Increased levels of APOA4 in cord blood in maternal major depressive disorder

doi:10.21203/rs.3.rs-3262467/v1

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Increased levels of APOA4 in cord blood in maternal major depressive disorder

https://doi.org/10.21203/rs.3.rs-3262467/v1

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Background: Prenatal maternal depression affects neurodevelopment in the offspring. This study aimed to investigate the cord blood profile of mothers with major depressive disorder (MDD).

Methods:Liquid chromatography-tandem mass spectrometry (LC-MS) was performed using umbilical cord blood from women with MDD and gestational age-matched controls (Control). The levels of several differentially expressed proteins in cord blood were compared between the two groups using enzyme-linked immunosorbent assays.

Results: The proteomic profiles of cord blood differed between the MDD and Control groups, including the pathways on regulation of plasma lipoprotein particle levels and synapse organisation. Only apolipoprotein A4 (APOA4) levels were significantly increased in the cord blood of the MDD group. APOA4 levels in the maternal serum were also significantly higher in the MDD group than in the control group (p <0.05). APOA4 levels were higher in cord blood than in maternal serum.

Conclusions: APOA4, a biomarker of depression, was increased in neonates at birth exposed to maternal MDD in utero. Thus, our results suggest that the risk of MDD in children born to MDD mothers might be related to increased APOA4 levels at birth, although further studies are required.

apolipoprotein A4

cord blood

major depressive disorder

pregnancy

Major depressive disorder (MDD) is common in women of reproductive age and affects maternal mental health during pregnancy and the postpartum period; a history of MDD increases the risk of suicidal ideation [1]. The importance of perinatal mental health has been recognised worldwide. Recent evidence has shown that exposure to maternal immune activation (MIA) results in neurodevelopmental disorders in the offspring, and various factors, including obesity, asthma, autoimmune disease, infection, and psychosocial stress are considered triggers of MIA [2]. Several systematic reviews have shown that antenatal maternal depression, anxiety, and stress in utero have been shown to increase behavioural and mental health problems later in life [3–7]. Most human studies have used magnetic resonance imaging (MRI). Antenatal maternal depression has a significant impact on the neurodevelopment of offspring including accelerated aging [8, 9], changes in the frontal and temporal lobes, and increase in amygdala volume [7]. Differential DNA methylation has also been observed in the cord blood of neonates exposed to antenatal maternal depression [10–12]. Many studies have suggested that the abnormal functioning of hypothalamic–pituitary–adrenal (HPA) axis is involved in pathological mechanisms [7]. However, it remains to be fully understood.

To prevent adverse outcomes in children born to mothers with MDD, the underlying pathological mechanisms must be clarified. In the present study, the proteome profiles of cord blood from mothers with MDD were compared with those from healthy control mother.

Participants

The study included participants that underwent singleton term-deliveries at the hospital between 2012 and 2019. Major depressive disorder (MDD, n = 5–10) and healthy controls (control, n = 5–10) were matched for maternal age, gestational age at birth, parity, and neonates’ sex.

Collection of clinical information and samples

The umbilical vein cord blood samples were obtained at birth and stored in vacuum blood collection tubes at 4°C until isolation. The serum was isolated within 16–24 h after blood collection, and then the samples were stored at − 80°C.

Mass spectrometry (MS)

MS was performed as previously reported [13–15]. Briefly, the proteins were subjected to trypsin digestion for 16 h at 37°C following reduction and alkylation. The resulting peptides were analysed using an Orbitrap Fusion mass spectrometer (ThermoFisher Scientific Inc., Waltham, MA, USA) coupled to an UltiMate3000 RSLCnano LC system (Dionex Co., Amsterdam, Netherlands). The LC system utilised a nano HPLC capillary column, 150 mm × 75 µm i.d (Nikkyo Technos Co., Japan). Reverse-phase chromatography was performed using a linear gradient (0 min with 5% B; 100 min, 40% B) of solvent A (2% acetonitrile with 0.1% formic acid), and B (95% acetonitrile with 0.1% formic acid) at 300 nL/min. Prior to MS/MS analysis, a precursor ion scan was performed using a mass-to-charge ratio (m/z) of 400–1,600. Tandem MS was conducted with an isolation width of 1.6 m/z using a quadrupole, HCD fragmentation with a normalised collision energy of 35%, and rapid scan MS analysis in the ion trap. Tandem MS was performed with a normalised collision energy of 35%. Only precursors with charge states between 2 and 6 were sampled for MS2. The dynamic exclusion time was set to 15 s and the tolerance was set to 10 ppm. The instrument was operated in top-speed mode with 3-second cycles.

