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Abstract
Maternal smoking causes several defects ranging from intrauterine growth restriction to sudden infant death syndrome and spontaneous abortion. While several studies have documented the effects of prenatal nicotine exposure in development and behavior, acute vasculature changes in the fetal brain due to prenatal nicotine exposure have not been evaluated yet. This study uses correlation mapping optical coherence angiography to evaluate changes in fetal brain vasculature flow caused by maternal exposure to nicotine during the second trimester-equivalent of gestation in a mouse model. The effects of two different doses of nicotine were evaluated. Results showed a decrease in the vasculature for both doses of nicotine, which was not seen in the case of the sham group.
© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement
1. Introduction
Maternal cigarette smoking has been regarded as one of the leading causes of congenital birth defects. In 2016, 7.2% of women in the United States reported smoking during pregnancy [1]. Maternal smoking during pregnancy is known to cause several defects, including intrauterine growth restriction (IUGR), placental abruption, stillbirth, preterm birth, low birth weight, sudden infant death syndrome, and spontaneous abortion [2–13]. Some defects are lifelong, including learning disabilities, cognitive dysfunction, behavioral problems, attention deficit disorders, and psychiatric disorders. [14–27]. Hence, smoking cessation is strongly recommended during pregnancy and lactation. Nevertheless, many women continue to smoke during their entire pregnancy, mostly due to nicotine addiction. Thus, even though 75% of pregnant smokers have reported the desire to quit smoking, only 20 to 30% have been successful [28–30].
Since the inability to quit smoking is mostly attributed to nicotine addiction, nicotine replacement therapy (NRT) is the recommended pharmacotherapy for smoking cessation [31–34]. A substantial number of women also use electronic cigarettes or e-cigarettes to help quit smoking [35–37]. Both these approaches are usually sought after because of the belief that pure nicotine [38] provides a safe and effective way for smoking cessation as they do not have the other hazardous materials present in a traditional cigarette. This approach remains popular even after the US Food and Drug Administration classified nicotine as a category D drug [39], which means that there is scientific evidence of this substance causing harm to the fetus. Depending upon the puff volume and the nicotine concentration, e-cigarettes deliver equal or higher amounts of nicotine compared to traditional cigarettes [40,41]. Recent surveys have shown that 40% of pregnant women using e-cigarettes did not realize that e-cigarettes contained nicotine or could be addictive, and 40% believed that these are less harmful than conventional cigarettes [35]. These methods are known to deliver nicotine in amounts equivalent to smoking ten cigarettes a day [42]. The emergence of NRT and e-cigarettes which can deliver extremely high doses of nicotine, emphasize the importance of studying the effects of nicotine specifically, on pregnancy and fetal development.
During embryogenesis, the cellular and architectural assembly of the central nervous system is controlled by several neurotransmitters [43,44]. These neurotransmitters perform multiple functions that aid in normal development, including promoting neural cell replication, initiating differentiation from the replication, initiation and termination of axonogenesis and synaptogenesis, evoking or retarding apoptosis, and enabling appropriate migration and localization of specific cell populations within the developing brain regions [45]. Due to the multitude of processes that occur during development, the brain is particularly vulnerable to neuroactive chemicals such as nicotine. Nicotine imitates the function of one such neurotransmitter, acetylcholine, by binding to acetylcholine receptors in the developing brain, thus interfering with brain development. Prenatal nicotine exposure is known to affect brain development in several ways, including triggering apoptosis, reducing the number of neuronal cells, truncation of axonogenesis, and deficient synaptogenesis [46–55]. Most importantly, nicotine causes delayed-onset changes [53,56]. In other words, its effects persist, causing damage to the developing brain in the postnatal period even when nicotine is no longer present in the system, thus changing the trajectory of brain development.
Apart from the teratogen itself, the gestational stage at which maternal exposure occurs is a significant factor in determining the severity and the type of defect. Initially, it was thought that nicotinic acetylcholine receptors (nAChRs) were not expressed in sufficient numbers during the first trimester. Hence, several studies concluded that exposure to nicotine during the first trimester would not cause a significant effect on the fetus [50,53,57]. However, recent studies have shown that not only are nAChRs present, but they are biologically active even during the development of the neural tube during the first trimester [58,59]. This emphasizes the need to study the effects of nicotine, and other teratogens’ exposure during the first trimester. The mid-first through second trimester, on the other hand, is a critical period for brain development as most neurons of the adult brain are born during this period [60]. Apart from this, the microvasculature invades the fetal brain during this period aids in several aspects of fetal development, including supporting the nutritional needs, providing endocrinal support, and neural development [61–63]. Even though there has been a wide variety of research focused on outcomes from prenatal nicotine exposure, there has been no research evaluating the effects of acute nicotine exposure on the developing fetal brain vasculature, during this early period of brain growth.
