- Email: [email protected]
Brain-derived neutrophic factor in adolescents smoking waterpipe: The Irbid TRY
International Journal of Developmental Neuroscience 67 (2018) 14–18
Contents lists available at ScienceDirect
International Journal of Developmental Neuroscience journal homepage: www.elsevier.com/locate/ijdevneu
Brain-derived neutrophic factor in adolescents smoking waterpipe: The Irbid TRY
T
⁎
Mahmoud A. Alomaria, , Nihaya A. Al-sheyabb, Omar F. Khabourc, Karem H. Alzoubid a
Division of Physical Therapy, Department of Rehabilitation Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan b Faculty of Nursing, Maternal and Child Health Department, Jordan University of Science and Technology, Irbid, Jordan c Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Jordan d Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
A R T I C LE I N FO
A B S T R A C T
Keywords: Waterpipe smoking BDNF Youth risk behavior survey Students Tobacco Jordan
Background: Brain-derived neutrophic factor (BDNF) and tobacco consumption can affect many body functions and health. However, the relationship of BDNF with waterpipe (Wp) smoking is unknown. Therefore, the current study examined the relationship between Wp smoking and BDNF in adolescents. Methods: Self-reported tobacco consumption and serum BDNF were determined in 195 waterpipe and 288 nonsmokers in 7th–10th grade students. Results: Stepwise regression that included Wp smoking, gender, BMI, and location, showed that only Wp smoking (p < 0.0001) and gender (p < 0.0001) were related to serum BDNF. In addition, the ANCOVA found a main effect for Wp smoking (p < 0.0001) and gender (p < 0.0001) with lower BDNF in males smoking waterpipe. Discussion: BDNF was diminished in adolescent Wp smokers, which might predispose adolescents for systematic adverse health and behavioral alterations. These results extend the negative health risks associated with cigarette smoking to that of water-pipe tobacco smoking.
1. Introduction Brain-derived neutrophic factor (BDNF) is most abundant and functions in the hippocampus and hypothalamus. It is pivotal for neuronal survival, migration, synaptogenesis, differentiation, and dendritic arborization (Yeom et al., 2016). It contributes immensely to data learning, retention, and processing, intelligence, and attention throughout the lifespan, including schoolchildren (Yeom et al., 2016). Additionally, BDNF appears to be involved in energy (Chaldakov et al., 2009), cardiovascular (Alomari et al., 2014; Alomari et al., 2015a), and musculoskeletal (Matthews et al., 2015) homeostasis. In fact, a study showed that women with higher plasma BDNF were at less risk of allcause mortality than women with lower plasma BDNF (Krabbe et al., 2009). Tobacco consumption is a serious public health concern. Waterpipe (Wp) smoking is a tobacco consumption style, during which smoke from burned “Moassel” tobacco on a charcoal, passes through a bowl of water into a hose then inhaled into the smoker's mouth. Contrary to developed countries, adolescent tobacco consumption in developing countries is on a steady rise (Mzayek et al., 2012; Al-Sheyab et al.,
⁎
2014). Similarly, Wp smoking among adolescents, in particular, has recently gained popularity. In fact, the prevalence of adolescent Wp smoking in many countries is greater than that in adults (Akl et al., 2011) and has surpassed cigarette smoking (Al-Sheyab et al., 2014; Alomari and Al-sheyab, 2017), reaching > 50% in some countries (AlSheyab et al., 2014; Alomari and Al-sheyab, 2017). Aroma, flavor, atmosphere, social acceptance, curiosity, novelty, accessibility, affordability, and alular, among other factors, have been implicated in the accelerated increase in Wp consumption (Jawad et al., 2013). However, health misconceptions have been pivotal in driving the worldwide spread of Wp, especially among adolescents (Jawad et al., 2013). Every so often, Wp has been promoted as a “less harmful” alternative to cigarettes. It is thought the passing of smoke through the water can “cleanse” the smoke from toxicant, thus minimize the adverse health effects of smoking (Shihadeh et al., 2012). Additionally, more than often, the fruit flavoring of Wp tobacco makes smokers believe that Wp smoking is healthier than cigarettes (Jawad et al., 2013). In fact, it is the harms from cigarettes combined with flavoring agents and the paraphernalia used in the Wp process (Kadhum et al., 2015). Smoking Wp presents a greater level of the same types of toxicants of cigarettes
Corresponding author. E-mail addresses: [email protected] (M.A. Alomari), [email protected] (N.A. Al-sheyab), [email protected] (O.F. Khabour), [email protected] (K.H. Alzoubi).
https://doi.org/10.1016/j.ijdevneu.2018.03.007 Received 4 January 2018; Received in revised form 9 March 2018; Accepted 11 March 2018 Available online 16 March 2018 0736-5748/ © 2018 Published by Elsevier Ltd on behalf of ISDN.
International Journal of Developmental Neuroscience 67 (2018) 14–18
M.A. Alomari et al.
Technology, the Jordanian Ministry of Education, and the relevant educational districts in North of Jordan. Socio-demographic characteristics, tobacco smoking patterns, and blood samples were taken from all participating adolescents, as described below.
including a surge of nicotine, metallic elements, particulate substances, and countless carcinogens (Kadhum et al., 2015). However, toxicants derived from charcoal combustion and, flavored smoking mixture with the infection risk due to sharing Wp gear (i.e. mouthpieces), certainly surpass the harms of cigarettes (Kadhum et al., 2015). Additionally, many Wp smokers don’t consider themselves smokers and can quit smoking any time (Jawad et al., 2016). Unfortunately, studies have shown that dependency is high (Aboaziza and Eissenberg, 2015) while quitting rate is low (Jawad et al., 2016) among Wp smokers. Previous studies have shown that Wp smoke contains substantial concentrations of toxic compounds compared to cigarette smoke (Shihadeh and Saleh, 2005; Kim et al., 2016). For example, the magnitude of “tar” from a single Wp session is typically several folds higher than that produced from a single cigarette (Primack et al., 2016). Similarly, the amount of CO exposure is estimated to be ∼3 folds higher during Wp versus cigarette smoking (Cobb et al., 2015) while polycyclic aromatic hydrocarbons are considerably higher (Sepetdjian et al., 2010). Importantly, Wp smokers inhale substantially more smoke in a single puff, thus is exposed to more toxicants then cigarette smoking (Eissenberg and Shihadeh, 2009). Adolescent tobacco consumption is associated with cardiovascular, respiratory, immune, metabolic, hormonal, and neural diseases and morbidity (Mathers and Loncar, 2006; Mortality, 2015), and accounts for > 20% of global mortality (Renteria et al., 2016; World Health Organization, 2011). Interestingly, a wide array of brain functional and structural alterations have been reported in smokers. These alterations include apoptosis, decreased synaptic activities, gray matter volume, and densities in the cerebral cortex and hippocampus regions (Durazzo et al., 2010). Obviously, these areas are essential for BDNF production and function, and data learning and retention (Yeom et al., 2016). Few studies examined the effect of cigarette smoking on BDNF. In adults, smoking was associated with an increase (Kim et al., 2007; Jamal et al., 2015) and a decrease (Colle et al., 2016) in BDNF level, but then again normalized with smoking cessation (Bhang et al., 2010). Despite the global spread (Al-Sheyab et al., 2014; Alomari and Alsheyab, 2017) and the adverse health effects (Kadhum et al., 2015) of Wp tobacco consumption, no studies have examined the effect of Wp smoking on BDNF level. Therefore, the current study examined the relationship of Wp smoking on serum BDNF levels among adolescents. Levels of BDNF are expected to be lower in adolescent smokers versus nonsmokers, which might provide additional knowledge about the health effects of Wp smoking among adolescents.
2.2. Smoking status The validated Arabic version of the Youth Risk Behavior Survey was used to obtain self-reporting of tobacco patterns (Mzayek et al., 2012; Brener et al., 2013). Two questions were used to assess Wp smoking pattern: “Have you ever smoked a waterpipe?”, and “have you smoked waterpipe in the past 30 days?”. Adolescents were considered current Wp only smokers when selected Wp smoking, but not any other type of tobacco consumption in the past month (Mzayek et al., 2012). Students reported other types of tobacco smoking were excluded. 2.3. Blood samples Blood samples were collected from the cubital vein in plain tubes for BDNF serum level analysis. After coagulation, samples were centrifuged at 1500 xg, serum were transferred into sterile 1.5 tubes and stored at −80 °C until used. 2.4. Serum BDNF measurements ELISA method was used to determine BDNF levels in serum, using commercially available kits (Human BDNF Duoset Kit R&D system, USA), according to the manufacturer’s instructions. Absorbance was measured at 450 nm using Epoch Biotek microplate reader (BioTek, Winooski, VT, USA). All samples and standards were measured in duplicates. Samples from smoker and non-smoker students were included in ELISA plates, and possible variability between different assays was controlled using 4 samples of known BDNF concentrations (Alomari et al., 2015a; Khalil et al., 2016). 2.5. Statistical analysis All statistical analyses were conducted using SPSS software for Windows (version 22.0; Chicago, IL). Data are expressed as means ± SD, and α was preset at P < 0.05. A series of simple linear regressions were used to determine the individual relationship of smoking status (i.e. none versus Wp only smoking), gender, age, location (rural versus urban), and BMI with BDNF. Subsequently, a stepwise regression was used for the factors were significantly related to BDNF in the simple linear regression to predict the BDNF level in participating adolescents. A 2-way ANCOVA was used to examine the differences in BDNF level according to smoking status (i.e. none versus Wp only smoking) and gender, while covariating for age, location (rural versus urban), and BMI.
