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Biochemical and Biophysical Research Communications 553 (2021) 65e71

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Biochemical and Biophysical Research Communications

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y b b r c

Maternal anesthesia with sevoflurane during the mid-gestation induces social interaction deficits in offspring C57BL/6 mice Qingcai Chen a, 1, Wei Chu b, 1, Rui Sheng b, Shaoyong Song a, Jianping Yang a, Fuhai Ji a, ** Xin Jin a, * a Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China b Department of Pharmacology, Soochow University School of Pharmaceutical Science, Suzhou, 215123, China

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a r t i c l e i n f o

a b s t r a c t

Article history: Received 17 January 2021 Accepted 11 March 2021 Available online 20 March 2021

Keywords: Anesthesia Sevoflurane Neurotoxicity Sociability Preference for social novelty Three-chambered social paradigm

Sevoflurane anesthesia in pregnant mice could induce neurotoxicity in the developing brain and disturb learning and memory in the offspring mice. Whether it could impair social behaviors in the offspring mice is uncertain. Therefore, we assessed the neurobehavioral effect of in-utero exposure to sevoflurane on social interaction behaviors in C57BL/6 mice. The pregnant mice were anesthetized with 2.5% sevo- flurane in 100% oxygen for 2 h, and their offspring mice were tested in three-chambered social paradigm, which includes three 10-min sessions of habituation, sociability, and preference for social novelty. At the juvenile age, the offspring mice showed abnormal sociability, as proved by not taking more time sniffing at the stranger 1 mouse compared with the empty enclosure (108.5 ± 25.4 vs. 108.2 ± 44.0 s, P ¼ 0.9876). Meanwhile, these mice showed impaired preference for social novelty, as evidenced by not taking more time sniffing at the stranger 2 compared with the stranger 1 mouse (92.1 ± 52.2 vs. 126.7 ± 50.8 s, P ¼ 0.1502). At the early adulthood, the offspring mice retrieved the normal sociability (145.6 ± 33.2 vs. 76.0 ± 31.8 s, P ¼ 0.0001), but remained the impaired preference for social novelty (100.6 ± 29.3 vs. 118.0 ± 47.9 s, P ¼ 0.3269). Collectively, these results suggested maternal anesthesia with sevoflurane could induce social interaction deficits in their offspring mice. Although the disturbance of sociability could be recoverable, the impairment of preference for social novelty could be long-lasting.

© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Preclinical studies suggested that anesthetic agents could induce the neurotoxicity in developing brain and cause neurobehavioral changes in adulthood [1e4]. Anesthetic-induced developmental neurotoxicity could be attributed to multiple factors, including anesthetic agents, anesthesia regimen (i.e., concentration and dura- tion), and brain vulnerability [2,5]. Sevoflurane is commonly used in parturient undergoing non-obstetric surgery, which incurs many concerns on neurodevelopmental consequences.

environmental toxicants including anesthetic agents should play an important role [8,9]. It was reported that in-utero exposure to isoflurane could impair the spatial working memory of the rat [5]. Therefore, we hypothesized that in-utero exposure to sevoflurane could induce social interaction deficit in offspring C57BL/6 mice. To verify this possibility, we performed maternal anesthesia with sev- oflurane in pregnant mice on gestational day 14. Next, we conducted social interaction test in their offspring mice at one- and two-month- old. The main objective was to determine whether in-utero exposure to sevoflurane was induce social interaction deficit in offspring mice.

In recent years, children with autistic spectrum disorders are increasing. The core symptom of autism is social interaction deficit [6,7], but the neuropathological mechanism remains uncertain. The combined effect of genetic predisposition and early exposure to

2. Methods and materials

2.1. Animals

Corresponding author. ** Corresponding author.

E-mail addresses: jifuhai@hotmail.com (F. Ji), jinxin@suda.edu.cn (X. Jin).

1 These authors contributed equally to this work (Q.C.C. and W.C.).

This study was approved by the Institutional Animal Care and Use Committee of Soochow University. Adult C57BL/6 mice in breeding age were purchased from Zhaoyan Laboratory (Taicang, Suzhou, China). One male and four female mice were housed per

https://doi.org/10.1016/j.bbrc.2021.03.063 0006-291X/© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Q. Chen, W. Chu, R. Sheng et al.

cage for breeding the offspring mice. Six pregnant mice on gesta- tional day 14 were randomly assigned to receive either 2.5% sevo- flurane in 100% oxygen or just 100% oxygen as the control. Their offspring mice were correspondingly assigned as the testing mice. Several pregnant mice without any treatment were chosen to produce the offspring mice as the stranger mice. The pups were fostered by their own dams till weaning on postnatal day 21. All mice were raised in a controlled condition (21e22 (cid:2)C, 12 h light/ dark cycle, light on at 7 a.m.), with access to standard mouse chow and water ad libitum.