Several imaging modalities, including histological staining [64,65], ultrasound biomicroscopy, micro-computed tomography (micro-CT), and micro-magnetic resonance imaging (micro-MRI) have been used for imaging small mammal embryonic development [66]. However, due to limitations, such as invasiveness, imaging depth, resolution, long acquisition times, need for external contrast agents, and ionizing radiations, these methods are not suitable for live imaging of small mammal embryos. Optical coherence tomography (OCT) [67], on the other hand, is a well-developed imaging modality that has been used successfully in imaging of embryonic development in animal models over the past decade [68–70]. Due to its noninvasive nature, relatively high spatial and temporal resolutions, and its ability to provide cross-sectional images of live embryos with no exogenous contrast agents, OCT has been preferred over other imaging modalities for live imaging of small mammal embryos [71–76]. Over the years, several functional extensions of OCT have been developed to extend its use from mere structural imaging. Angiographic OCT is one of the most notable extensions, which was developed to image microvasculature and blood flow [77–87]. Our previous work has used two different types of angiographic OCT to evaluate changes in the murine fetal brain vasculature due to prenatal exposure to alcohol and a synthetic cannabinoid [88,89].
This study uses in utero angiographic OCT to evaluate fetal brain vasculature flow changes due to maternal exposure to nicotine alone, during the first-to-second trimester equivalent period in a mouse model. A dose-response analysis was also performed, including a dose that corresponds to an average human dose. Results showed a decrease in vasculature in both doses of nicotine, which was not observed in the control group.
2. Materials and methods
2.1 OCT system
A phase-stabilized swept-source OCT system (PhS-SSOCT) was used for imaging the fetal brain. In summary, the system consisted of a broadband swept-source laser, with a central wavelength of 1310 nm, a scan range of 150 nm, a scan rate of 30 kHz, an axial resolution of 11 µm in air, a transverse resolution of 16 µm in air, an incident power on the sample of 11 mW, and sensitivity of approximately 98.5 dB. A balanced photodetector recorded the interference pattern, which was digitized by a high-speed analog-to-digital converter. More information on this system, including a schematic can be found in our previous work [89,90].
2.2 Animal manipulations and dosing
CD-1 IGS mice (Crl:CD1(ICR), Charles River Laboratories, Inc. Wilmington, MA) were mated overnight, and the presence of a vaginal plug was considered gestational day (GD) 0.5. On GD 14.5, pregnant female mice were anesthetized using isoflurane inhalation and were placed on a heated surgical platform to maintain body temperature throughout the surgical procedure. This gestational stage was chosen because it corresponds to the end of the first trimester and beginning of the second trimester encompassing the peak period for fetal neurogeneisis and angiogenesis. Abdominal fur was removed, and a small incision was made in the abdomen, exposing the uterine horn for imaging. The selected fetus was stabilized using forceps to reduce bulk motion due to maternal respiration and heartbeat. Initial OCT images were recorded, and the mother was administered nicotine at the corresponding dose via intragastric gavage. Subsequent measurements were taken for a total period of 45 minutes at 5-minute intervals. The uterus was hydrated with 1X PBS, one minute before every measurement. For the sham group, distilled water was used instead of nicotine. After completing all measurements, the animal was euthanized by an isoflurane overdose followed by cervical dislocation. All procedures were performed under an approved protocol by the University of Houston Institutional Animal Care and Use Committee.
Two doses of nicotine were tested. For the first study, a dose of 1 mg/kg of nicotine (dissolved in distilled water) was used, which is a relatively high dose in comparison to the levels of nicotine achieved by an average human who smokes. However, mice are known to metabolize nicotine faster [45], hence this dose could be considered a moderate dose for a mouse model. An average smoker receives approximately 8 to 20 mg of nicotine per 80 to 100 kg of body weight [91–93]. Hence, 0.1 mg/kg was the next dose that was tested to simulate human smoking. The sham group was given the equivalent volume of distilled water.
