Particulate matter (PM) is one of the most widespread and harmful air pollutants, consisting of a complex mixture of airborne particles and various chemicals, such as organic chemicals, transition metal oxides, acids, dust, and sulfates (Daellenbach et al., 2020). The toxicity of PM is closely related to the properties of the particles, such as the composition, quantity, mass, shape, size, and surface area concentration (Gao et al., 2020). PM2.5 is defined as the aerodynamic diameter of less than 2.5 μm. PM2.5 has been proven to penetrate into the alveoli through inhalation, depositing on the alveolar wall and eventually enter the systemic blood circulation, leading to negative effects on primary organs, including the lung, cardiovascular, immune system, nervous system and genital system (Chu et al., 2019; Yue et al., 2019; Qiu et al., 2018). Moreover, the respirable particles have been classified as a known human carcinogen by the International Agency for Research on Cancer, with a growing number of studies uncovering the adverse effects in human and animals (Loomis et al., 2013; Jeong et al., 2021). Globally, China is considered to be one of the most severely polluting countries by PM2.5 as a result of the rapid economic development it has experienced. Long-term exposure to PM2.5 is estimated to cause around one million premature deaths annually (Xue et al., 2019). In response, the Chinese Government enacted a series of strict laws in 2013 to combat environment pollution (Huang et al., 2018). As a result, the annual average PM2.5 level in China dropped to 45.5 μg/m³ in 2017, compared to 67.4 μg/m³ in 2013 (Zhang et al., 2019). However, according to the air quality monitoring system of the United Nations Environment Program (UNEP) in cooperation with the Swiss technology company IQAir (https://www.iqair.com/), the 2021 average PM2.5 concentration in China was still 6.5 multiples of the World Health Organization’s annual air quality guideline value. PM2.5 pollution continues to be significant due to economic development and geographical conditions especially in the northern plains of China (Jin et al., 2022).

Due to the toxic action of PM2.5, mounting evidence attests that exposure to PM2.5 during pregnancy leads to a variety of adverse pregnancy outcomes, such as placental dysfunction, ovarian dysfunction, impaired fetal development, lower birth weights, preterm births, reduced gestational age, congenital disability, and stillbirth (Zhou et al., 2020; Bekkar et al., 2020; Leung et al., 2022; Wang et al., 2017). Exposure to PM2.5 during gestation can also have adversely effects on the health of the offspring, such as cardiovascular disease, respiratory damage, and neurodevelopmental impairment, as it has been reported that the etiology of many adult diseases may originate in the fetal period (Hart et al., 2021; Lavigne et al., 2016). However, most of the present research on PM2.5 in adverse obstetric outcomes is focused on the epidemiological aspects, and thus the underlying mechanisms are not yet clear. The placenta is the most important organ from the mother to deliver oxygen and nutrients to the fetus to support its regular growth. Additionally, the placenta is uniquely able to adapt to environmental changes through active metabolism to guarantee the needs of the mother and fetus (Blake et al., 2020). When exceeding the regulatory range of the placenta, PM2.5 can adversely affect the development of the placenta and the fetal growth (Iyengar and Rapp, 2001). In in vivo human placenta perfusion studies, the PM2.5 could enter the circulating bloodstream through the alveolar wall and deposited in the placenta, thus negatively affecting or even destroying placental function and creating a potential risk to the fetus (Martens et al., 2017; Michikawa et al., 2022). Previous studies have found that urban PM2.5 affects the function of the placenta, such as placental thrombosis, chorioamnionitis, and inadequate trophoblast formation and invasion, which adversely impacts fetal growth by interfering with mother-fetus interactions (Martens et al., 2017; Ghosh et al., 2021; Guo et al., 2021). PM2.5 exposure during pregnancy also induces abnormal alterations in the placental genome DNA methylation profile, which is primarily concentrated in genes associated with reproductive development, immune regulation and material metabolism (Nawrot et al., 2018). Moreover, Nääv Å et al. demonstrated that PM2.5 caused placental trophoblast cytotoxicity, impaired hormone regulation, inflammation and oxidative stress (Nääv et al., 2020). However, as a significant target of PM2.5 stimulation, the underlying molecular mechanisms associated with placental trophoblastic PM2.5 exposure have not been completely elucidated.

