA. Electronic address: andrey.massarsky@duke.edu.
authors.forename: Andrey
authors.initials: A
authors.lastname: Massarsky
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, NC 27708, USA. Electronic address: nishad.jayasundara@duke.edu.
authors.forename: Nishad
authors.initials: N
authors.lastname: Jayasundara
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: jordan.bailey@duke.edu.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Bailey
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: anthony.olivery@duke.edu.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Oliveri
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: edlevin@duke.edu.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.affiliation: R&D Department, R.J. Reynolds Tobacco Company, Winston-Salem, NC 27102, USA. Electronic address: prasadg@rjrt.com.
authors.forename: G L
authors.initials: GL
authors.lastname: Prasad
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, NC 27708, USA. Electronic address: richd@duke.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Di Giulio
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D006454:Hemoglobins / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009538:Nicotine / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D052638:Particulate Matter / Q000633:toxicity*; D013723:Teratogens; D015262:Xenobiotics / Q000378:metabolism; D015027:Zebrafish
chemical_list: D006454:Hemoglobins; D018722:Nicotinic Agonists; D052638:Particulate Matter; D013723:Teratogens; D015262:Xenobiotics; D009538:Nicotine; D019363:Cytochrome P-450 CYP1A1
keywords: Behavior; Cigarette smoke; Early development; Total particulate matter; Toxicity; Zebrafish