2. Method 2.1. Design and recruitment This study is of a descriptive, cross-sectional design, aimed to examine the relationship between Wp smoking and serum BDNF in adolescents. The current data is part of the “Irbid Tobacco Risk in Youth (Irbid-TRY)” longitudinal project (Alomari and Al-sheyab, 2017; Alomari and Al-Sheyab, 2016); aiming at identifying the health-related risks of tobacco smoking. The study used a multistage cluster sampling technique with the educational district, school, and class were the unit of cluster. A closed envelope technique was used to randomly select eight representative public high schools in North of Jordan after schools were stratified by sex (4 of each sex). Subsequently, 7th-10th grade classrooms (average classroom size is 30 students) were randomly selected within each participating school, through which healthy high school students were invited to participate. The exclusion criteria were student self-reporting of acute medical conditions of hyperglycemia, hypertension, hyperlipidemia, hypercholesterolemia, cardiac conditions, and psychiatric and stress-related mood disorders. Written informed consents as well as child assents were sought from parents and participating children, respectively. The study was approved by the Institutional Review Board of Jordan University of Science and
3. Results 3.1. Participants The participant characteristics are presented in Table 1. Blood samples and smoking status were collected from 483 adolescents, 195 of which were Wp smokers, whereas 264 were females. Data were collected from adolescents attending four rural (n = 261) and four urban (n = 222) public schools, four of which were exclusively for males and four were exclusively for females. Recruitment was from 68 classrooms, 36 of which were for females. Two male and female schools were invited from each area (i.e. rural vs. urban). The students volunteered from 7th (n = 132), 8th (n = 120), 9th (n = 136), and 10th (n = 94) grades. 15
International Journal of Developmental Neuroscience 67 (2018) 14–18
M.A. Alomari et al.
Table 1 The participant demographic (n = 483). Gender (% male) Age (yrs, mean (SD)) Weight (kg, mean (SD)) Height (cm, mean (SD)) BMI (kg/m2, mean (SD)) Underweight (%) Normal weight (%) Overweight (%) Obese (%) Grade (%) 7 8 9 10 Location (%) Rural Urban Smoking Status (%) Never smoked Waterpipe smokers
45.3 14.4 (1.1) 56.8 (13.8) 160.7 (8.9) 21.8 (4.3) 6.2 72.5 13.9 6.2 27.3 24.8 28.2 19.5 53.7 46.3 59.6 40.4
Fig. 1. Differences in Serum BDNF (μg/dL) levels among male and female waterpipe smokers versus nonsmokers, after controlling for age, location, and BMI. BDNF was measured in serum samples (Wp smokers = 195, nonsmokers = 288) *: p < 0.0001 versus nonsmokers. No (p < 0.800) interaction effect between Wp smoking and gender was found.
3.2. Relationship of waterpipe smoking with serum BDNF As in Table 2, simple linear regression analysis revealed that BDNF was related to Wp smoking (R2 = 0.056; p < 0.0001), gender (R2 = 0.128; p < 0.0001), BMI (R2 = 0.005; p < 0.04), location (urban versus rural) (R2 = 0.08; p < 0.0001), but not age (R2 = 0.001; p < 0.3). A subsequent descending (using the F-value from the previous analysis) stepwise regression that included Wp smoking, gender, BMI, and location, showed that only Wp smoking (R2 = 0.17; p < 0.0001) and gender (R2 = 0.12; p < 0.0001) were related to BDNF. After controlling for age, location, and BMI, ANCOVA analysis, shown in Fig. 1, reveals a main effect for Wp smoking (p < 0.0001) and gender (p < 0.0001) with lower BDNF in male Wp smokers. However, the analysis showed no (p < 0.800) interaction effect between Wp smoking and gender.
disease status, and socio-demographics are some of the factors that determines of BDNF production and levels (Bus et al., 2011). The lower BDNF level among the adolescents smoking Wp is quite unique yet alarming. Given the worldwide spreading of Wp smoking among adolescents (Alomari and Al-sheyab, 2017) and importance of BDNF for health (Yeom et al., 2016; Chaldakov et al., 2009; Matthews et al., 2015; Alomari and Al-Sheyab, 2016), approaches to restrain the spread of tobacco smoking, especially Wp, among adolescents are warranted. Additionally, strategies are needed to increase BDNF level among adolescent smokers. Given this popularity of Wp smoking, researchers are increasingly interested in exploring the health effects of Wp smoking (Kadhum et al., 2015). Among adults, Wp smoking is associated with altered body toxicity (Khabour et al., 2015), metabolic syndrome profile (Shafique et al., 2012), periodontal health (Bibars et al., 2015) and cognitive function (Alzoubi et al., 2015). Additionally, cardiovascular (Alomari et al., 2014; Alomari and Al-Sheyab, 2016; Alomari et al., 2015b; Blank et al., 2011), respiratory (Layoun et al., 2014), hormonal (Fawzy et al., 2011), neural (Al-Kubati et al., 2006), immune (Nabi et al., 2015), and musculoskeletal (Munshi et al., 2015) functions are affected with exposure to Wp. The current results suggest a negative impact of Wp smoking on circulatory BDNF, which might affect cognitive function in adolescents. This is consistent with studies from animal models showing that blood BDNF levels are positively correlated with brain BDNF levels (Klein et al., 2011). In addition, correlations between serum BDNF levels and affective cognitive symptoms have been reported (Teixeira et al., 2010). Moreover, studies have documented altered levels of BDNF in the blood of individuals with major neurological diseases (Teixeira et al., 2010). To the best of the author's knowledge, no studies examined the effect of tobacco consumption, Wp or otherwise, on BDNF among adolescents. Human studies have shown that maternal cigarette smoking was associated with downregulation of BDNF expression during adolescence (Toledo-Rodriguez et al., 2010). This alteration was attributed to higher rates of DNA methylation in the BDNF-6 exon (ToledoRodriguez et al., 2010) and linked to BDNF genotype (Lotfipour et al., 2009). In animals, parental (Yochum et al., 2014) and postnatal (Torres et al., 2015) exposure to tobacco have resulted in decreased BDNF mRNA and protein, which were associated with mesocorticolimbic dopamine pathway (Harrod et al., 2011) and behavioral changes. These behavioral changes include aggression (Yochum et al., 2014), drug abuse vulnerability (Lotfipour et al., 2009), hyperactivity pattern
4. Discussion The study examined the relationship of Wp smoking with serum BDNF levels. The data show that Wp smoking and gender predicted 12.4% and 17.1%, respectively, of BDNF level among adolescents. Furthermore, BDNF levels were lower among males and Wp smokers, which indicate that Wp smoking might lower circulatory BDNF. These results are unique given no previous studies examined the effect of active tobacco consumption, Wp or otherwise, on BDNF in males and females. BDNF is vital for several body systems including neural, cognitive (Yeom et al., 2016), metabolic (Chaldakov et al., 2009), musculoskeletal (Matthews et al., 2015), and cardiovascular (Alomari and AlSheyab, 2016) homeostasis. Age, alcohol consumption, exercise, Table 2 Linear regression for BDNF Predictors. Simple linear regression b2-value Waterpipe smoking −0.4 Gender 6.3 BMI −0.8 location −4.9 Age −0.26 Stepwise linear regression Waterpipe smoking −0.3 Gender 5.6
F-value
95% CI
P-value
28.7 158 4.1 91.7 1.1
−0.5/−0.23 5.3/−7.2 1.5/−0.02 −5.9/−3.9 −0.7/0.23
0.0001 0.0001 0.0400 0.0001 0.3000
49.3 68.2
−0.46/−0.21 4.3/7.0
0.0001 0.0001
16
International Journal of Developmental Neuroscience 67 (2018) 14–18
M.A. Alomari et al.
4.1. Clinical implications
(Yochum et al., 2014), and cognitive (Torres et al., 2015) among animal offspring and adolescents. The effect of smoking on BDNF levels was examined mostly in adults using cigarette as a way of tobacco consumption. Few studies found that circulatory BDNF was elevated (Jamal et al., 2015; Colle et al., 2016) in adult smokers. This elevation was dependent on years of smoking (Jamal et al., 2015) but independent of nicotine addiction, daily smoked cigarettes, BDNF genotype (Jamal et al., 2015), and depression (Colle et al., 2016). Alternatively, elevated BDNF among smokers has been attributed to nicotine dependence and was more obvious in men than women (Beuten et al., 2005). Additional explanations include increased brain BDNF expression due to nicotine administration (Czubak et al., 2009), hypoxia, (Kushwah et al., 2016), and lower alpha-2 adrenoceptors and tyrosine hydroxylase enzyme concentrations (Klimek et al., 2001), usually associated with tobacco consumption. In other studies, plasma BDNF was lower in adult smokers compared to nonsmokers (Kim et al., 2007). However, after 2 months of smoking cessation it rose but remained lower than nonsmokers (Kim et al., 2007), whereas Bhang et al., reported similar levels as none and previous smokers after 4 and 12 weeks of smoking cessation (Bhang et al., 2010). Obviously, adolescents are physiologically (i.e. size, growth, and hormones) different from adults, thus body responses to tobacco consumption. Thus, studies are needed to verify these results and speculations in adolescents. In the current study, the effect of Moassel flavor on the results was not examined. However, this can certainly be explored in future studies. The relationship of BDNF with gender is also not clear in adults and not known in adolescents. To the best of the researchers' knowledge, no studies reported gender differences in circulatory BDNF in adolescents. One study, however found that BDNF was related to physical activity in males but not females (Huang et al., 2017). In one of the earlier studies determined confounding factors for the circulatory BDNF in human, reported greater whole-blood BDNF in women (Trajkovska et al., 2007). However, BDNF was less in women (Karege et al., 2002; Elfving et al., 2012). Additionally, the relationship of BDNF level with BDNF gene (Val66Met) (Bus et al., 2012), childhood stressful incidences (van Oostrom et al., 2012), attention deficit, and hyperactivity (Li et al., 2014) was male-specific. The differences diminished when controlled for depression (Karege et al., 2002) and obesity (Lommatzsch et al., 2005). These results were further confirmed as BDNF was similar in both genders among older (Ziegenhorn et al., 2007) and younger (Lang et al., 2005) adults. It is worth to mention here that blood was collected from students in the morning. Since smoking is not allowed at schools in Jordan, it is highly unlikely that student have smoked prior to blood sampling. Although with such design, the impact of smoking prior to blood withdrawing on BDNF levels cannot be excluded, the reported effect of Wp smoking is most probably due to chronic use. More studies are required to confirm this finding though. With the current study design as well as the conflicting and scarcity of information, lower serum BDNF in the males, found herein, is difficult to explain. Additionally, in the current study, no data were collected regarding gender differences in Wp use, flavors preferences, type of Moassel (herbal versus tobacco) and topography of smoking. Therefore, we could not correlate BDNF levels in both genders with such parameters. Previous studies, however, attributed gender variations in BDNF to hormonal differences. Begliuomini et al., reported that plasma BDNF was greater in fertile than amenorrhoeic and postmenopausal women. Additionally, BDNF levels correlated positively with estradiol and progesterone and negatively with menopausal age, and restored with hormone replacement therapy during the follicular phase (Begliuomini et al., 2007). However, certainly more studies are needed to verify the current findings and to reveal explanations for the effect of gender on BDNF level.