Metabolism of xenobiotics by cytochrome P450 signaling pathway is mainly responsible for the intracellular degradation of exogenous substances such as polycyclic aromatic hydrocarbons (PAHs), halogen-containing organic compounds and heterocyclic amines (Lu et al., 2021). As a cytochrome P450 (CYP) enzyme, CYP1A1 plays an essensial role in the metabolism of endogenous substrates (such as hormones 17β estradiol [Kisselev et al., 2005], melatonin [Goh et al., 2021], inflammatory mediators arachidonic acid [Sroczyńska et al., 2022] and eicosapentaenoic acid [Schwarz et al., 2004]) and exogenous substrates (such as PAHs [Chen et al., 2022b], doxin [Molcan et al., 2017], and halogenated aromatic hydrocarbons [Kasai et al., 2008]). Many PAH compounds, such as benzo[a]pyrene, are not toxic in themselves and only become cytotoxic and carcinogenic after activation by CYP1A1. For example, CYP1A1 converts benzo[a]pyrene into the carcinogenic 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene by multiple oxidation steps which causes severe oxidative damage to cells by generating excess reactive oxygen species (ROS) (Zajda et al., 2019; Gastelum et al., 2020). It has been proven that PM2.5 contributes to the increase of CYP1A1 in human neutrophils, bronchial epithelial cells, and alveolar macrophage due to the adsorption of adsorbs aromatic hydrocarbons on their surface, which in-turn inducing oxidative stress, inflammatory responses, and apoptosis (Chen et al., 2019; Van Winkle et al., 2015; Abbas et al., 2009). Yue C et al. also found that PM2.5 induced malformations in zebrafish embryonic heart development by activating CYP1A1 (Yue et al., 2017). However, very little research has examined the role of CYP1A1 in PM2.5 induced placental dysplasia and adverse pregnancies.

Our previous epidemiological study identified that prenatal exposure to increased PM2.5 could shorten the gestation period and increased the risk of preterm birth in Jinan, the capital of Shandong Province, China (Wang et al., 2022). Jinan is a large city in northern China, with an area of 7.6×10³ km² and a population of more than 9 million, and its geographical structure is a typical basin texture surrounded by mountains on 3 of its 4 sides, hindering the dispersion of environmental pollutants. In this study, we collected PM2.5 from the atmosphere in the urban area of Jinan to investigate its effects on the placenta and on pregnancy outcomes. First, scanning electron microscope (SEM) and energy dispersive spectroscopy (EDS) were used to analyze the morphology of PM2.5 particles and the elemental composition. We then investigated the effects of PM2.5 on pregnancy outcomes, placental function of mice and trophoblast cell line HTR8/SVneo. Subsequently, we performed a comprehensive analysis of the transcriptional landscape of PM2.5-exposed trophoblast cells by RNA-Seq. We found that the activation of the cytochrome P450 pathway was most prominent after PM2.5 exposure and verified that PM2.5 could trigger oxidative stress resulting in mitochondrial apoptosis, with CYP1A1 being the key gene involved in this process. Based on bioinformatics analysis, we further found for the first time that PM2.5 activated the transcription factor KLF9, which transcriptionally promoted the expression of CYP1A1, thereby modulating oxidative stress damage and mitochondrial apoptosis. Overall, this research elucidated the mechanism of PM2.5-mediated trophoblast apoptosis and adverse pregnancy outcomes, suggesting that the KLF9/CYP1A1-related pathway could be a promising target for clinical prevention and treatment.