Proteome Discoverer 1.4 (Thermo Fisher Scientific Inc.) in conjunction with the MASCOT search engine was used for protein identification. The human protein database UniProt (release 2019_11) was used to identify peptides and proteins with a precursor mass tolerance of 10 ppm and fragment ion mass tolerance of 0.8 Da. Carbamidomethylation of cysteine was set as a fixed modification and oxidation of methionine was set as a variable modification. Two missed cleavages were detected by trypsinisation.

Proteomic analysis and visualization

Protein abundance with |log₂FC| > 1 in the MDD group compared to that in the control group was analysed. Based on these criteria, the proteins were identified as differentially expressed proteins (DEPs). Functional enrichment analysis was performed using Metascape 3.5 (accessed on 7 January 2021).

Enzyme-Linked Immunosorbent Assay (ELISA)

Titin (TTN, #OKEH01204; Aviva Systems Biology, San Diego, CA, USA), protocadherin-23 (DCHS2, #OKCA00787; Aviva Systems Biology), apolipoprotein A-IV (APOA4, #NBP2-68246; Novus Biologicals, Centennial, CO, USA), thrombospondin 1 (TSP1, #DTSP10; R&D Systems Inc., Minneapolis, MN, USA), apolipoprotein AI (APOA1, #ab189576; Abcam plc, Cambridge, UK), apolipoprotein B (APOB, #ab190806; Abcam plc), apolipoprotein E (APOE, #ELH-ApoE, RayBiotech, Inc, Norcross, GA, USA), and complement factor H (CFH, #ab252359; Abcam plc) were examined using ELISA kits. Serum samples were diluted 1:2 for the detection of TTN, 1:100 for TSP1, 1:250,000 for APOA1, 1:2000 for APOA4, and 1:1000 for APOB and APOE. The absorbance was measured at 450 nm using a multiple plate reader according to the manufacturer's protocol (Thermo ScientificTM MultiskanTM FC; ThermoFisher Scientific Inc.).

Statical analysis

Statistical analyses were performed using SPSS software version 28.0 (IBM, Armonk, NY, USA). Continuous variables with normal or non-normal distribution are shown as mean ± standard deviation (SD) or median [minimum – maximum] and were compared using Student’s t-test or Mann–Whitney U-test, respectively. Matched paired values of maternal and cord blood samples were compared using a paired t-test. The correlation coefficients (r) of each value between the maternal and cord blood samples were calculated using the Pearson's test. Categorical variables were expressed as numbers (%) and analysed using the chi-square test or Fisher’s exact test, as appropriate. Statistical significance was set at p < 0.05.

Participants

The participant characteristics are shown in Tables 1, 2, and S1. Maternal background, including age, pre-pregnancy BMI, smoking and drinking habits, and delivery methods, was similar between the MDD and Control groups. Neonatal characteristics were also not significantly different between the groups. However, two patients in the MDD group received psychotropics at delivery.

Table 1

Clinical characteristics of MDD and Control groups in a proteome analysis.
	MDD	Control
	n = 5	n = 5	p-value
Maternal characteristics
Age (years)	34.8 ± 2.8	34.8 ± 2.8	1.00
Pre-pregnancy BMI (kg/m²)	20.8 [18.9–9.6]	18.9 [15.1–23.5]	0.42
Gestational age at delivery (weeks)	39.3 [37.7–40.7]	39.9 [37.6–40.3]	1.00
Primipara	4 (80.0)	3 (60.0)	0.50
Married	4 (80.0)	5 (100.0)	0.50
Smoking during pregnancy	0 (0.0)	0 (0.0)	1.00
Drinking alcohol during pregnancy	0 (0.0)	0 (0.0)	1.00
Blood loss at delivery (ml)	927 [420–1238)	598 [460–1419]	0.84
Vaginal delivery	4 (80.0)	4 (80.0)	0.78
Psychotropics use at delivery	2 (40.0)	0 (0.0)	0.22
Neonatal characteristics
Male	4 (80.0)	4 (80.0)	0.78
Birth weight (g)	2839 ± 217	2980 ± 416	0.52
Apgar score at 5 min < 7	0 (0.0)	0 (0.0)	1.00
MDD, major depressive disorder; BMI, body mass index.