BDNF is pivotal for cognitive function and implicated in behavioral changes including aggression, drug abuse, attention deficit, and hyperactivity. Additionally, it is involved in metabolic, musculoskeletal, and cardiovascular homeostasis. Therefore, the lowering effect of smoking Wp on BDNF, found herein, might result in numerous adverse behavioral and health effects among adolescents. Thus, approaches to restrain the spread of tobacco smoking, especially Wp, among adolescents are warranted. Additionally, strategies are needed to increase BDNF level among adolescent smokers. Evidence, demonstrating the adverse health effects of smoking Wp, are accumulating. Still, however, many believe it is a safer alternative to cigarettes, while others don’t even consider themselves smokers. These beliefs have resulted in elevated prevalence of smoking Wp among naïve/vulnerable populations, including adolescents. The current findings can further improve public awareness about adverse health effects of Wp smoking. 5. Conclusion The current study found that Wp smoking is associated with lower circulatory BDNF. These findings are unique, since no previous studies examined the effect of tobacco smoking, especially Wp on BDNF among adolescents. Given the importance of BDNF in various body systems, reduced BDNF among Wp smokers might predispose adolescents for systematic adverse health alterations. Additionally, the findings further confirm the negative health effects of tobacco consumption, particularly Wp, among adolescents. However, studies are warranted to verify these results and confirm these speculations. Fundings The current manuscript was supported by Deanship of Scientific Research at Jordan University of Science and Technology with fund no: MA/173/2017. The authors report no conflict of interests. Declarations The authors declare no conflict of interest. Acknowledgment The authors would like to thank the school students, parents, teachers, and principles for participating in the study. References Aboaziza, E., Eissenberg, T., 2015. Waterpipe tobacco smoking: what is the evidence that it supports nicotine/tobacco dependence? Tob. Control 24 (Suppl 1), i44–i53. Akl, E.A., Gunukula, S.K., Aleem, S., Obeid, R., Jaoude, P.A., Honeine, R., et al., 2011. The prevalence of waterpipe tobacco smoking among the general and specific populations: a systematic review. BMC Public Health 11, 244. Al-Kubati, M., Al-Kubati, A.S., al'Absi, M., Fiser, B., 2006. The short-term effect of waterpipe smoking on the baroreflex control of heart rate in normotensives. Auton. Neurosci. 126–127, 146–149. Al-Sheyab, N., Alomari, M.A., Shah, S., Gallagher, P., Gallagher, R., 2014. Prevalence, patterns and correlates of cigarette smoking in male adolescents in northern Jordan, and the influence of waterpipe use and asthma diagnosis: a descriptive cross-sectional study. Int. J. Environ. Res. Public Health 11, 9008–9023. Alomari, M.A., Al-Sheyab, N.A., 2016. Cigarette smoking lowers blood pressure in adolescents: the Irbid-TRY. Inhal. Toxicol. 28, 140–144. Alomari, M.A., Al-sheyab, N.A., 2017. Dual tobacco smoking is the new trend among adolescents: update from the Irbid-TRY. J. Substance Use 23 (1), 92–98. http://dx. doi.org/10.1080/14659891.2017.13485. Alomari, M.A., Khabour, O.F., Alzoubi, K.H., Shqair, D.M., Eissenberg, T., 2014. Central and peripheral cardiovascular changes immediately after waterpipe smoking. Inhal. Toxicol. 26, 579–587. Alomari, M.A., Khabour, O.F., Maikano, A., Alawneh, K., 2015a. Vascular function and brain-derived neurotrophic factor: the functional capacity factor. Vasc. Med. 20 (6), 518–526. Alomari, M.A., Khabour, O.F., Alzoubi, K.H., Shqair, D.M., Stoner, L., 2015b. Acute vascular effects of waterpipe smoking: importance of physical activity and fitness
17
International Journal of Developmental Neuroscience 67 (2018) 14–18
M.A. Alomari et al.
Psychiatry 58, 821–827. Krabbe, K.S., Mortensen, E.L., Avlund, K., Pedersen, A.N., Pedersen, B.K., Jorgensen, T., et al., 2009. Brain-derived neurotrophic factor predicts mortality risk in older women. J. Am. Geriatr. Soc. 57, 1447–1452. Kushwah, N., Jain, V., Deep, S., Prasad, D., Singh, S.B., Khan, N., 2016. Neuroprotective role of intermittent hypobaric hypoxia in unpredictable chronic mild stress induced depression in rats. PLoS One 11, e0149309. Lang, U.E., Hellweg, R., Gallinat, J., 2005. Association of BDNF serum concentrations with central serotonergic activity: evidence from auditory signal processing. Neuropsychopharmacology 30, 1148–1153. Layoun, N., Saleh, N., Barbour, B., Awada, S., Rachidi, S., Al-Hajje, A., et al., 2014. Waterpipe effects on pulmonary function and cardiovascular indices: a comparison to cigarette smoking in real life situation. Inhal. Toxicol. 26, 620–627. Li, H., Liu, L., Tang, Y., Ji, N., Yang, L., Qian, Q., et al., 2014. Sex-specific association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and plasma BDNF with attention-deficit/hyperactivity disorder in a drug-naive Han Chinese sample. Psychiatry Res. 217, 191–197. Lommatzsch, M., Zingler, D., Schuhbaeck, K., Schloetcke, K., Zingler, C., Schuff-Werner, P., et al., 2005. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol. Aging 26, 115–123. Lotfipour, S., Ferguson, E., Leonard, G., Perron, M., Pike, B., Richer, L., et al., 2009. Orbitofrontal cortex and drug use during adolescence: role of prenatal exposure to maternal smoking and BDNF genotype. Arch. Gen. Psychiatry 66, 1244–1252. Mathers, C.D., Loncar, D., 2006. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 3, e442. Matthews, V.B., Astrom, M.B., Chan, M.H., Bruce, C.R., Krabbe, K.S., Prelovsek, O., et al., 2015. Erratum to: brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMPactivated protein kinase. Diabetologia 58, 854–855. Mortality, G.B.D., 2015. Causes of Death C. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385, 117–171. Munshi, T., Heckman, C.J., Darlow, S., 2015. Association between tobacco waterpipe smoking and head and neck conditions: a systematic review. J. Am. Dent. Assoc. 146, 760–766. Mzayek, F., Khader, Y., Eissenberg, T., Al Ali, R., Ward, K.D., Maziak, W., 2012. Patterns of water-pipe and cigarette smoking initiation in schoolchildren: Irbid longitudinal smoking study. Nicotine Tob. Res. 14, 448–454. Nabi, G., Aziz, T., Ullah, W., Saleem, K., Ullah, S., 2015. A mini-review on Sheesha smoking: a potent cancer inducer. Am. Eur. J. Toxicol. Sci. 7, 63–67. Primack, B.A., Carroll, M.V., Weiss, P.M., Shihadeh, A.L., Shensa, A., Farley, S.T., et al., 2016. Systematic review and meta-analysis of inhaled toxicants from waterpipe and cigarette smoking. Public Health Rep. 131, 76–85. Renteria, E., Jha, P., Forman, D., Soerjomataram, I., 2016. The impact of cigarette smoking on life expectancy between 1980 and 2010: a global perspective. Tob. Control 25 (5 (Sep.)), 551–557. Sepetdjian, E., Saliba, N., Shihadeh, A., 2010. Carcinogenic PAH in waterpipe charcoal products. Food Chem. Toxicol. 48, 3242–3245. Shafique, K., Mirza, S.S., Mughal, M.K., Arain, Z.I., Khan, N.A., Tareen, M.F., et al., 2012. Water-pipe smoking and metabolic syndrome: a population-based study. PLoS One 7, e39734. Shihadeh, A., Saleh, R., 2005. Polycyclic aromatic hydrocarbons, carbon monoxide, tar, and nicotine in the mainstream smoke aerosol of the narghile water pipe. Food Chem. Toxicol. 43, 655–661. Shihadeh, A., Salman, R., Jaroudi, E., Saliba, N., Sepetdjian, E., Blank, M.D., et al., 2012. Does switching to a tobacco-free waterpipe product reduce toxicant intake? A crossover study comparing CO, NO, PAH, volatile aldehydes, tar and nicotine yields. Food Chem. Toxicol. 50, 1494–1498. Teixeira, A.L., Barbosa, I.G., Diniz, B.S., Kummer, A., 2010. Circulating levels of brainderived neurotrophic factor: correlation with mood, cognition and motor function. Biomark. Med. 4, 871–887. Toledo-Rodriguez, M., Lotfipour, S., Leonard, G., Perron, M., Richer, L., Veillette, S., et al., 2010. Maternal smoking during pregnancy is associated with epigenetic modifications of the brain-derived neurotrophic factor-6 exon in adolescent offspring. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B, 1350–1354. Torres, L.H., Garcia, R.C., Blois, A.M., Dati, L.M., Durao, A.C., Alves, A.S., et al., 2015. Exposure of neonatal mice to tobacco smoke disturbs synaptic proteins and spatial learning and memory from late infancy to early adulthood. PLoS One 10, e0136399. Trajkovska, V., Marcussen, A.B., Vinberg, M., Hartvig, P., Aznar, S., Knudsen, G.M., 2007. Measurements of brain-derived neurotrophic factor: methodological aspects and demographical data. Brain Res. Bull. 73, 143–149. van Oostrom, I., Franke, B., Rijpkema, M., Gerritsen, L., Arias-Vasquez, A., Fernandez, G., et al., 2012. Interaction between BDNF Val66Met and childhood stressful life events is associated to affective memory bias in men but not women. Biol. Psychol. 89, 214–219. World Health Organization, 2011. WHO urges more countries to require large, graphic health warnings on tobacco packaging: the WHO report on the global tobacco epidemic, 2011 examines anti-tobacco mass-media campaigns. Cent. Eur. J. Public Health 19 (133), 151. Yeom, C.W., Park, Y.J., Choi, S.W., Bhang, S.Y., 2016. Association of peripheral BDNF level with cognition, attention and behavior in preschool children. Child Adolesc. Psychiatry Ment. Health 10, 10. Yochum, C., Doherty-Lyon, S., Hoffman, C., Hossain, M.M., Zelikoff, J.T., Richardson, J.R., 2014. Prenatal cigarette smoke exposure causes hyperactivity and aggressive behavior: role of altered catecholamines and BDNF. Exp. Neurol. 254, 145–152. Ziegenhorn, A.A., Schulte-Herbruggen, O., Danker-Hopfe, H., Malbranc, M., Hartung, H.D., Anders, D., et al., 2007. Serum neurotrophins–a study on the time course and influencing factors in a large old age sample. Neurobiol. Aging 28, 1436–1445.