Exposure to PM2.5 during pregnancy has been widely reported to result in an increased risk of adverse outcomes such as gestational hypertension, fetal growth restriction, preterm birth and stillbirth. Studies in Florida have shown that the closer one lives to a PM2.5 emitting plant, the greater the risk of low birth weight in the fetus (Salihu et al., 2012). A study of more than 350,000 newborns in Ohio found that exposure to PM2.5 even in late gestation resulted in stillbirths (Grippo et al., 2018). Studies conducted in Beijing and Shanghai suggested that PM2.5 exposure during pregnancy is strongly related to smaller ultrasound parameters of fetal growth. Similarly, our previous research analyzed the association between preterm birth and environmental air pollutants in Jinan, which revealed a strong correlation between preterm birth and PM2.5 (Wang et al., 2022). To investigate the impact of ambient PM2.5 on pregnancy in depth, we extracted PM2.5 from the atmosphere of Jinan and constructed a PM2.5-exposed pregnant mouse model using intratracheal perfusion in vivo. The selection of appropriate PM2.5 exposure dosage in mice was critical for our experiments. We combined the PM2.5 exposure level of pregnant women from the Jinan (Wang et al., 2022) (where we collected PM2.5 particles) with physiological indicators of mice (Vermillion et al., 2018), then multiplied by 100-fold uncertainty factor to obtain the corresponding PM2.5 exposure dosage during mice pregnancy. The 100-fold uncertainty factor ( =10 fold interspecies difference ×10 fold interindividual variation) is used to convert a no-observed-adverse-effect level (NOAEL) from an animal toxicity study to a safe value for human intake (ADI), which is the criteria for determining experimental dosages in toxicological studies involving animals. It was originally proposed, over 60 years ago, by Lehman and Fitzhugh, 1954, and still forms the basis of the uncertainty factors which are in use today. Also, the 100-uncertainty factor is considered one of the criteria for in vivo experiments in authoritative studies related to PM2.5 (Chen et al., 2022a; Zhang et al., 2018; Zhang et al., 2017). We found that PM2.5 caused different adverse pregnancy outcomes in mice, such as an increased rate of stillbirths, a reduced number of fetuses, and a reduced fetal size. Additionally, we revealed that PM2.5 caused placental oxidative stress damage and trophoblast apoptosis. In addition, we performed RNA-Seq analysis and verified that PM2.5 regulated CYP1A1-mediated oxidative stress and mitochondrial apoptosis via the transcription factor KLF9 in vitro, which resulted in structural damage and functional alterations to the placenta and contributes to a poor outcome of the pregnancy.

It is well known that the placenta is a vital organ for securing the growth and development of the fetus, and its dysfunction often results in adverse perinatal outcomes. The placenta is also the target for a multitude of environmental pollutants such as PAHs, heavy metals, microplastics, perfluoroalkyl substances, and trichloroethylene, which can accumulate in the placenta and disrupt its function, thereby affecting the survival and growth of the fetus (Vrooman et al., 2016). PM2.5 is a mixture of several environmental pollutants, and due to the small size, it can penetrate the alveoli and pass through the bloodstream to be deposited in the placenta, making the placenta an organ of interest for studying the impact of PM2.5 on pregnancy. Previous studies have identified that prenatal exposure to PM2.5 resulted in an increased odds of having a placental abruption, inflammation, and hypercoagulability with vascular thrombosis and imbalances of immune cells in the placenta (Ibrahimou et al., 2017; Liu et al., 2016). Further, we found that PM2.5-induced oxidative stress damage in mouse placenta was strongly demonstrated by a significant reduction in GSH and SOD levels, an elevation in MDA production, and decreased expression of antioxidant proteins, such as HO-1, GCLC, NQO-1, and SOD-1. The levels of apoptosis were also increased in the placental trophoblast cells, so we selected the HTR8/Svneo trophoblast cell line for PM2.5 cytotoxicity assays in vitro. HTR8/Svneo cells are perpetuated by the SV40 Tag and not only maintain many of the essential and key features of the parental cells, but are also devoid of any features of neoplastic transformation (Bilban et al., 2010; Dong et al., 2021). Therefore, HTR8/Svneo cells are a more suitable model for this study than choriocarcinoma BeWo, JEG-3, and JAR cells. In the present study, PM2.5 caused severe oxidative stress damage in HTR8/Svneo cells, as evidenced by decreased SOD and GSH levels, significantly elevated intracellular MDA and ROS levels, and decreased expression of antioxidant-related proteins. Consistently, previous studies have also reported that PM2.5 or particulate air pollution could cause trophoblast cytotoxicity, inflammation and oxidative stress (Nääv et al., 2020; Familari et al., 2019). However, its downstream signaling pathways and their potential mechanisms have not been explored in detail in previous studies. In the current study, we revealed that PM2.5 not only induced the induction of elevated intracellular ROS levels, but also significantly increased mitochondrial ROS levels. This resulted in a decrease in mitochondrial membrane potential, triggering the flow of cytochrome C from the mitochondria to the cytosol and inducing the downstream cell mitochondrial apoptosis. Our study demonstrated that exposure to PM2.5 induced oxidative stress in placental trophoblast, leading to mitochondrial apoptosis and impairment of cell biological functions.