2.2. Maternal anesthesia

A clinically-retired anesthesia machine was used to supply one- way gas flow. A transparent plastic box (20 L (cid:3) 20 W (cid:3) 6 H cm) was used as the anesthetizing chamber, with three holes for gas inflow, gas outflow, and gas monitoring. A heating-pad was placed un- derneath the anesthetizing chamber to keep mice warm during anesthesia. Sevoflurane anesthesia on pregnant mice in this study was strictly performed by the protocols of previous study [10], in which arterial blood pressure and blood gas analysis were demonstrated within normal limits. The pregnant mice retained spontaneous respiration during inhalational anesthesia. Sevo- flurane was washed out with pure oxygen for 15 min, and the pregnant mice with right reflex were put back to home cages.

2.3. Social apparatus

The three-chambered social box (40L (cid:3) 60W (cid:3) 22H cm) with two enclosures (7D (cid:3) 15H cm) was used for social interaction test (Fig. 1AeC). An improved video-tracking system programed by ANY-maze (Stoelting Co., USA) was used to capture the movement of mouse. Given the testing mouse initiates social approaching to the stranger mouse by nose-to-nose or nose-to-tail sniffing (Fig. 1D), the animal’s head was tracked by the video-tracking system. Four behavioral parameters was automatically measured by ANY-maze program, including the time sniffing at the enclosure and number of sniffs at the enclosure, the time exploring in the side-chamber and number of entries into side chamber. Specifically, “at the enclosure” is defined as the mouse head entering an area of 3 cm around the enclosure.

2.4. Social interaction test

The offspring mice (N ¼ 17 Control, 9 males and 8 females; N ¼ 14 Sevoflurane, 9 males and 5 females) were tested at one- and two-month-old (i.e., the juvenile and early-adult age). In advance, the testing mouse was housed single for 1-h isolation in the behavioral room. The stranger mice were the identical background, same gender and similar age as the testing mouse, and they had exactly no contact before. Social interaction test is composed of three 10-min sessions of habituation, sociability, and preference for social novelty. Firstly, the testing mouse was allowed to freely explore in social box with two doorways opening. Next, an unfa- miliar conspecific (Stranger 1) was introduced into one enclosure, and the testing mouse was allowed to sniff the stranger 1 or explore the empty enclosure (Fig. 1E, G). After that, another unfamiliar conspecific (Stranger 2) was introduced into the other enclosure, and the testing mouse was allowed to sniff the stranger 1 and stranger 2 (Fig. 1F, H). Placement of the stranger 1 on the left or right side was systematically altered between trials, and social apparatus was cleaned after each trial to minimize olfactory disturbance.

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2.5. Statistical analysis

Data were shown as Mean ± SD. Graphpad Prism 5.0 software (San Diego, USA) was used for statistical analyses. Social data ob- tained from the left and right side were mutually exclusive in each 10-min session and they were normally distributed by Kolmogorov-Smirnov tests. Therefore, two-tailed paired t-test was used to compare the side preferences (stranger 1 vs. the opposite). Two-way repeated measures (RM) ANOVAs were used to analyze the interaction effects of treatment (control or sevoflurane) (cid:3) side (stranger 1 or the opposite). Based on the preliminary study, a sample size of more than 5 (sociability) and 13 (preference for so- cial novelty) could lead to a 90% power to detect a difference in side preference with 5% type I error. P values less than 0.05 (*), 0.01 (**) and 0.001 (***) were considered statistically significant.