status. Atherosclerosis 240, 472–476. Alzoubi, K.H., Khabour, O.F., Alharahshah, E.A., Alhashimi, F.H., Shihadeh, A., Eissenberg, T., 2015. The effect of waterpipe tobacco smoke exposure on learning and memory functions in the rat model. J. Mol. Neurosci. 57, 249–256. Begliuomini, S., Casarosa, E., Pluchino, N., Lenzi, E., Centofanti, M., Freschi, L., et al., 2007. Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor. Hum. Reprod. 22, 995–1002. Beuten, J., Ma, J.Z., Payne, T.J., Dupont, R.T., Quezada, P., Huang, W., et al., 2005. Significant association of BDNF haplotypes in European-American male smokers but not in European-American female or African-American smokers. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 139B, 73–80. Bhang, S.Y., Choi, S.W., Ahn, J.H., 2010. Changes in plasma brain-derived neurotrophic factor levels in smokers after smoking cessation. Neurosci. Lett. 468, 7–11. Bibars, A.R., Obeidat, S.R., Khader, Y., Mahasneh, A.M., Khabour, O.F., 2015. The effect of waterpipe smoking on periodontal health. Oral Health Prev. Dent. 13, 253–259. Blank, M.D., Cobb, C.O., Kilgalen, B., Austin, J., Weaver, M.F., Shihadeh, A., et al., 2011. Acute effects of waterpipe tobacco smoking: a double-blind, placebo-control study. Drug Alcohol Depend. 116, 102–109. Brener, N.D., Eaton, D.K., Flint, K.H., Hawkins, J., Kann, L., Kinchen, S., et al., 2013. Methodology of the Youth Risk Behavior Surveillance System-2013. US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA, USA (30341). Bus, B.A., Molendijk, M.L., Penninx, B.J., Buitelaar, J.K., Kenis, G., Prickaerts, J., et al., 2011. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology 36, 228–239. Bus, B.A., Arias-Vasquez, A., Franke, B., Prickaerts, J., de Graaf, J., Voshaar, R.C., 2012. Increase in serum brain-derived neurotrophic factor in met allele carriers of the BDNF Val66Met polymorphism is specific to males. Neuropsychobiology 65, 183–187. Chaldakov, G.N., Tonchev, A.B., Aloe, L., 2009. NGF and BDNF: from nerves to adipose tissue, from neurokines to metabokines. Riv. Psichiatr. 44, 79–87. Cobb, C.O., Blank, M.D., Morlett, A., Shihadeh, A., Jaroudi, E., Karaoghlanian, N., et al., 2015. Comparison of puff topography, toxicant exposure, and subjective effects in low- and high-frequency waterpipe users: a double-blind, placebo-control study. Nicotine Tob. Res. 17, 667–674. Colle, R., Trabado, S., Rotenberg, S., Brailly-Tabard, S., Benyamina, A., Aubin, H.J., et al., 2016. Tobacco use is associated with increased plasma BDNF levels in depressed patients. Psychiatry Res. 246, 370–372. Czubak, A., Nowakowska, E., Kus, K., Burda, K., Metelska, J., Baer-Dubowska, W., et al., 2009. Influences of chronic venlafaxine, olanzapine and nicotine on the hippocampal and cortical concentrations of brain-derived neurotrophic factor (BDNF). Pharmacol. Rep. 61, 1017–1023. Durazzo, T.C., Meyerhoff, D.J., Nixon, S.J., 2010. Chronic cigarette smoking: implications for neurocognition and brain neurobiology. Int. J. Environ. Res. Public Health 7, 3760–3791. Eissenberg, T., Shihadeh, A., 2009. Waterpipe tobacco and cigarette smoking: direct comparison of toxicant exposure. Am. J. Prev. Med. 37, 518–523. Elfving, B., Buttenschon, H.N., Foldager, L., Poulsen, P.H., Andersen, J.H., Grynderup, M.B., et al., 2012. Depression, the Val66Met polymorphism, age, and gender influence the serum BDNF level. J. Psychiatr. Res. 46, 1118–1125. Fawzy, I.A., Kamal, N.N., Abdulla, A.M., 2011. Reproductive toxicity of tobacco shisha smoking on semen parameters and hormones levels among adult Egyptian men. Res. J. Environ. Toxicol. 5, 282. Harrod, S.B., Lacy, R.T., Zhu, J., Hughes, B.A., Perna, M.K., Brown, R.W., 2011. Gestational IV nicotine produces elevated brain-derived neurotrophic factor in the mesocorticolimbic dopamine system of adolescent rat offspring. Synapse 65, 1382–1392. Huang, T., Gejl, A.K., Tarp, J., Andersen, L.B., Peijs, L., Bugge, A., 2017. Cross-sectional associations of objectively measured physical activity with brain-derived neurotrophic factor in adolescents. Physiol. Behav. 171, 87–91. Jamal, M., Van der Does, W., Elzinga, B.M., Molendijk, M.L., Penninx, B.W., 2015. Association between smoking, nicotine dependence, and BDNF Val66Met polymorphism with BDNF concentrations in serum. Nicotine Tob. Res. 17, 323–329. Jawad, M., McEwen, A., McNeill, A., Shahab, L., 2013. To what extent should waterpipe tobacco smoking become a public health priority. Addiction 108, 1873–1884. Jawad, M., Jawad, S., Waziry, R.K., Ballout, R.A., Akl, E.A., 2016. Interventions for waterpipe tobacco smoking prevention and cessation: a systematic review. Sci. Rep. 6, 25872. Kadhum, M., Sweidan, A., Jaffery, A.E., Al-Saadi, A., Madden, B., 2015. A review of the health effects of smoking shisha. Clin. Med. (Lond.) 15, 263–266. Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G., Aubry, J.M., 2002. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 109, 143–148. Khabour, O.F., Alzoubi, K.H., Abu Thiab, T.M., Al-Husein, B.A., Eissenberg, T., Shihadeh, A.L., 2015. Changes in the expression and protein level of matrix metalloproteinases after exposure to waterpipe tobacco smoke. Inhal. Toxicol. 27, 689–693. Khalil, H., Alomari, M.A., Khabour, O.F., Al-Hieshan, A., Bajwa, J.A., 2016. Relationship of circulatory BDNF with cognitive deficits in people with Parkinson's disease. J. Neurol. Sci. 362, 217–220. Kim, T.S., Kim, D.J., Lee, H., Kim, Y.K., 2007. Increased plasma brain-derived neurotrophic factor levels in chronic smokers following unaided smoking cessation. Neurosci. Lett. 423, 53–57. Kim, K.H., Kabir, E., Jahan, S.A., 2016. Waterpipe tobacco smoking and its human health impacts. J. Hazard. Mater. 317, 229–236. Klein, A.B., Williamson, R., Santini, M.A., Clemmensen, C., Ettrup, A., Rios, M., et al., 2011. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int. J. Neuropsychopharmacol. 14, 347–353. Klimek, V., Zhu, M.Y., Dilley, G., Konick, L., Overholser, J.C., Meltzer, H.Y., et al., 2001. Effects of long-term cigarette smoking on the human locus coeruleus. Arch. Gen.