In contrast to our results, many studies have found that PM2.5 did not trigger oxidative stress. For instance, Liu Y et al. found that PM2.5 evoked placental inflammation and hypercoagulability with vascular thrombosis but not oxidative stress in rats (Liu et al., 2016). Scientists may have reached these different conclusions because PM2.5 surfaces absorb different environmental pollutants. Studies have indicated that the morphological characteristics of PM2.5 are closely related to its components. For example, organic pollutant particles are irregularly clustered, fly ash particles from coal combustion were mostly spherical in shape, and construction particles were mostly sharp-edge (Ghadikolaei et al., 2020; Liu et al., 2009). SEM of the PM2.5 samples in this study showed that they primarily consisted of flocculent structures. Elemental composition by EDS revealed that the elements O, N, and C were prominent in the gathered PM2.5. These results, in addition to the presence of a chemical plant nearby the sampling site, strongly suggested that a large number of organic pollutants had adhered to the surface of the PM2.5 we collected. Studies have shown that the toxicological effects of PM2.5 on cells could depend on the pollutant composition of PM2.5. In particular, organic pollutants can lead towards the development of oxidative stress in cells. For example, PM2.5 containing benzo[b]fluoranthene, chrysene, and fluoranthene impair the antioxidant system of lung epithelial cells, leading to increased cellular ROS levels and reduced cellular activity Deng et al., 2013; exposure to PM2.5, which contains high concentrations of, metals, and polar organic compounds, can lead to elevated levels of 8-OHdG in the urine and elevated levels of oxidative stress Wei et al., 2009; motor vehicle exhaust in traffic congestion contributes to elevated levels of organic pollutants in PM2.5 levels, causing severe oxidative stress damage and genotoxicity to human lung cells (Oh et al., 2011). In the present study, we observed that PM2.5 exposure caused intracellular and mitochondrial oxidative stress. We speculated that this was due to the organic pollutants on the surface of PM2.5.

Mitochondria were involved in a wide range of critical cellular functions, including the oxidative phosphorylation of ATP synthesis and the metabolic degradation of sugars and lipids, and it is also damaged by a variety of environmental pollutants. PM2.5 can trigger oxidative stress damage to cells with increased levels of ROS, which in turn continues to damage mitochondrial membranes, further leading to increased release of cytochrome C from mitochondria and ultimately apoptosis. PM2.5 has been found to cause cellular mitochondrial damage in a variety of studies. For example, PM2.5 induced mitochondrial oxidative stress damage in hepatic stellate cells through the PINK1/Parking pathway, which led to cellular autophagy and liver fibrosis (Qiu et al., 2019). PM2.5 also induced an increase in ROS levels and a decrease in mitochondrial membrane potential in human bronchial epithelial cells, causing the cells to undergo mitochondrial apoptosis (Shan et al., 2022).A significant increase in PM2.5-exposed mitochondrial ROS was also found in macrophages, which inhibited M2 polarization and induced immune disorders (Zhao et al., 2016). In our study, it was apparent that the mitochondrial morphology of the cells was significantly altered, including a thickening and shortening of the cristae and a reduction in the volume. Importantly, Mito-SOX and JC-1 fluorescent probe staining revealed that PM2.5 induced an elevation in mitochondrial ROS and reduced mitochondrial membrane potential (MMP) in HTR8/SVneo cells. Moreover, mitochondrial-mediated endogenous apoptosis was also observed. Our results reinforced that PM2.5 promoted mitochondrial oxidative stress and mitochondrial apoptosis in trophoblast cells.