Table 2

Clinical characteristics of MDD and Control groups in ELISA.
	MDD	Control
	n = 10	n = 10	p-value
Maternal characteristics
Age (years)	33.1 ± 4.6	32.7 ± 3.9	0.84
Pre-pregnancy BMI (kg/m²)	20.8 [18.9–29.6]	19.2 [15.1–23.5]	0.39
Gestational age at delivery (weeks)	39.7 ± 1.0	39.3 ± 1.0	0.33
Primipara	8 (80.0)	5 (50.0)	0.18
Married	8 (80.0)	10 (100.0)	0.24
Smoking during pregnancy	0 (0.0)	0 (0.0)	1.00
Drinking alcohol during pregnancy	0 (0.0)	0 (0.0)	1.00
Blood loss at delivery (ml)	682 [327–1450]	603 [415–1419]	0.63
Vaginal delivery	9 (90.0)	7 (70.0)	0.29
Psychotropics use at delivery	3 (30.0)	0 (0.0)	0.11
Neonatal characteristics
Male	7 (70.0)	7 (70.0)	0.69
Birth weight (g)	2900 ± 296	2970 ± 355	0.64
Apgar score at 5 min < 7	0 (0.0)	0 (0.0)	1.00
BMI, body mass index.

Lipoprotein particle levels pathways changed in the MDD group

We detected 175 proteins with |log₂FC| >1 (88 upregulated and 87 downregulated proteins) in patient with MDD. The top 20 pathways with significant changes are shown in Fig. 1A. Regulation of plasma lipoprotein particle levels and synapse organisation were revealed as the altered pathways. In Fig. 1B, several proteins are shown in significantly changed proteins, including APOA4 [16, 17], CFH [18–20], TTN [21, 22], TSP1 [23–25], and DCHS2 [26–28], which are known to be related to mental dysfunction or neurodevelopment.

APOA4 induction in MDD cord blood

Five new participants have been added to the validation experiment (Table 2). Five proteins (Fig. 1B) were examined. APOA4 expression was significantly increased in the cord blood of patients with MDD (Fig. 2A, p < 0.05). However, the CFH and TSP1 levels were not significantly different between the two groups (Fig. 2B and C, respectively). In addition, DCHS2 and TTN were undetectable because their levels were low in the cord blood of both groups (data not shown).

The levels of other apolipoproteins in the cord blood, including APOA1, APOB, and APOE, were not significantly different between the MDD and Control groups (Fig. S1A-C).

APOA4 increased in MDD maternal blood

We examined whether APOA4 levels in the maternal blood also increased near delivery in the MDD group (Table S1). Maternal APOA4 levels near delivery in the MDD group were also significantly higher in those in the control group (Fig. 3A, p < 0.001). However, maternal APOA4 levels near delivery were significantly lower than those in the cord blood (Fig. 3B, p < 0.001), and they showed a weak correlation with those in the cord blood (Fig. S2, r = 0.294). Additionally, maternal APOA4 levels showed an increasing trend with advancing gestational age in both groups, and higher levels were observed in the MDD group throughout pregnancy (Fig. S3).

To our knowledge, this is the first study to demonstrate that APOA4 levels are significantly increased in neonates born to mothers with MDD. Increased APOA4 levels were also observed in the maternal blood of the MDD group compared to those in the control group. However, the maternal levels were lower than those in cord blood. Proteomic profiles of cord blood also altered between the MDD and control groups. Both regulation of plasma lipoprotein particle levels and synapse organisation were detected in the top 20 altered pathways.

APOA4, a glycoprotein component of chylomicrons, is primarily synthesised in the small intestine. Most APOA4 circulates in a lipid-free manner; however, its receptor has not been fully identified. Increasing evidence indicates various physiological functions of APOA4; anti-oxidant, anti-inflammation effects, protection against atherosclerosis, reversal of cholesterol transport, absorption of intestinal lipids, slowing stomach emptying, promotion of insulin secretion, and suppression of hepatic gluconeogenesis [29]. These functions appear to protect against cardiovascular diseases and metabolic syndrome. In contrast, several studies have reported an association between serum levels of APOA4 and psychological diseases; its levels have been reported to be lower in Alzheimer’s disease [30] but higher in post-stroke depression [31], when compared with that in healthy controls. Previous serum proteomic profiling has shown that APOA4 levels are significantly increased in patients with MDD [32]. Patients with MDD and lower APOA4 levels before treatment reportedly respond better to treatment [33]. Furthermore, APOA4 levels are reduced after electroconvulsive therapy as an antidepressant treatment [34]. Some studies have suggested that APOA4 can be used as a biomarker for depression screening by improving the sensitivity and specificity of the measurement [35–37].

APOA4 polymorphisms have also been reported to be associated with depression [38, 39], but its pathological role in depression remains unclear. A study using APOA4-deficient mice suggested that APOA4 reduced stress responses [40]. Thus, APOA4 increased levels may indicate a self-defence response to stress in patients with MDD. Chronic systemic inflammation is thought to be associated with lipid profiles in MDD [41], which may have an impact on APOA4.