18
Contents lists available at ScienceDirect
International Journal of Developmental Neuroscience journal homepage: www.elsevier.com/locate/ijdevneu
Brain-derived neutrophic factor in adolescents smoking waterpipe: The Irbid TRY
T
⁎
Mahmoud A. Alomaria, , Nihaya A. Al-sheyabb, Omar F. Khabourc, Karem H. Alzoubid a
Division of Physical Therapy, Department of Rehabilitation Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan b Faculty of Nursing, Maternal and Child Health Department, Jordan University of Science and Technology, Irbid, Jordan c Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Jordan d Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
A R T I C LE I N FO
A B S T R A C T
Keywords: Waterpipe smoking BDNF Youth risk behavior survey Students Tobacco Jordan
Background: Brain-derived neutrophic factor (BDNF) and tobacco consumption can affect many body functions and health. However, the relationship of BDNF with waterpipe (Wp) smoking is unknown. Therefore, the current study examined the relationship between Wp smoking and BDNF in adolescents. Methods: Self-reported tobacco consumption and serum BDNF were determined in 195 waterpipe and 288 nonsmokers in 7th–10th grade students. Results: Stepwise regression that included Wp smoking, gender, BMI, and location, showed that only Wp smoking (p < 0.0001) and gender (p < 0.0001) were related to serum BDNF. In addition, the ANCOVA found a main effect for Wp smoking (p < 0.0001) and gender (p < 0.0001) with lower BDNF in males smoking waterpipe. Discussion: BDNF was diminished in adolescent Wp smokers, which might predispose adolescents for systematic adverse health and behavioral alterations. These results extend the negative health risks associated with cigarette smoking to that of water-pipe tobacco smoking.
1. Introduction Brain-derived neutrophic factor (BDNF) is most abundant and functions in the hippocampus and hypothalamus. It is pivotal for neuronal survival, migration, synaptogenesis, differentiation, and dendritic arborization (Yeom et al., 2016). It contributes immensely to data learning, retention, and processing, intelligence, and attention throughout the lifespan, including schoolchildren (Yeom et al., 2016). Additionally, BDNF appears to be involved in energy (Chaldakov et al., 2009), cardiovascular (Alomari et al., 2014; Alomari et al., 2015a), and musculoskeletal (Matthews et al., 2015) homeostasis. In fact, a study showed that women with higher plasma BDNF were at less risk of allcause mortality than women with lower plasma BDNF (Krabbe et al., 2009). Tobacco consumption is a serious public health concern. Waterpipe (Wp) smoking is a tobacco consumption style, during which smoke from burned “Moassel” tobacco on a charcoal, passes through a bowl of water into a hose then inhaled into the smoker's mouth. Contrary to developed countries, adolescent tobacco consumption in developing countries is on a steady rise (Mzayek et al., 2012; Al-Sheyab et al.,
⁎
2014). Similarly, Wp smoking among adolescents, in particular, has recently gained popularity. In fact, the prevalence of adolescent Wp smoking in many countries is greater than that in adults (Akl et al., 2011) and has surpassed cigarette smoking (Al-Sheyab et al., 2014; Alomari and Al-sheyab, 2017), reaching > 50% in some countries (AlSheyab et al., 2014; Alomari and Al-sheyab, 2017). Aroma, flavor, atmosphere, social acceptance, curiosity, novelty, accessibility, affordability, and alular, among other factors, have been implicated in the accelerated increase in Wp consumption (Jawad et al., 2013). However, health misconceptions have been pivotal in driving the worldwide spread of Wp, especially among adolescents (Jawad et al., 2013). Every so often, Wp has been promoted as a “less harmful” alternative to cigarettes. It is thought the passing of smoke through the water can “cleanse” the smoke from toxicant, thus minimize the adverse health effects of smoking (Shihadeh et al., 2012). Additionally, more than often, the fruit flavoring of Wp tobacco makes smokers believe that Wp smoking is healthier than cigarettes (Jawad et al., 2013). In fact, it is the harms from cigarettes combined with flavoring agents and the paraphernalia used in the Wp process (Kadhum et al., 2015). Smoking Wp presents a greater level of the same types of toxicants of cigarettes
Corresponding author. E-mail addresses: [email protected] (M.A. Alomari), [email protected] (N.A. Al-sheyab), [email protected] (O.F. Khabour), [email protected] (K.H. Alzoubi).
https://doi.org/10.1016/j.ijdevneu.2018.03.007 Received 4 January 2018; Received in revised form 9 March 2018; Accepted 11 March 2018 Available online 16 March 2018 0736-5748/ © 2018 Published by Elsevier Ltd on behalf of ISDN.
International Journal of Developmental Neuroscience 67 (2018) 14–18
M.A. Alomari et al.
Technology, the Jordanian Ministry of Education, and the relevant educational districts in North of Jordan. Socio-demographic characteristics, tobacco smoking patterns, and blood samples were taken from all participating adolescents, as described below.
including a surge of nicotine, metallic elements, particulate substances, and countless carcinogens (Kadhum et al., 2015). However, toxicants derived from charcoal combustion and, flavored smoking mixture with the infection risk due to sharing Wp gear (i.e. mouthpieces), certainly surpass the harms of cigarettes (Kadhum et al., 2015). Additionally, many Wp smokers don’t consider themselves smokers and can quit smoking any time (Jawad et al., 2016). Unfortunately, studies have shown that dependency is high (Aboaziza and Eissenberg, 2015) while quitting rate is low (Jawad et al., 2016) among Wp smokers. Previous studies have shown that Wp smoke contains substantial concentrations of toxic compounds compared to cigarette smoke (Shihadeh and Saleh, 2005; Kim et al., 2016). For example, the magnitude of “tar” from a single Wp session is typically several folds higher than that produced from a single cigarette (Primack et al., 2016). Similarly, the amount of CO exposure is estimated to be ∼3 folds higher during Wp versus cigarette smoking (Cobb et al., 2015) while polycyclic aromatic hydrocarbons are considerably higher (Sepetdjian et al., 2010). Importantly, Wp smokers inhale substantially more smoke in a single puff, thus is exposed to more toxicants then cigarette smoking (Eissenberg and Shihadeh, 2009). Adolescent tobacco consumption is associated with cardiovascular, respiratory, immune, metabolic, hormonal, and neural diseases and morbidity (Mathers and Loncar, 2006; Mortality, 2015), and accounts for > 20% of global mortality (Renteria et al., 2016; World Health Organization, 2011). Interestingly, a wide array of brain functional and structural alterations have been reported in smokers. These alterations include apoptosis, decreased synaptic activities, gray matter volume, and densities in the cerebral cortex and hippocampus regions (Durazzo et al., 2010). Obviously, these areas are essential for BDNF production and function, and data learning and retention (Yeom et al., 2016). Few studies examined the effect of cigarette smoking on BDNF. In adults, smoking was associated with an increase (Kim et al., 2007; Jamal et al., 2015) and a decrease (Colle et al., 2016) in BDNF level, but then again normalized with smoking cessation (Bhang et al., 2010). Despite the global spread (Al-Sheyab et al., 2014; Alomari and Alsheyab, 2017) and the adverse health effects (Kadhum et al., 2015) of Wp tobacco consumption, no studies have examined the effect of Wp smoking on BDNF level. Therefore, the current study examined the relationship of Wp smoking on serum BDNF levels among adolescents. Levels of BDNF are expected to be lower in adolescent smokers versus nonsmokers, which might provide additional knowledge about the health effects of Wp smoking among adolescents.
2.2. Smoking status The validated Arabic version of the Youth Risk Behavior Survey was used to obtain self-reporting of tobacco patterns (Mzayek et al., 2012; Brener et al., 2013). Two questions were used to assess Wp smoking pattern: “Have you ever smoked a waterpipe?”, and “have you smoked waterpipe in the past 30 days?”. Adolescents were considered current Wp only smokers when selected Wp smoking, but not any other type of tobacco consumption in the past month (Mzayek et al., 2012). Students reported other types of tobacco smoking were excluded. 2.3. Blood samples Blood samples were collected from the cubital vein in plain tubes for BDNF serum level analysis. After coagulation, samples were centrifuged at 1500 xg, serum were transferred into sterile 1.5 tubes and stored at −80 °C until used. 2.4. Serum BDNF measurements ELISA method was used to determine BDNF levels in serum, using commercially available kits (Human BDNF Duoset Kit R&D system, USA), according to the manufacturer’s instructions. Absorbance was measured at 450 nm using Epoch Biotek microplate reader (BioTek, Winooski, VT, USA). All samples and standards were measured in duplicates. Samples from smoker and non-smoker students were included in ELISA plates, and possible variability between different assays was controlled using 4 samples of known BDNF concentrations (Alomari et al., 2015a; Khalil et al., 2016). 2.5. Statistical analysis All statistical analyses were conducted using SPSS software for Windows (version 22.0; Chicago, IL). Data are expressed as means ± SD, and α was preset at P < 0.05. A series of simple linear regressions were used to determine the individual relationship of smoking status (i.e. none versus Wp only smoking), gender, age, location (rural versus urban), and BMI with BDNF. Subsequently, a stepwise regression was used for the factors were significantly related to BDNF in the simple linear regression to predict the BDNF level in participating adolescents. A 2-way ANCOVA was used to examine the differences in BDNF level according to smoking status (i.e. none versus Wp only smoking) and gender, while covariating for age, location (rural versus urban), and BMI.