CYP1A1 is an important metabolic enzyme involved in the metabolism and degradation of PAHs (Ugartondo et al., 2021). It was found that CYP1A1 contributes to oxidative stress in cells. For example, CYP1A1 induction enhanced gefitinib-induced oxidative stress and apoptosis in A549 cells and was implicated with chronic obstructive pulmonary disease (Callaway et al., 2020). Furthermore, aromatic hydrocarbons in PM2.5 could increase the expression level of CYP1A1, inducing oxidative stress and inflammation in several cells, such as human bronchial epithelial cells (Gu et al., 2021), neutrophils (Vogel et al., 2016), and epithelial cells (Toydemir et al., 2021), amongst others. Activation of CYP1A1 mediates oxidative stress exacerbating the production and accumulation of toxic metabolic intermediates such as ROS and causes mitochondrial apoptosis (Zhao et al., 2020). In this study, RNA-Seq analysis and validation tests indicated that CYP1A1 in the cytochrome P450 pathway was critically involved in PM2.5-induced cellular damage. Knockdown of CYP1A1 expression not only abolished PM2.5-induced oxidative stress and mitochondrial apoptosis but also alleviated the disruption of cell biological functions via PM2.5.

Transcription factors play an important part in the modulation of the cytochrome P450 pathway. For example, AHR is an essential ligand-activated transcription factor of the cytochrome P450 pathway, controlling the expression of CYP1A1, CYP1B1, CYP1A2 and other genes in the cytochromes P450 family (Torti et al., 2021; Al-Dhfyan et al., 2017; Zhang et al., 2022; Jin et al., 2021). AHR could be activated by many environmental pollutants, including PM2.5 (Ren et al., 2020). Before the AHR is activated, it forms a complex with two heat shock protein 90 (Hsp90) molecules in the cytoplasm. Following activation, the AHR breaks free from binding and enters the nucleus, forming a dimer with the AHR nuclear translocator protein (Arnt) and binding to an enhancer to form a xenobiotic response element (XRE) involved in the regulation of cytochromes P450 family genes. In addition, multiple studies have found that intracellular CYP1A1 expression is regulated by various transcription factors, such as upstream stimulatory factor 1 (USF1), and Nuclear Factor erythroid 2-Related Factor 2 (Nrf2) (Familari et al., 2019; Kyoreva et al., 2021; Takahashi and Kamataki, 2001). In our study, actinomycin D was used to show that PM2.5 regulates CYP1A1 expression at transcriptional initiation rather than by modifying its mRNA stability. Then we used three databases, JASPAR, HOCOMOCO MoLoTool, and hTFtarget, to predict the upstream transcription factors of CYP1A1 and compared them with the RNA-Seq sequencing results. As a result, we found that KLF9 emerged as the only potential transcriptional regulator of CYP1A1.

Kruppel-like factor 9 (KLF9), also named Basic Transcription Element Binding protein 1 (BTEB1), is a transcription factor regulates development, differentiation and apoptosis by binding to GC-rich sites via three C₂H₂-type zinc fingers. KLF9 transcriptionally activates or represses downstream genes depending on the cellular environment and partner co-regulators. For example, KLF9 activated the gluconeogenic program in primary hepatocytes by directly binding to the PAC1A promoter (Cui et al., 2019). KLF9 also regulates p53 gene expression positively by binding to the GC box proximal to the P53 promoter in HepG2 and SK-Hep1 cells (Sun et al., 2014). Conversely, KLF9 works as a transcriptional repressor inhibiting AKT transcription in prostate cancer cells, thereby suppressing the growth of PCa cells (Shen et al., 2014). There are very few studies on the relationship between KLF9 and CYP1A1, those that have assessed this have only reported it in rat liver cells. KLF9 was characterized as a trans-repressor of CYP1A1 gene in rat liver (Imataka et al., 1992). Importantly, our study has revealed that KLF9 exerted a positive regulatory effect on CYP1A1 in humans, which is in contrast to its previously reported transcriptional repression of CYP1A1 in rat liver. Furthermore, we identified the –64 bp to –49 bp region of the CYP1A1 promoter, GAAGGAGGCGTGGCC, was the binding site of the KLF9 protein. In support of the above findings, we observed that KLF9 expression in pregnancy placental tissue was positively correlated with CYP1A1, which further supports that KLF9 regulates CYP1A1 expression in trophoblasts. Moreover, KLF9 knockdown was able to reverse the oxidative stress and mitochondrial apoptosis caused by PM2.5, as well as the impaired proliferation, migration, invasion, and tube formation of trophoblasts. Indeed, KLF9 has been consistently reported to exacerbate oxidative stress damage in cells by disrupting ROS scavenging. For example, the knockdown of KLF9 in cardiomyocytes protects them from ischemic injury (Yan et al., 2019), and a KLF9-dependent increase in ROS can result in cell death in lung tissues (Zucker et al., 2014) and induce proliferation of melanoma (Bagati et al., 2019). There are also numerous studies indicating the critical role of KLF9 in toxicological research. For example, Yue Gu et al. found that Klf9 is involved in BLM-induced pulmonary toxicity in human lung fibroblasts, Daqian Yang et al. identified that KLF9 was essential in allicin resisting against arsenic trioxide-Induced hepatotoxicity, but little is known regarding its role in the occurrence of PM2.5-induced toxicological processes. Here, our study not only identified KLF9 as a transcription factor of CYP1A1 for the first time in humans, but also revealed a novel mechanism of oxidative stress in trophoblast cells induced by PM2.5, providing a new target for future clinical treatment.