2.3 Imaging, quantifications, and statistics
The imaging and processing steps are similar to our previous work [88]. A 3D OCT image was acquired, which consisted of 600 B-scans per volume with 600 A-scans per B-scan. In order to perform angiographic imaging, five B-scans were recorded at each spatial position. The time for each B-scan was 20 ms, and the total acquisition time was 84 seconds, including the galvanometer flyback time between B-scans. An approximate total area of 6.0 mm x 6.2 mm of the fetal brain was imaged. The vasculature maps were obtained using a post-processing correlation mapping optical coherence angiography (cm-OCA) algorithm [94]. A discrete Fourier transform-based sub-pixel registration technique [95] was used to correct the axial shift caused due to bulk motion between each pair of 5 B-scans that were recorded at the same spatial position. The average temporal correlation between these 5 B-scans, in pairs, was calculated to obtain the correlation coefficient. The SNR-dependent artifacts were corrected by using the temporal variance of the background noise as a function of imaging depth [94]. Angiograms with a global correlation value below a threshold of the difference between the mean and the SD were disregarded. The 3D vasculature maps were obtained from the spatial distribution of the temporal correlation coefficients of the entire 3D image. A maximum intensity projection (MIP) was calculated to obtain the en face images of the dorsal surface arterial blood vessels on the fetal brain. A frequency rejection filter [96] was applied to the 2D MIPs to remove bulk motion artifacts due to maternal respiration and heartbeat. Amira software (EFI Co., Portland, Oregon) was used for denoising and to form final MIPs.
For this study, three different parameters, vessel area density (VAD), vessel length fraction (VLF), and vessel diameter (VD) were used to quantify the vasculature. VAD is defined as the area of the image that corresponds to the vasculature, Avessel, divided by the total area of the image, Aimage, (VAD = Avessel/Aimage), and VLF is defined as the total length of the vessels Lvessel, divided by the total area of the image (VLF = Lvessel/Aimage). Image J was used to calculate the VAD (from the binarized MIP) and VLF (from the skeletonized binary MIP), while Amira was used to calculate the VD. Only a portion of the MIP, including the main vessel, was used for quantifications. All VD quantifications were made on the main branch of the vessel only.
First, two nonparametric Kruskal-Wallis ANOVAs were performed to assess the effects of different doses and time on the vasculature respectively. This was followed by a 2-sided Mann-Whitney U test that was performed to test for statistically significant changes between every nicotine group and the sham group, and the 2 nicotine groups, for all quantification parameters, at 45 minutes post-exposure. Bonferroni correction was performed to correct for multiple testing for the pair-wise tests.
3. Results
Vasculature maps from one fetus from each of the groups are first shown, followed by the quantifications and statistics. The total number of fetuses in the sham group was 6, the nicotine group at a dose of 0.1 mg/kg was 6, and the nicotine group at a dose of 1 mg/kg was 5.
Figure 1 shows the results from one fetus from the sham group. Figures 1(a) and 1(b) are MIPs of 3D cm-OCA images before and 45 minutes after maternal exposure to distilled water, i.e. sham, respectively. Results from the sham group showed almost no change in vasculature 45 minutes after exposure to distilled water. Figures 2(a) and 2(b) show MIPs of 3D cm-OCA images before and after maternal exposure to nicotine at a dose of 1 mg/kg. Unlike the sham group, there was a dramatic decrease in vasculature within 45 minutes after exposure to nicotine at a dose of 1 mg/kg. Not only was vasoconstriction observed in the main vessel under investigation, but there was also a disappearance of the surrounding smaller tributaries.
Fig. 1. 2D MIP of cm-OCA images of fetal brain vasculature (a) before and (b) 45 minutes after maternal exposure to distilled water. The large dashed rectangle depicts the region of VAD and VLF quantifications whereas the small squares depicts the regions of VD quantifications.
Fig. 2. 2D MIP of cm-OCA images of fetal brain vasculature (a) before and (b) 45 minutes after maternal exposure to nicotine at a dose of 1 mg/kg. The large dashed rectangle depicts the region of VAD and VLF quantifications whereas the small squares depict the regions of VD quantifications.
Figures 3(a) and 3(b) show MIPs of 3D cm-OCA images before and 45 minutes after maternal exposure to nicotine at a dose of 0.1 mg/kg. A reduction in vasculature was observed, unlike the sham group. However, there was no disappearance in the smaller tributaries, as seen in the case of the fetuses exposed to nicotine at a dose of 1 mg/ kg.