2. Method 2.1. Design and recruitment This study is of a descriptive, cross-sectional design, aimed to examine the relationship between Wp smoking and serum BDNF in adolescents. The current data is part of the “Irbid Tobacco Risk in Youth (Irbid-TRY)” longitudinal project (Alomari and Al-sheyab, 2017; Alomari and Al-Sheyab, 2016); aiming at identifying the health-related risks of tobacco smoking. The study used a multistage cluster sampling technique with the educational district, school, and class were the unit of cluster. A closed envelope technique was used to randomly select eight representative public high schools in North of Jordan after schools were stratified by sex (4 of each sex). Subsequently, 7th-10th grade classrooms (average classroom size is 30 students) were randomly selected within each participating school, through which healthy high school students were invited to participate. The exclusion criteria were student self-reporting of acute medical conditions of hyperglycemia, hypertension, hyperlipidemia, hypercholesterolemia, cardiac conditions, and psychiatric and stress-related mood disorders. Written informed consents as well as child assents were sought from parents and participating children, respectively. The study was approved by the Institutional Review Board of Jordan University of Science and
3. Results 3.1. Participants The participant characteristics are presented in Table 1. Blood samples and smoking status were collected from 483 adolescents, 195 of which were Wp smokers, whereas 264 were females. Data were collected from adolescents attending four rural (n = 261) and four urban (n = 222) public schools, four of which were exclusively for males and four were exclusively for females. Recruitment was from 68 classrooms, 36 of which were for females. Two male and female schools were invited from each area (i.e. rural vs. urban). The students volunteered from 7th (n = 132), 8th (n = 120), 9th (n = 136), and 10th (n = 94) grades. 15
International Journal of Developmental Neuroscience 67 (2018) 14–18
M.A. Alomari et al.
Table 1 The participant demographic (n = 483). Gender (% male) Age (yrs, mean (SD)) Weight (kg, mean (SD)) Height (cm, mean (SD)) BMI (kg/m2, mean (SD)) Underweight (%) Normal weight (%) Overweight (%) Obese (%) Grade (%) 7 8 9 10 Location (%) Rural Urban Smoking Status (%) Never smoked Waterpipe smokers
45.3 14.4 (1.1) 56.8 (13.8) 160.7 (8.9) 21.8 (4.3) 6.2 72.5 13.9 6.2 27.3 24.8 28.2 19.5 53.7 46.3 59.6 40.4
Fig. 1. Differences in Serum BDNF (μg/dL) levels among male and female waterpipe smokers versus nonsmokers, after controlling for age, location, and BMI. BDNF was measured in serum samples (Wp smokers = 195, nonsmokers = 288) *: p < 0.0001 versus nonsmokers. No (p < 0.800) interaction effect between Wp smoking and gender was found.
3.2. Relationship of waterpipe smoking with serum BDNF As in Table 2, simple linear regression analysis revealed that BDNF was related to Wp smoking (R2 = 0.056; p < 0.0001), gender (R2 = 0.128; p < 0.0001), BMI (R2 = 0.005; p < 0.04), location (urban versus rural) (R2 = 0.08; p < 0.0001), but not age (R2 = 0.001; p < 0.3). A subsequent descending (using the F-value from the previous analysis) stepwise regression that included Wp smoking, gender, BMI, and location, showed that only Wp smoking (R2 = 0.17; p < 0.0001) and gender (R2 = 0.12; p < 0.0001) were related to BDNF. After controlling for age, location, and BMI, ANCOVA analysis, shown in Fig. 1, reveals a main effect for Wp smoking (p < 0.0001) and gender (p < 0.0001) with lower BDNF in male Wp smokers. However, the analysis showed no (p < 0.800) interaction effect between Wp smoking and gender.
disease status, and socio-demographics are some of the factors that determines of BDNF production and levels (Bus et al., 2011). The lower BDNF level among the adolescents smoking Wp is quite unique yet alarming. Given the worldwide spreading of Wp smoking among adolescents (Alomari and Al-sheyab, 2017) and importance of BDNF for health (Yeom et al., 2016; Chaldakov et al., 2009; Matthews et al., 2015; Alomari and Al-Sheyab, 2016), approaches to restrain the spread of tobacco smoking, especially Wp, among adolescents are warranted. Additionally, strategies are needed to increase BDNF level among adolescent smokers. Given this popularity of Wp smoking, researchers are increasingly interested in exploring the health effects of Wp smoking (Kadhum et al., 2015). Among adults, Wp smoking is associated with altered body toxicity (Khabour et al., 2015), metabolic syndrome profile (Shafique et al., 2012), periodontal health (Bibars et al., 2015) and cognitive function (Alzoubi et al., 2015). Additionally, cardiovascular (Alomari et al., 2014; Alomari and Al-Sheyab, 2016; Alomari et al., 2015b; Blank et al., 2011), respiratory (Layoun et al., 2014), hormonal (Fawzy et al., 2011), neural (Al-Kubati et al., 2006), immune (Nabi et al., 2015), and musculoskeletal (Munshi et al., 2015) functions are affected with exposure to Wp. The current results suggest a negative impact of Wp smoking on circulatory BDNF, which might affect cognitive function in adolescents. This is consistent with studies from animal models showing that blood BDNF levels are positively correlated with brain BDNF levels (Klein et al., 2011). In addition, correlations between serum BDNF levels and affective cognitive symptoms have been reported (Teixeira et al., 2010). Moreover, studies have documented altered levels of BDNF in the blood of individuals with major neurological diseases (Teixeira et al., 2010). To the best of the author's knowledge, no studies examined the effect of tobacco consumption, Wp or otherwise, on BDNF among adolescents. Human studies have shown that maternal cigarette smoking was associated with downregulation of BDNF expression during adolescence (Toledo-Rodriguez et al., 2010). This alteration was attributed to higher rates of DNA methylation in the BDNF-6 exon (ToledoRodriguez et al., 2010) and linked to BDNF genotype (Lotfipour et al., 2009). In animals, parental (Yochum et al., 2014) and postnatal (Torres et al., 2015) exposure to tobacco have resulted in decreased BDNF mRNA and protein, which were associated with mesocorticolimbic dopamine pathway (Harrod et al., 2011) and behavioral changes. These behavioral changes include aggression (Yochum et al., 2014), drug abuse vulnerability (Lotfipour et al., 2009), hyperactivity pattern
4. Discussion The study examined the relationship of Wp smoking with serum BDNF levels. The data show that Wp smoking and gender predicted 12.4% and 17.1%, respectively, of BDNF level among adolescents. Furthermore, BDNF levels were lower among males and Wp smokers, which indicate that Wp smoking might lower circulatory BDNF. These results are unique given no previous studies examined the effect of active tobacco consumption, Wp or otherwise, on BDNF in males and females. BDNF is vital for several body systems including neural, cognitive (Yeom et al., 2016), metabolic (Chaldakov et al., 2009), musculoskeletal (Matthews et al., 2015), and cardiovascular (Alomari and AlSheyab, 2016) homeostasis. Age, alcohol consumption, exercise, Table 2 Linear regression for BDNF Predictors. Simple linear regression b2-value Waterpipe smoking −0.4 Gender 6.3 BMI −0.8 location −4.9 Age −0.26 Stepwise linear regression Waterpipe smoking −0.3 Gender 5.6
F-value
95% CI
P-value
28.7 158 4.1 91.7 1.1
−0.5/−0.23 5.3/−7.2 1.5/−0.02 −5.9/−3.9 −0.7/0.23
0.0001 0.0001 0.0400 0.0001 0.3000
49.3 68.2
−0.46/−0.21 4.3/7.0
0.0001 0.0001
16
International Journal of Developmental Neuroscience 67 (2018) 14–18
M.A. Alomari et al.
4.1. Clinical implications
(Yochum et al., 2014), and cognitive (Torres et al., 2015) among animal offspring and adolescents. The effect of smoking on BDNF levels was examined mostly in adults using cigarette as a way of tobacco consumption. Few studies found that circulatory BDNF was elevated (Jamal et al., 2015; Colle et al., 2016) in adult smokers. This elevation was dependent on years of smoking (Jamal et al., 2015) but independent of nicotine addiction, daily smoked cigarettes, BDNF genotype (Jamal et al., 2015), and depression (Colle et al., 2016). Alternatively, elevated BDNF among smokers has been attributed to nicotine dependence and was more obvious in men than women (Beuten et al., 2005). Additional explanations include increased brain BDNF expression due to nicotine administration (Czubak et al., 2009), hypoxia, (Kushwah et al., 2016), and lower alpha-2 adrenoceptors and tyrosine hydroxylase enzyme concentrations (Klimek et al., 2001), usually associated with tobacco consumption. In other studies, plasma BDNF was lower in adult smokers compared to nonsmokers (Kim et al., 2007). However, after 2 months of smoking cessation it rose but remained lower than nonsmokers (Kim et al., 2007), whereas Bhang et al., reported similar levels as none and previous smokers after 4 and 12 weeks of smoking cessation (Bhang et al., 2010). Obviously, adolescents are physiologically (i.e. size, growth, and hormones) different from adults, thus body responses to tobacco consumption. Thus, studies are needed to verify these results and speculations in adolescents. In the current study, the effect of Moassel flavor on the results was not examined. However, this can certainly be explored in future studies. The relationship of BDNF with gender is also not clear in adults and not known in adolescents. To the best of the researchers' knowledge, no studies reported gender differences in circulatory BDNF in adolescents. One study, however found that BDNF was related to physical activity in males but not females (Huang et al., 2017). In one of the earlier studies determined confounding factors for the circulatory BDNF in human, reported greater whole-blood BDNF in women (Trajkovska et al., 2007). However, BDNF was less in women (Karege et al., 2002; Elfving et al., 2012). Additionally, the relationship of BDNF level with BDNF gene (Val66Met) (Bus et al., 2012), childhood stressful incidences (van Oostrom et al., 2012), attention deficit, and hyperactivity (Li et al., 2014) was male-specific. The differences diminished when controlled for depression (Karege et al., 2002) and obesity (Lommatzsch et al., 2005). These results were further confirmed as BDNF was similar in both genders among older (Ziegenhorn et al., 2007) and younger (Lang et al., 2005) adults. It is worth to mention here that blood was collected from students in the morning. Since smoking is not allowed at schools in Jordan, it is highly unlikely that student have smoked prior to blood sampling. Although with such design, the impact of smoking prior to blood withdrawing on BDNF levels cannot be excluded, the reported effect of Wp smoking is most probably due to chronic use. More studies are required to confirm this finding though. With the current study design as well as the conflicting and scarcity of information, lower serum BDNF in the males, found herein, is difficult to explain. Additionally, in the current study, no data were collected regarding gender differences in Wp use, flavors preferences, type of Moassel (herbal versus tobacco) and topography of smoking. Therefore, we could not correlate BDNF levels in both genders with such parameters. Previous studies, however, attributed gender variations in BDNF to hormonal differences. Begliuomini et al., reported that plasma BDNF was greater in fertile than amenorrhoeic and postmenopausal women. Additionally, BDNF levels correlated positively with estradiol and progesterone and negatively with menopausal age, and restored with hormone replacement therapy during the follicular phase (Begliuomini et al., 2007). However, certainly more studies are needed to verify the current findings and to reveal explanations for the effect of gender on BDNF level.