3. Results

3.1. Maternal anesthesia with sevoflurane induced abnormal sociability in the offspring mice at one-month-old

The offspring mice in the control showed normal sociability, as proved by taking more time sniffing (Fig. 2A left, 167.7 ± 55.4 vs. 102.5 ± 35.4 s, P ¼ 0.001) and sniffing more frequently (Fig. 2B left, 42.9 ± 16.2 vs. 27.9 ± 9.1, P ¼ 0.0078) at the enclosure containing the stranger 1, as compared to the empty enclosure. Meanwhile, these testing mice spent more time exploring in the chamber with stranger 1 than in the empty chamber (Fig. 2C left, 298.5 ± 60.7 vs. 215.0 ± 45.8 s, P ¼ 0.0034). However, the offspring mice undergoing in-utero exposure to sevoflurane showed no side preference be- tween the stranger 1 and empty side, in terms of the time sniffing (Fig. 2A right, 108.5 ± 25.4 vs. 108.2 ± 44.0 s, P ¼ 0.9876) or the number of sniffs (Fig. 2B right, 43.2 ± 11.7 vs. 44.4 ± 12.9, P ¼ 0.8089) at the enclosure, or the time exploring in the chamber (Fig. 2C right, 240.2 ± 42.5 vs. 237.5 ± 50.7 s, P ¼ 0.9122).

In addition, two-way ANOVAs showed the significant interaction effects of treatment (control or sevoflurane) (cid:3) side (the stranger 1 or empty side), in terms of the time taken sniffing (Fig. 2A, F ¼ 7.7070, P ¼ 0.0095), the number of sniffs (Fig. 2B, F ¼ 5.3030, P ¼ 0.0287) and the time spent exploring (Fig. 2C, F ¼ 5.4560, P ¼ 0.0266). As for the number of entries into the chamber, the offspring mice in either group displayed no significant differences between two sides (Fig. 3D), which indicated the similar probabilities of exploration in the left and right chamber. Together, these data suggested that maternal anesthesia with 2.5% sevoflurane could induce the socia- bility deficit in their offspring mice at juvenile age.

3.2. Maternal anesthesia with sevoflurane induced abnormal preference for social novelty in the offspring mice at one-month-old

The offspring mice in the control showed normal preference for social novelty, as evidenced by taking more time sniffing (Fig. 2E left, 92.9 ± 33.5 vs. 193.6 ± 61.1 s, P < 0.0001) and sniffing more frequently (Fig. 2F left, 26.7 ± 6.8 vs. 45.6 ± 20.7, P ¼ 0.0013) at the enclosure containing stranger 2, as compared to the stranger 1. Meanwhile, these testing mice spent more time exploring in the chamber with stranger 2 than in the chamber with stranger 1 (Fig. 2G left, 194.5 ± 33.4 vs. 323.8 ± 54.5 s, P < 0.0001). However, the offspring mice undergoing in-utero exposure to sevoflurane showed no side preference between the stranger 2 and stranger 1 mouse, in terms of the time sniffing (Fig. 2E right, 92.1 ± 52.2 vs. 126.7 ± 50.8 s, P ¼ 0.1502) or the number of sniffs (Fig. 2F right, 29.1 ± 12.5 vs. 35.0 ± 11.2, P ¼ 0.2354) at the enclosure, or the time exploring in the chamber (Fig. 2G right, 204.8 ± 77.5 vs. 286.0 ± 88.6 s, P ¼ 0.0785).

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Fig. 1. Social interaction test in the three-chambered social box. (A) Schematic view of the three-chambered social box with two video-cameras hung right above two enclosures. (B) Schematic view of two enclosures in the left and right chambers. (C) One testing mouse is exploring in the social box with two doorways opening. (D) One testing mouse is sniffing the stranger mouse in the manner of nose-to-nose or nose-to-tail. (E) One testing mouse shows normal sociability as proved by preferring the stranger 1 mouse to the empty enclosure. (F) The testing mouse shows normal preference for social novelty as evidenced by preferring the stranger 2 to stranger 1 mouse. (G) One testing mouse shows impaired sociability as proved by no side preference between the stranger 1 mouse and the empty enclosure. (H) The testing mouse shows impaired preference for social novelty as evidenced by no side preference between the stranger 2 and stranger 1 mouse. Unit of dimension: millimeters. E ¼ the empty enclosure, S1 ¼ Stranger 1, S2 ¼ Stranger 2.