Fig. 3. 2D MIP of cm-OCA images of fetal brain vasculature (a) before and (b) 45 minutes after maternal exposure to nicotine at a dose of 0.1 mg/kg. The large dashed rectangle depicts the region of VAD and VLF quantifications whereas the small squares depict the regions of VD quantifications.
Figures 4(a), 4(b), and 4(c) show the percentage change in VAD, VLF, and VD respectively, over a period of 45 minutes at 5 minute intervals. All samples from all groups were used for these calculations. The inter-sample mean and standard deviation bars are presented here. As expected, the percentage decrease in all three parameters was higher for nicotine at a dose of 1 mg/kg compared to nicotine at a dose of 0.1 mg.kg. The results of overall Kruskal-Wallis ANOVAs (for time and dose) are presented in Table 1. The P values in bold indicate statistical significance (P < 0.05).
Fig. 4. Percentage change in (a) VAD, (b) VLF, and (c) VD after exposure, every 5 minutes for 45 minutes. The error bars represent the standard deviation.
Table 1. Results of the Kruskal Wallis ANOVAs. P values in bold indicates statistical significance.
Figure 5 shows a comparison of percentage changes in the quantification parameters at 45 minutes after exposure between all three groups. Figures 5(a), 5(b), and 5(c) depict the changes in VAD, VLF, and VD, respectively.
Fig. 5. Comparisons of the percentage change in (a) VAD, (b) VLF, and (c) VD at 45 minutes after maternal exposure to distilled water and nicotine at doses of 0.1 mg/kg and 1 mg/kg. The asterisk indicates statistical significance by a 2-sided Mann-Whitney U test.
The 2-sided Mann-Whitney U test was performed between each pair of the groups (3 pairs in total) for each VAD, VLF, and VD for pairwise testing. For VLF, there was no statistically significant difference between any of the three pairs. For VAD, while there was a statistically significant difference between the sham and 1 mg/kg nicotine dose, no significant change was seen between the sham group and the nicotine group at a dose of 0.1 mg/kg as well as both the nicotine groups. Percentage change in VD showed statistically significant differences between all three pairs. Table 2 shows a summary of results from the Mann-Whitney U test. The values in bold indicate statistical significance.
Table 2. Results of the Mann-Whitney U test. P values in bold indicate statistical significance.
4. Discussion
Vasculature that develops in the brain at the end of the first trimester through the second trimester-equivalent period is vulnerable to teratogens as this period is crucial for fetal angiogenesis. Moreover, these early developing vessels are critically important for transporting nutrition from the placenta to the developing fetal brain. Thus, it is important to study the changes in the vasculature that occur due to maternal exposure to various teratogens during the second trimester. This study evaluates the acute changes in fetal brain vasculature in a mouse model caused due to maternal exposure to nicotine at a gestational stage corresponding to the second trimester, using cm-OCA. The vasoconstrictive response to nicotine and the imaging plane are both consistent with the distribution of the terminal anterior and middle cerebral arterial tributaries on the dorsolateral pial surface of the fetal brain.
All VAD and VLF quantifications were performed over the area depicted by the dashed rectangle in Figs. 1,2, and 3 to prevent the influence of external noise caused by maternal heartbeat and respiration as well as changes in vasculature in the uterus. All VD quantifications were performed on the main branch of the vessel to ensure that the effects of clamping and anesthesia that could sometimes be seen in the smaller tributaries did not introduce a bias in the results. Moreover, the main vessel was consistently imaged across all samples, so VD quantifications were made on this vessel to ensure consistency. However, since the clamping procedure that was performed to stabilize the fetus and reduce bulk motion was utilized uniformly across all samples from all groups, any influence due to clamping would have affected every sample. Thus, sham groups were utilized as direct comparisons.
The ANOVA results (Table 1) showed an overall significant effect of nicotine exposure on all three parameters used to quantify vasculature. However, a significant effect of time was only seen in one parameter, VD. Subsequesnt post-hoc testing at 45 minutes showed that there was a significant dose-related decrease in VAD and VD, but not in VLF.
Although there was a drastic reduction in vasculature when exposed to the higher dose of nicotine, as seen from Fig. 2, there seemed to be no radical change in the overall length of the major vessel under investigation. This could possibly be the reason why the VLF calculations did not show any statistically significant differences between any of the three dose groups at 45 minutes. However, the complete disappearance of smaller tributaries could have been the reason for the drastic reduction in VLF mean values between the sham and nicotine group at a dose of 1 mg/kg, seen in Fig. 5(b).