BDNF is pivotal for cognitive function and implicated in behavioral changes including aggression, drug abuse, attention deficit, and hyperactivity. Additionally, it is involved in metabolic, musculoskeletal, and cardiovascular homeostasis. Therefore, the lowering effect of smoking Wp on BDNF, found herein, might result in numerous adverse behavioral and health effects among adolescents. Thus, approaches to restrain the spread of tobacco smoking, especially Wp, among adolescents are warranted. Additionally, strategies are needed to increase BDNF level among adolescent smokers. Evidence, demonstrating the adverse health effects of smoking Wp, are accumulating. Still, however, many believe it is a safer alternative to cigarettes, while others don’t even consider themselves smokers. These beliefs have resulted in elevated prevalence of smoking Wp among naïve/vulnerable populations, including adolescents. The current findings can further improve public awareness about adverse health effects of Wp smoking. 5. Conclusion The current study found that Wp smoking is associated with lower circulatory BDNF. These findings are unique, since no previous studies examined the effect of tobacco smoking, especially Wp on BDNF among adolescents. Given the importance of BDNF in various body systems, reduced BDNF among Wp smokers might predispose adolescents for systematic adverse health alterations. Additionally, the findings further confirm the negative health effects of tobacco consumption, particularly Wp, among adolescents. However, studies are warranted to verify these results and confirm these speculations. Fundings The current manuscript was supported by Deanship of Scientific Research at Jordan University of Science and Technology with fund no: MA/173/2017. The authors report no conflict of interests. Declarations The authors declare no conflict of interest. Acknowledgment The authors would like to thank the school students, parents, teachers, and principles for participating in the study. References Aboaziza, E., Eissenberg, T., 2015. Waterpipe tobacco smoking: what is the evidence that it supports nicotine/tobacco dependence? Tob. Control 24 (Suppl 1), i44–i53. Akl, E.A., Gunukula, S.K., Aleem, S., Obeid, R., Jaoude, P.A., Honeine, R., et al., 2011. The prevalence of waterpipe tobacco smoking among the general and specific populations: a systematic review. BMC Public Health 11, 244. Al-Kubati, M., Al-Kubati, A.S., al'Absi, M., Fiser, B., 2006. The short-term effect of waterpipe smoking on the baroreflex control of heart rate in normotensives. Auton. Neurosci. 126–127, 146–149. Al-Sheyab, N., Alomari, M.A., Shah, S., Gallagher, P., Gallagher, R., 2014. Prevalence, patterns and correlates of cigarette smoking in male adolescents in northern Jordan, and the influence of waterpipe use and asthma diagnosis: a descriptive cross-sectional study. Int. J. Environ. Res. Public Health 11, 9008–9023. Alomari, M.A., Al-Sheyab, N.A., 2016. Cigarette smoking lowers blood pressure in adolescents: the Irbid-TRY. Inhal. Toxicol. 28, 140–144. Alomari, M.A., Al-sheyab, N.A., 2017. Dual tobacco smoking is the new trend among adolescents: update from the Irbid-TRY. J. Substance Use 23 (1), 92–98. http://dx. doi.org/10.1080/14659891.2017.13485. Alomari, M.A., Khabour, O.F., Alzoubi, K.H., Shqair, D.M., Eissenberg, T., 2014. Central and peripheral cardiovascular changes immediately after waterpipe smoking. Inhal. Toxicol. 26, 579–587. Alomari, M.A., Khabour, O.F., Maikano, A., Alawneh, K., 2015a. Vascular function and brain-derived neurotrophic factor: the functional capacity factor. Vasc. Med. 20 (6), 518–526. Alomari, M.A., Khabour, O.F., Alzoubi, K.H., Shqair, D.M., Stoner, L., 2015b. Acute vascular effects of waterpipe smoking: importance of physical activity and fitness
17
International Journal of Developmental Neuroscience 67 (2018) 14–18
M.A. Alomari et al.
Psychiatry 58, 821–827. Krabbe, K.S., Mortensen, E.L., Avlund, K., Pedersen, A.N., Pedersen, B.K., Jorgensen, T., et al., 2009. Brain-derived neurotrophic factor predicts mortality risk in older women. J. Am. Geriatr. Soc. 57, 1447–1452. Kushwah, N., Jain, V., Deep, S., Prasad, D., Singh, S.B., Khan, N., 2016. Neuroprotective role of intermittent hypobaric hypoxia in unpredictable chronic mild stress induced depression in rats. PLoS One 11, e0149309. Lang, U.E., Hellweg, R., Gallinat, J., 2005. Association of BDNF serum concentrations with central serotonergic activity: evidence from auditory signal processing. Neuropsychopharmacology 30, 1148–1153. Layoun, N., Saleh, N., Barbour, B., Awada, S., Rachidi, S., Al-Hajje, A., et al., 2014. Waterpipe effects on pulmonary function and cardiovascular indices: a comparison to cigarette smoking in real life situation. Inhal. Toxicol. 26, 620–627. Li, H., Liu, L., Tang, Y., Ji, N., Yang, L., Qian, Q., et al., 2014. Sex-specific association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and plasma BDNF with attention-deficit/hyperactivity disorder in a drug-naive Han Chinese sample. Psychiatry Res. 217, 191–197. Lommatzsch, M., Zingler, D., Schuhbaeck, K., Schloetcke, K., Zingler, C., Schuff-Werner, P., et al., 2005. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol. Aging 26, 115–123. Lotfipour, S., Ferguson, E., Leonard, G., Perron, M., Pike, B., Richer, L., et al., 2009. Orbitofrontal cortex and drug use during adolescence: role of prenatal exposure to maternal smoking and BDNF genotype. Arch. Gen. Psychiatry 66, 1244–1252. Mathers, C.D., Loncar, D., 2006. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 3, e442. Matthews, V.B., Astrom, M.B., Chan, M.H., Bruce, C.R., Krabbe, K.S., Prelovsek, O., et al., 2015. Erratum to: brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMPactivated protein kinase. Diabetologia 58, 854–855. Mortality, G.B.D., 2015. Causes of Death C. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385, 117–171. Munshi, T., Heckman, C.J., Darlow, S., 2015. Association between tobacco waterpipe smoking and head and neck conditions: a systematic review. J. Am. Dent. Assoc. 146, 760–766. Mzayek, F., Khader, Y., Eissenberg, T., Al Ali, R., Ward, K.D., Maziak, W., 2012. Patterns of water-pipe and cigarette smoking initiation in schoolchildren: Irbid longitudinal smoking study. Nicotine Tob. Res. 14, 448–454. Nabi, G., Aziz, T., Ullah, W., Saleem, K., Ullah, S., 2015. A mini-review on Sheesha smoking: a potent cancer inducer. Am. Eur. J. Toxicol. Sci. 7, 63–67. Primack, B.A., Carroll, M.V., Weiss, P.M., Shihadeh, A.L., Shensa, A., Farley, S.T., et al., 2016. Systematic review and meta-analysis of inhaled toxicants from waterpipe and cigarette smoking. Public Health Rep. 131, 76–85. Renteria, E., Jha, P., Forman, D., Soerjomataram, I., 2016. The impact of cigarette smoking on life expectancy between 1980 and 2010: a global perspective. Tob. Control 25 (5 (Sep.)), 551–557. Sepetdjian, E., Saliba, N., Shihadeh, A., 2010. Carcinogenic PAH in waterpipe charcoal products. Food Chem. Toxicol. 48, 3242–3245. Shafique, K., Mirza, S.S., Mughal, M.K., Arain, Z.I., Khan, N.A., Tareen, M.F., et al., 2012. Water-pipe smoking and metabolic syndrome: a population-based study. PLoS One 7, e39734. Shihadeh, A., Saleh, R., 2005. Polycyclic aromatic hydrocarbons, carbon monoxide, tar, and nicotine in the mainstream smoke aerosol of the narghile water pipe. Food Chem. Toxicol. 43, 655–661. Shihadeh, A., Salman, R., Jaroudi, E., Saliba, N., Sepetdjian, E., Blank, M.D., et al., 2012. Does switching to a tobacco-free waterpipe product reduce toxicant intake? A crossover study comparing CO, NO, PAH, volatile aldehydes, tar and nicotine yields. Food Chem. Toxicol. 50, 1494–1498. Teixeira, A.L., Barbosa, I.G., Diniz, B.S., Kummer, A., 2010. Circulating levels of brainderived neurotrophic factor: correlation with mood, cognition and motor function. Biomark. Med. 4, 871–887. Toledo-Rodriguez, M., Lotfipour, S., Leonard, G., Perron, M., Richer, L., Veillette, S., et al., 2010. Maternal smoking during pregnancy is associated with epigenetic modifications of the brain-derived neurotrophic factor-6 exon in adolescent offspring. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B, 1350–1354. Torres, L.H., Garcia, R.C., Blois, A.M., Dati, L.M., Durao, A.C., Alves, A.S., et al., 2015. Exposure of neonatal mice to tobacco smoke disturbs synaptic proteins and spatial learning and memory from late infancy to early adulthood. PLoS One 10, e0136399. Trajkovska, V., Marcussen, A.B., Vinberg, M., Hartvig, P., Aznar, S., Knudsen, G.M., 2007. Measurements of brain-derived neurotrophic factor: methodological aspects and demographical data. Brain Res. Bull. 73, 143–149. van Oostrom, I., Franke, B., Rijpkema, M., Gerritsen, L., Arias-Vasquez, A., Fernandez, G., et al., 2012. Interaction between BDNF Val66Met and childhood stressful life events is associated to affective memory bias in men but not women. Biol. Psychol. 89, 214–219. World Health Organization, 2011. WHO urges more countries to require large, graphic health warnings on tobacco packaging: the WHO report on the global tobacco epidemic, 2011 examines anti-tobacco mass-media campaigns. Cent. Eur. J. Public Health 19 (133), 151. Yeom, C.W., Park, Y.J., Choi, S.W., Bhang, S.Y., 2016. Association of peripheral BDNF level with cognition, attention and behavior in preschool children. Child Adolesc. Psychiatry Ment. Health 10, 10. Yochum, C., Doherty-Lyon, S., Hoffman, C., Hossain, M.M., Zelikoff, J.T., Richardson, J.R., 2014. Prenatal cigarette smoke exposure causes hyperactivity and aggressive behavior: role of altered catecholamines and BDNF. Exp. Neurol. 254, 145–152. Ziegenhorn, A.A., Schulte-Herbruggen, O., Danker-Hopfe, H., Malbranc, M., Hartung, H.D., Anders, D., et al., 2007. Serum neurotrophins–a study on the time course and influencing factors in a large old age sample. Neurobiol. Aging 28, 1436–1445.