Additionally, two-way ANOVAs showed the significant interac- tion effect of treatment (control or sevoflurane) (cid:3) side (stranger 2 or stranger 1) in terms of time taken sniffing at the enclosure (Fig. 2E and F ¼ 5.248, P ¼ 0.0294). As for the number of entries into the chamber, the offspring mice in either group displayed no sig- nificant differences between two sides (Fig. 2H), which reflected the equal opportunities of exploration in the left and right chamber. Together, these data suggested that maternal anesthesia with 2.5% sevoflurane could impair the preference for social novelty in their offspring mice at juvenile age.

showed normal sociability, as evidenced by taking more time sniffing the stranger 1 over the empty enclosure (Fig. 3A right, 145.6 ± 33.2 vs. 76.0 ± 31.8 s, P ¼ 0.0001). This recovery of sociability was sup- ported by the number of sniffs at the enclosure (Fig. 3B right, 57.0 ± 16.9 vs. 35.7 ± 6.2, P ¼ 0.0009) and the time spent exploring in the chamber (Fig. 3C right, 305.0 ± 43.2 vs. 185.1 ± 35.7 s, P < 0.0001). In addition, two-way ANOVAs detected no interaction effect of treatment (cid:3) side in either parameter (Fig. 3AeC), which supported the recovery of sociability in a certain extent. Collectively, these data suggested that the offspring mice exposed to sevoflurane in-utero could retrieve normal sociability at early-adulthood.

3.3. The offspring mice exposed to sevoflurane in-utero retrieved normal sociability at two-month-old

The offspring mice undergoing fetal exposure to sevoflurane

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Fig. 2. The offspring mice undergoing in-utero exposure to sevoflurane show abnormal sociability and impaired preference for social novelty at one-month-old. The offspring mice exposed to sevoflurane in-utero show no side preference between the stranger 1 mouse and the empty side, in terms of time sniffing at the enclosure (A, right), number of sniffs (B, right), and time exploring in the chamber (C, right). Additionally, these offspring mice show no side preference between the stranger 2 and stranger 1 mouse, in terms of time sniffing at the enclosure (E, right), number of sniffs (F, right), and time exploring in the chamber (G, right). As for the number of entries into chamber, there are not significant differences between two sides in the session of either sociability (D) or preference for social novelty (H). Data are expressed as Mean ± SD. N ¼ 17 Control and 14 Sevoflurane. **P < 0.01, ***P < 0.001.

3.4. The offspring mice exposed to sevoflurane in-utero remained abnormal preference for social novelty at two-month-old

The offspring mice undergoing fetal exposure to sevoflurane

showed again no side preference between the stranger 2 and stranger 1 mouse, in terms of the time sniffing (Fig. 3E right, 100.6 ± 29.3 vs. 118.0 ± 47.9 s, P ¼ 0.3269) or the number of sniffs (Fig. 3F right, 42.9 ± 15.6 vs. 52.2 ± 14.1, P ¼ 0.1074) at the enclosure,

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Fig. 3. The offspring mice undergoing in-utero exposure to sevoflurane retrieve normal sociability, but remained abnormal preference for social novelty at two-month-old. The offspring mice exposed to sevoflurane in-utero take more time sniffing (A, right) and sniff more frequently (B, right) at the enclosure containing stranger 1, and they spend more time exploring in the chamber with stranger 1 (C, right), as compared to the empty side. However, these offspring mice show no side preference between the stranger 2 and stranger 1 mouse, in terms of time sniffing at the enclosure (E, right), number of sniffs (F, right), and time exploring in the chamber (G, right). As for the number of entries into chamber, there are not significant differences between two sides in the session of either sociability (D) or preference for social novelty (H). Data are expressed as Mean ± SD. N ¼ 17 Control and 14 Sevoflurane. *P < 0.05, ***P < 0.001.

or the time exploring in the chamber (Fig. 3G right, 248.7 ± 64.6 vs. 250.7 ± 67.3 s, P ¼ 0.9558). Collectively, these data suggested that the offspring mice exposed to sevoflurane in-utero could not re- covery the normal preference for social novelty at early-adulthood,

indicating that maternal anesthesia with 2.5% sevoflurane might cause the long-term impairment of social memory in offspring mice.

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4. Discussions

Clinical anesthesia facilitates a variety of surgical procedures by bringing patients into an unconscious and painless state, which is usually regarded as a safe and reversible process [11]. However, it may not be the truth in two extremes of life, including the pediatric and geriatric patients [12,13]. A great number of pregnant women are receiving non-obstetric surgeries and fetal intervention pro- cedures under general anesthesia [1]. As many anesthetic agents are lipophilic, they can easily cross placenta and cause fetal expo- sure to anesthetics. Several studies have suggested anesthetic- induced developmental neurotoxicity, ranging from human em- bryonic stem cells in vitro to rodents and non-human primates in vivo [14e18]. It was reported that sevoflurane anesthesia in pregnant mice on gestation day 14 induced the learning and memory impairment in offspring mice [10]. Therefore, we anes- thetized the pregnant mice on gestational day 14, and tested social interaction behaviors of the offspring mice at one- and two-month- old. As a result, we found that maternal anesthesia with 2.5% sev- oflurane for 2 h was able to induce social deficits in offspring mice. In recent decades, children with autism spectrum disorders are largely increasing [7,8,19]. Autism is clincally diagnosed by social interaction deficit, communicative impairment, and repetitive stereotyped behaviors [20e22]. As a core symptom of autism, many preclinical studies were conducted to determine the mechanism of social interaction deficit [23,24]. A three-chambered social para- digm is well-designed to test social behaviors in mouse model [25,26]. Two video-cameras were hung right above two enclosures, which could montage two video-images and capture the moment of testing mice in ANY-maze program.