In the present study, APOA4 levels were elevated in the cord blood of mothers with MDD. A previous study reported that depression increases the concentration of plasma APOA4 in female adolescents carrying the G allele of APOA4 rs5104 in Chinese populations [42], which was consistent with the ethnicity of Asian women in our study population. Genetic factors have been suggested to contribute to differential susceptibility to environmental effects in utero [6]. However, in the present study, APOA4 levels showed only a weak correlation between the maternal and cord blood. Thus, the results cannot be explained only by genetic effects but also by environmental factors. In addition, the present study showed higher levels in cord blood than in maternal blood, which might suggest increased foetal production of APOA4 in mothers with MDD. APOA4, a 46 kDa protein, is thought to be unable to pass through the placental barrier. APOA4 is also increased by hydrocortisone [43, 44]. Increased cortisol levels due to the dysregulation of the HPA axis in the foetus by antenatal maternal depression [45] may be related to increased foetal production of APOA4.

The consequences of increased APOA4 levels in cord blood remain unknown, and its relationship with ASD is controversial. A previous proteomic study reported that APOA4 levels were increased in the serum of children with ASD [17]. However, other studies have reported that APOA4 levels are lower in children with low-functioning ASD than in those with high-functioning ASD [16]. Furthermore, APOA4 levels are reportedly low in patients with schizophrenia [46], which overlaps with ASD. Thus, increased APOA4 levels in the cord blood may not lead to the development of ASD or schizophrenia later in life. However, higher levels of APOA4 may be related to the development of MDD in their mothers, although further research is needed.

In addition, the present study also showed that maternal APOA4 has an increasing trend with gestational age, which is consistent with previous results in amniotic fluid [47]. Therefore, gestational age-matched controls were used to eliminate this effect.

The strength of this study is that it is the first to show a significant increase in APOA4 levels in cord blood exposed to MDD in utero. This will lead to new findings regarding the role of APOA4 in neurodevelopment. This study has several limitations. First, this was a retrospective study, and the study population was small. However, we adjusted for the neonates’ sex, gestational week at birth, and birth weight, which are known to be confounding factors for neurodevelopmental disorders. Therefore, we consider the effects of these factors to be minimal. Second, we were unable to investigate the association between APOA4 levels in cord blood and the severity of maternal MDD because of the small sample size. Further studies are needed to determine whether APOA4 levels in cord blood are decreased by antidepressant.

APOA4 levels in the cord blood increased in neonates born to mother with MDD. APOA4 is a well-known biomarker of depression. This suggests that a higher risk of MDD in children born to mothers with MDD might be related to increased APOA4 levels at birth, although further studies are required.

MDD

major depressive disorder

LC-MS

Liquid chromatography-tandem mass spectrometry

APOA4

apolipoprotein A4

MIA

maternal immune activation

HPA

hypothalamic–pituitary–adrenal

MRI

Magnetic resonance imaging

Ethics approval and consent to participate.

This study was approved by the Ethics Committee of the Nagoya University Graduate School of Medicine (approval number:2015-0471. Pre-existing samples and medical records were used. Informed consent was obtained at the time of sample collection. We also provided information on the methods of this study and provided the subjects with opportunities to reject enrolment in accordance with the ethical guidelines of the Japanese Ministry of Health, Labor, and Welfare.

Consent for publication

Not applicable.

Availability of data and material

Raw data in the present study is available from Table S2.

Competing interests: The authors declare no competing interests.

Funding: The work was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (Grant Number: 20K18187) and Research and Development Grants for Comprehensive Research for Persons with Disabilities from the Japan Agency for Medical Research and Development (AMED, Grant Number: JP20dk0307077).

Authors' contributions: SM, YM and TK conceived the study. SM, YM and RM performed experiments. SM and TK performed the statistical analyses. SM, YM, TU, KI, ST, KY, AY collected clinical samples and interpreted the data. HK provided supervision. SM and TK drafted the manuscript. All authors contributed to the interpretation of the results and the approval of the final manuscript.

Acknowledgements: We thank Mrs Sachiko Morisaki (Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine) for her secretary support and Mr Kentaro Taki (Division for Medical Research Engineering, Nagoya University Graduate School of Medicine) for technical support. We would like to thank Editage (www.editage.jp) for English language editing.

Data Availability Statement: The data are available upon reasonable request from the corresponding author. The datasets generated and analysed during the present study are shown in Table S2.

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No competing interests reported.

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You are reading this latest preprint version

Increased levels of APOA4 in cord blood in maternal major depressive disorder

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Version 1

Abstract

Figures

Background

Methods

Participants

Collection of clinical information and samples

Mass spectrometry (MS)

Proteomic analysis and visualization

Enzyme-Linked Immunosorbent Assay (ELISA)

Statical analysis

Results

Participants

Lipoprotein particle levels pathways changed in the MDD group

APOA4 induction in MDD cord blood

APOA4 increased in MDD maternal blood

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

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