Due to the limitations of our laboratory, our current research unavoidably possesses certain deficiencies. For instance, the administration of intratracheal instillation may induce adverse effects on pregnant mice. In the future study, we will collaborate with other research institutions to employ meteorological and environmental animal exposure system that not only mitigate harm to pregnant mice but also more realistically simulate the process of inhaling PM2.5 particles in humans. We also lack the utilization of primary cells in our in vitro experiments. Furthermore, our current article lacks investigations on the regulatory effect of PM2.5 on KLF9. These limitations should be further investigated in future.

In conclusion, we collected PM2.5 from the urban atmosphere of Jinan city and found that it caused various adverse gestational outcomes in mice as well as impaired placental structure and increased placental trophoblast apoptosis. In the trophoblast cell line HTR8/SVneo, PM2.5 induced oxidative stress damage and mitochondrial apoptosis, and affected cell proliferation, invasion, migration and angiogenesis. The KLF9/CYP1A1 transcriptional axis was involved in PM2.5-induced oxidative stress and mitochondrial apoptosis. This is not only the first study to demonstrate the molecular mechanism of PM2.5-induced oxidative stress damage in trophoblast cells, but also the first time to identify that KLF9 acts as a transcriptional factor positively modulating the expression of CYP1A1 in humans.

The RNA sequencing data were deposited into the Gene Expression Omnibus (GEO) database (accession number: GSE237795).

1. 1. Shuxian L
   2. Lingbing L
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   (2023) NCBI Gene Expression Omnibus

   ID GSE237795. PM2.5 leads to adverse pregnancy outcomes by inducing trophoblast oxidative stress and mitochondrial apoptosis via KLF9/CYP1A1 transcriptional axis.

   https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE237795

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Author details

1. Shuxian Li

   Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China

   Contribution

   Conceptualization, Data curation, Writing – original draft, Funding acquisition

   Contributed equally with

   Lingbing Li

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2601-6126

2. Lingbing Li

   The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

   Contribution

   Formal analysis, Supervision

   Contributed equally with

   Shuxian Li

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0640-8328

3. Changqing Zhang

   Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China

   Contribution

   Writing – review and editing

   Competing interests

   No competing interests declared

4. Huaxuan Fu

   Jinan Environmental Monitoring Center of Shandong Province, Jinan, China

   Contribution

   Resources

   Competing interests

   No competing interests declared

5. Shuping Yu

   School of Public Health, Weifang Medical University, Weifang, China

   Contribution

   Data curation

   Competing interests

   No competing interests declared

6. Meijuan Zhou

   Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China

   Contribution

   Validation

   Competing interests

   No competing interests declared

7. Junjun Guo

   Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China

   Contribution

   Software

   Competing interests

   No competing interests declared

8. Zhenya Fang

   Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China

   Contribution

   Validation

   Competing interests

   No competing interests declared

9. Anna Li

   Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China

   Contribution

   Investigation

   Competing interests

   No competing interests declared

10. Man Zhao

    Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

11. Meihua Zhang

    Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China

    Contribution

    Supervision, Funding acquisition, Validation

    For correspondence

    meihua2013@163.com

    Competing interests

    No competing interests declared

12. Xietong Wang

    1. Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China
    2. Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China

    Contribution

    Project administration, Supervision

    For correspondence

    xietong789656@163.com

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8811-3792

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