In this study, we examined two biological profiles of testing mice, including sociability and preference for social novelty. In detail, sociability, reflecting social affiliation, is primarily judged by the testing mouse taking more time sniffing the stranger 1 over the empty enclosure. Similarly, preference for social novelty, reflecting social recognition memory, is largely judged by the testing mouse taking more time sniffing the stranger 2 over the stranger 1. In early studies, side preferences were mainly determined by the time spent exploring in the left or right chamber [25,27]. The testing mice might spend much time wandering in side chambers, instead of directly interacting with the stranger mouse. Then, the time sniffing the stranger mouse was used to reflect side preference in social studies [22,24,28e30]. Meanwhile, the number of sniffs acted as an auxiliary parameter, like the entries into open arms in elevated plus maze [5,31,32].

In this study, we found that the offspring mice undergoing in- utero exposure to sevoflurane showed abnormal sociability at ju- venile age, whereas these offspring mice retrieved normal socia- bility at early-adulthood. The disturbance of sociability in offspring mice displayed in a time-dependent manner, and the retrieving of sociability might be explained by an environmental stimuli. It was reported ameliorate sevoflurane-induced neurotoxicity and reverse learning and memory impairment in mice [10,33].

that

environmental

enrichment

can

In contrast, the offspring mice exposed to sevoflurane in-utero showed abnormal preference for social novelty at juvenile age, and these mice remained this abnormality at early-adulthood. This long-term impairment of social recognition memory was in line with sevoflurane-induced impairment in learning and memory, as indicated by water-maze task or fear-conditioning test [10,33,34]. Notably, sevoflurane anesthesia in this study was conducted by the protocols of previous studies, in which blood gas analysis denied any hypoxemia in anesthetized mice [10,35]. Admittedly, this study has several limitations. Firstly, we did not investigate social inter- action behaviors of the offspring mice at more time points. Given

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the recovery of sociability at two-month-old, it was possible that the testing mice undergoing in-utero exposure to sevoflurane could regain normal preference for social novelty in later life or amelio- rated by environmental stimuli [10]. However, our findings have detected the detrimental effects of in-utero exposure to sevo- flurane on social behaviors of offspring mice. Secondly, it should be cautious to extrapolate our findings in mice to human being. Given that the gestational period is 21 days in mice, the anesthesia duration of 2 h in mice (nearly 27 h in humans) is much longer than the average time of sevoflurane anesthesia in humans. In addition, the sequence and timing of neurodevelopmental processes are different between species. For instance, the neurogenesis and neural migration is predominant in the 2nd trimester for humans, but in the 3rd trimester for rodents [1]. Thirdly, we had no idea of whether the anesthetized dams might have difficulties in fostering pups. To rule out this confounding factor, we will arrange cross- nursing between the anesthetized and control dams in future study. Finally, we did not investigate the underlying mechanisms of social like the altered expression of special receptor proteins in developing brain. How- ever, we will explore the detailed mechanism of social deficits in offspring mice based on the current observations, and determine specific brain regions including the anesthetic-related GABA metabolism and social memory-related NMDA expression [5].

interaction deficits in offspring mice,

In conclusion, maternal anesthesia with sevoflurane during the interaction deficits in the mid-gestation could induce social offspring mice. In particular, the sociability of the offspring mice could be abnormal at juvenile age, and it could return normally at early-adulthood. However, the preference for social novelty of these mice could be impaired for much longer time.

Declaration of competing interest

The authors declare no conflict of interest.

Acknowledgements

This study was supported by grants from Natural Science

Foundation of China (81471835).

Appendix A. Supplementary data

Supplementary data to this article can be found online at

https://doi.org/10.1016/j.bbrc.2021.03.063.

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