Impact of maternal smoking associated lyso-phosphatidylcholine 20:3 on offspring brain development

https://doi.org/10.1016/j.jsbmb.2020.105591Get rights and content

Highlights

  • We used flow injection analysis tandem mass spectrometry to identify smoking related metabolites in cord blood.

  • Male newborns of smoking mothers had a reduced head circumference compared to newborns from former and never smoking mothers.

  • The smoking related metabolite LPC 20:3 was independently associated with head circumference in male offspring only.

  • Results suggest sex specific effects of intrauterine smoke exposure on head circumference and the cord blood metabolome.

Abstract

Maternal smoking during pregnancy affects fetal neurological development. Metabolomic studies in the general population suggest that smoking is associated with characteristic metabolic alterations. We investigated the association between the maternal smoking status, the fetal metabolome and head circumference at birth, as a surrogate parameter of brain development. 320 mother/newborn pairs of the Berlin Birth Cohort were investigated. Anthropometric parameters, including head circumference, of newborns of smoking mothers, former smoking mothers, and never smoking mothers were compared to assess the impact of maternal smoking behavior. Associations between maternal smoking behavior and 163 cord blood metabolites and associations between newborn head circumference and concentrations of smoking behavior related metabolites were analysed. Male newborns of smoking mothers had a reduced head circumference when compared with newborns from former smoking and never smoking mothers (p < 0.05). Using linear regression models corrected for established confounding factors, maternal smoking during pregnancy showed an independent association with head circumference (95% CI: -0.75~-0.41 cm, p = 2.45×10−11). In a stepwise linear regression model corrected for known confounding factors of brain growth lyso-phosphatidylcholine 20:3 (95% CI: 6.68~39.88 cm, p = 4.62×10-4) was associated with head circumference in male offspring only. None of the metabolites were associated with head circumference of female newborns. In conclusion, maternal smoking during pregnancy impacted on male offspring’s development including brain development. The smoking related metabolite lyso-phosphatidylcholine 20:3 was associated with head circumference of male offspring.

Introduction

Maternal smoking during pregnancy is one of the most severe factors to influence offspring health. Smoking during pregnancy has been shown to expose the fetus to harmful chemicals which can influence brain development [1], and is associated with cognitive deficits [2], attention deficit hyperactivity disorder (ADHD) [3], and various psychiatric disorders [4] in children and young adults. Interestingly, the effects of gestational smoking on the offspring appear to be sex specific. Compared to female offspring, male offspring from mothers who smoked during pregnancy display a significantly smaller head circumference [5] and a higher incidence of intellectual disabilities [6].

In order to potentially discover targeted therapies, it is important to uncover the biological mechanisms that connect fetal smoke exposure and impaired fetal brain development. By a detailed characterization of the metabolome, metabolomics, a new ‘omics’ technology, allows to systematically monitor physiological and pathophysiological conditions and the impact of environmental factors, genetic regulation, and enzymatic activity states [7]. The analysis of the metabolome in choice diseases provides a useful tool for preclinical and clinical research, aiding in drug discovery and drug development [8]. An identification of smoking-related metabolites may help better characterizing the role of maternal smoking in offspring brain development. Several previous studies identified distinct serum metabolites in smokers [[9], [10], [11]]. However, there is still a lack of data about the impact of smoking during pregnancy on maternal and especially fetal metabolites.

We first characterized the impact of maternal smoking status (never smoker/former smoker/current smoker) on neonatal anthropometric parameters with a special focus on newborn head circumference. Furthermore, the cord blood metabolome of newborns at birth was analysed aiming to address two points: 1) Does the maternal smoking behavior influence the cord blood metabolome? 2) Are smoking-related metabolites associated with head circumference, a surrogate parameter of brain development?

Section snippets

Clinic data and sample collection

This observational cohort study was conducted at the Department of Obstetrics, Charité Universitaetsmedizin Berlin (Berlin, Germany). The Berlin Birth Cohort study [12] was approved by the local ethics committee and performed in accordance with the Declaration of Helsinki. A total of 320 singleton pregnancy mothers without gestational diabetes and hypertension and their newborns were investigated. Informed consent was obtained and a structured interview was performed with partaking mothers. The

Maternal smoking behavior and newborn birth outcome

Descriptive data of the study population are given Table 1. Key biometric data of the newborns such as gestational age, preterm birth (gestational age < 37 weeks), birth weight, low birth weight (birth weight < 2500 g), birth length, ponderal index, head circumference, cord blood pH, and APGAR scores at 5 min were analysed.

Male newborns of smoking mothers had a smaller head circumference and a significantly higher prevalence of microcephaly compared to newborns of formerly and never smoking

Discussion

We analysed sex specific associations between maternal smoking behavior and newborn head circumference as a surrogate parameter for brain development in 320 singleton pregnancy mothers and their newborns. Moreover, we investigated if smoking related alterations of the cord blood metabolome are associated with newborns’ head circumference. Maternal smoking was independently associated with reductions in male newborn head circumference. Stepwise linear regression models corrected for known

Strengths and limitations

One limitation of the present study is that maternal smoking status was based on a self-report. Previous studies have shown that pregnant mothers under-report smoking during pregnancy showing that between 7 and 22 % of the self-reported non-smokers were actually smokers according to blood and urine cotinine levels [32,33]. Since we had information about maternal smoking on a yes/no level, we are unable to figure out potential dose dependencies of the observed effects of maternal smoking.

Conclusions

Maternal smoking during pregnancy was associated with reductions in head circumference in male offspring. Metabolomic analysis of cord blood samples revealed a significant association of maternal smoking and the fetal metabolome. Furthermore, it could be demonstrated that one of the identified smoking related metabolites, LPC 20:3, was independently associated with head circumference in male newborns. Interestingly, all associations - maternal smoking/head circumference, maternal smoking/cord

Funding

This study was supported in part by the Deutsche Forschungsgemeinschaft (DFG; Grant No. Ho 1665 2-3) to Dr. B. Hocher, a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.), Postdoctoral Fund of the First Affiliated Hospital, Jinan University, China (Grant No. 809001), Young innovative talents project of general colleges and universities in Guangdong Province, China (Grant No. 2018KQNCX010).

Author contribution statement

Prof Hocher conceptualized and designed the study, interpreted the data, supervised data collection, and critically reviewed the manuscript for important intellectual content.

Dr Lu and Dr Reichetzeder generated and analysed the data, interpreted the data and drafted the initial manuscript, and reviewed and revised the manuscript.

Dr Prehn, Dr Elitok, Prof. Yin and Ms Chu collected data, drafted the initial manuscript.

Prof Krämer and Prof Adamski supervised data collection, and critically

Declaration of Competing Interest

The authors have no conflicts of interest relevant to this article to disclose.

Acknowledgements

Not applicable.

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    Dr Lu and Dr Reichetzeder contributed equally as co-first authors.

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