For this study, the effects of only two doses of nicotine were evaluated. The dose was chosen as the higher dose that causes IUGR. Since drastic effects were seen within a period of 45 minutes after exposure to 1 mg/kg of nicotine, a lower dose of 0.1 mg/kg (which is equivalent to what an average smoker receives from one cigarette) was also used. However, rodents metabolize nicotine much faster than humans [45]. Thus, these drastic effects seen with a dose of 1 mg/kg are the consequence of administering a moderate dose for a mouse. Several studies that use rodent models have used higher doses of 6 mg/kg per day [97,98]. A dose of 6 mg/kg is equivalent to human smoking around 2 packs of cigarettes per day [99]. Studies have also shown that at higher doses, nicotine desensitizes the nAChRs, which renders them unresponsive to nicotine [100]. These points emphasize the need to test higher doses of nicotine to evaluate whether changes in fetal brain vasculature also become saturated at high doses. Apart from testing higher doses of nicotine, our future work will also involve longitudinal studies to test the reversibility of the effects of nicotine.
Another important factor involved in studying the effects of prenatal exposure to nicotine in animals is the route of administration. Typically, smokers have random highs and lows of nicotine concentration in their plasma during the day, followed by a long period of no exposure during the night [100]. This work used intragastric gavage to administer nicotine because the mother is exposed to the entire dose of nicotine within a few seconds. This causes a sudden increase in plasma nicotine concentration in a few seconds, which is not similar to the nicotine received by smokers, where nicotine exposure happens in a few minutes. Nicotine can also be administered by subcutaneous injection which results in a spike in nicotine concentration compareable to intragastric gavage [101]. Two other methods to administer nicotine include subcutaneously implanted osmotic pumps and nicotine administration through drinking water. The osmotic pumps release a constant amount of nicotine into the animal, resulting in persistent exposure to the drug without drastic variations [102]. Although this is not what is seen in smokers, these pumps provide a good model to simulate nicotine patches and for studying mechanisms. Nicotine administration through drinking water offers less control over timing and dosing of nicotine across animals. However, this method creates realistic dynamics in a 24-hour period without creating artificial spikes [100]. Hence the mode of nicotine administration is an important contributor to the validity of the experimental model. Since this study was focused on imaging the acute effects of nicotine, intragastric gavage was selected as a means for delivering a controlled bolus of nicotine and for generating an easily comparable sham control group.
One limitation to the imaging technique used in the current study is the system sensitivity and sensitivity roll-off, which affects phase stability [103] and hence the quality of the cm-OCA map. To improve SNR for better visualization of vessels in deeper regions of the fetal brain, the fetus was oriented such that there was good visualization of the dorsal vessels in the brain. To reduce shadowing artifacts and image deeper vessels, one might use a projection resolved algorithm [104]. A phase correction scheme [87,94] and a 2D Gabor wavelet filter [105] could be implemented to image microvasculature, to help enhance vessel contrast and connectivity. Other angiographic techniques, including split spectrum imaging to further improve the SNR can also be implemented [106].
Finally, our current study focused on the acute effects of maternal nicotine consumption on fetal cerebral blood flow. However, nicotine use often co-occurs with other risk factors for impaired fetal development like maternal stress [101,107–109], cardiovascular [110,111] and metabolic disease [112] . Moreover, nicotine is often co-abused with other drugs including alcohol [113,114]. These co-occuring conditions may amplify the effects of maternal nicotine on fetal cerebral blood flow, and their contributory effects need further investigation.
5. Conclusion
This study evaluated changes in fetal brain vasculature due to prenatal exposure to different doses of nicotine during the second trimester equivalent period of gestation in a mouse model. Results showed a decrease in vasculature caused by both doses of nicotine compared to the sham group. However, as expected, the effect seen increased with dose. Similar to our previous work evaluating the effects of ethanol and the synthetic cannabinoid CP-55,940, this study showed that nicotine too, at the doses tested, acts as a vasoconstrictor on the developing fetal brain during the peak period of fetal neurogenesis and angiogenesis.
Funding
National Institutes of Health (P30EY007551, R01HD086765, R01HD095520, R01HD096335, R01HL120140).
Ackowledgments
The authors would like to thank Ms. Amur Kouka, Ms. Noemi Bustamante, and Ms. Connie Yan at the University of Houston for their technical assistance.
Disclosures
The authors declare that there are no conflicts of interest related to this article.
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