status. Atherosclerosis 240, 472–476. Alzoubi, K.H., Khabour, O.F., Alharahshah, E.A., Alhashimi, F.H., Shihadeh, A., Eissenberg, T., 2015. The effect of waterpipe tobacco smoke exposure on learning and memory functions in the rat model. J. Mol. Neurosci. 57, 249–256. Begliuomini, S., Casarosa, E., Pluchino, N., Lenzi, E., Centofanti, M., Freschi, L., et al., 2007. Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor. Hum. Reprod. 22, 995–1002. Beuten, J., Ma, J.Z., Payne, T.J., Dupont, R.T., Quezada, P., Huang, W., et al., 2005. Significant association of BDNF haplotypes in European-American male smokers but not in European-American female or African-American smokers. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 139B, 73–80. Bhang, S.Y., Choi, S.W., Ahn, J.H., 2010. Changes in plasma brain-derived neurotrophic factor levels in smokers after smoking cessation. Neurosci. Lett. 468, 7–11. Bibars, A.R., Obeidat, S.R., Khader, Y., Mahasneh, A.M., Khabour, O.F., 2015. The effect of waterpipe smoking on periodontal health. Oral Health Prev. Dent. 13, 253–259. Blank, M.D., Cobb, C.O., Kilgalen, B., Austin, J., Weaver, M.F., Shihadeh, A., et al., 2011. Acute effects of waterpipe tobacco smoking: a double-blind, placebo-control study. Drug Alcohol Depend. 116, 102–109. Brener, N.D., Eaton, D.K., Flint, K.H., Hawkins, J., Kann, L., Kinchen, S., et al., 2013. Methodology of the Youth Risk Behavior Surveillance System-2013. US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA, USA (30341). Bus, B.A., Molendijk, M.L., Penninx, B.J., Buitelaar, J.K., Kenis, G., Prickaerts, J., et al., 2011. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology 36, 228–239. Bus, B.A., Arias-Vasquez, A., Franke, B., Prickaerts, J., de Graaf, J., Voshaar, R.C., 2012. Increase in serum brain-derived neurotrophic factor in met allele carriers of the BDNF Val66Met polymorphism is specific to males. Neuropsychobiology 65, 183–187. Chaldakov, G.N., Tonchev, A.B., Aloe, L., 2009. NGF and BDNF: from nerves to adipose tissue, from neurokines to metabokines. Riv. Psichiatr. 44, 79–87. Cobb, C.O., Blank, M.D., Morlett, A., Shihadeh, A., Jaroudi, E., Karaoghlanian, N., et al., 2015. Comparison of puff topography, toxicant exposure, and subjective effects in low- and high-frequency waterpipe users: a double-blind, placebo-control study. Nicotine Tob. Res. 17, 667–674. Colle, R., Trabado, S., Rotenberg, S., Brailly-Tabard, S., Benyamina, A., Aubin, H.J., et al., 2016. Tobacco use is associated with increased plasma BDNF levels in depressed patients. Psychiatry Res. 246, 370–372. Czubak, A., Nowakowska, E., Kus, K., Burda, K., Metelska, J., Baer-Dubowska, W., et al., 2009. Influences of chronic venlafaxine, olanzapine and nicotine on the hippocampal and cortical concentrations of brain-derived neurotrophic factor (BDNF). Pharmacol. Rep. 61, 1017–1023. Durazzo, T.C., Meyerhoff, D.J., Nixon, S.J., 2010. Chronic cigarette smoking: implications for neurocognition and brain neurobiology. Int. J. Environ. Res. Public Health 7, 3760–3791. Eissenberg, T., Shihadeh, A., 2009. Waterpipe tobacco and cigarette smoking: direct comparison of toxicant exposure. Am. J. Prev. Med. 37, 518–523. Elfving, B., Buttenschon, H.N., Foldager, L., Poulsen, P.H., Andersen, J.H., Grynderup, M.B., et al., 2012. Depression, the Val66Met polymorphism, age, and gender influence the serum BDNF level. J. Psychiatr. Res. 46, 1118–1125. Fawzy, I.A., Kamal, N.N., Abdulla, A.M., 2011. Reproductive toxicity of tobacco shisha smoking on semen parameters and hormones levels among adult Egyptian men. Res. J. Environ. Toxicol. 5, 282. Harrod, S.B., Lacy, R.T., Zhu, J., Hughes, B.A., Perna, M.K., Brown, R.W., 2011. Gestational IV nicotine produces elevated brain-derived neurotrophic factor in the mesocorticolimbic dopamine system of adolescent rat offspring. Synapse 65, 1382–1392. Huang, T., Gejl, A.K., Tarp, J., Andersen, L.B., Peijs, L., Bugge, A., 2017. Cross-sectional associations of objectively measured physical activity with brain-derived neurotrophic factor in adolescents. Physiol. Behav. 171, 87–91. Jamal, M., Van der Does, W., Elzinga, B.M., Molendijk, M.L., Penninx, B.W., 2015. Association between smoking, nicotine dependence, and BDNF Val66Met polymorphism with BDNF concentrations in serum. Nicotine Tob. Res. 17, 323–329. Jawad, M., McEwen, A., McNeill, A., Shahab, L., 2013. To what extent should waterpipe tobacco smoking become a public health priority. Addiction 108, 1873–1884. Jawad, M., Jawad, S., Waziry, R.K., Ballout, R.A., Akl, E.A., 2016. Interventions for waterpipe tobacco smoking prevention and cessation: a systematic review. Sci. Rep. 6, 25872. Kadhum, M., Sweidan, A., Jaffery, A.E., Al-Saadi, A., Madden, B., 2015. A review of the health effects of smoking shisha. Clin. Med. (Lond.) 15, 263–266. Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G., Aubry, J.M., 2002. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 109, 143–148. Khabour, O.F., Alzoubi, K.H., Abu Thiab, T.M., Al-Husein, B.A., Eissenberg, T., Shihadeh, A.L., 2015. Changes in the expression and protein level of matrix metalloproteinases after exposure to waterpipe tobacco smoke. Inhal. Toxicol. 27, 689–693. Khalil, H., Alomari, M.A., Khabour, O.F., Al-Hieshan, A., Bajwa, J.A., 2016. Relationship of circulatory BDNF with cognitive deficits in people with Parkinson's disease. J. Neurol. Sci. 362, 217–220. Kim, T.S., Kim, D.J., Lee, H., Kim, Y.K., 2007. Increased plasma brain-derived neurotrophic factor levels in chronic smokers following unaided smoking cessation. Neurosci. Lett. 423, 53–57. Kim, K.H., Kabir, E., Jahan, S.A., 2016. Waterpipe tobacco smoking and its human health impacts. J. Hazard. Mater. 317, 229–236. Klein, A.B., Williamson, R., Santini, M.A., Clemmensen, C., Ettrup, A., Rios, M., et al., 2011. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int. J. Neuropsychopharmacol. 14, 347–353. Klimek, V., Zhu, M.Y., Dilley, G., Konick, L., Overholser, J.C., Meltzer, H.Y., et al., 2001. Effects of long-term cigarette smoking on the human locus coeruleus. Arch. Gen.
18