Polyomic Analyses of Human Fetal Endocrine Organs Predict Persistent Fetal Inflammation and Reduced Fetal Vitamin D Signalling in Pregnancies of Mothers with High BMI.

Introduction: Around half of expectant mothers worldwide are overweight or obese. Children born to mothers with high maternal body mass index (BMI) are more likely to develop obesity, cardiovascular disease, and Autism Spectrum Disorders. While it is widely accepted that many adult health-related issues originate during fetal life, the mechanisms linking maternal obesity to development of post-natal disorders remain unclear. Studies targeting fetal development can describe mechanisms and identify interventions to ameliorate adverse health effects associated with maternal lifestyle. Here we measured transcripts and proteins using high-throughput approaches in key fetal endocrine organs to examine how high maternal BMI affects the fetus.
Methods: RNA and protein extracts were prepared from placentas, livers,
adrenal glands and plasma from electively terminated fetuses of normally progressing pregnancies (12-20 weeks gestation) (NHS Grampian, REC
04/S0802/21). Transcripts were measured using Illumina RNA sequencing
in fetal livers and adrenal glands. Proteins were measured using liquid
chromatography coupled to mass spectrometry in adrenal glands, livers,
placentas and plasma. Informatics were performed using Ingenuity
Pathway Analysis. Multivariate regression analyses incorporating age,
sex and maternal BMI were used to identify differentially expressed
factors. Numbers ranged from 40-80 fetuses equally distributed across
age, sex and maternal BMI.
Results: Increased inflammation, insulin, estradiol, and PPARgamma
signalling, and decreased Vitamin D signalling pathways were predicted
in livers, adrenals and placentas in the BMI≥25 group. Liver transcripts
of pro-inflammatory cytokines (CXCL2, IL8, IL33, IL6, TGFB1, CCL2),
nitric oxide synthases (NOS1, NOS2, NOS3), and plasma levels of soluble
CD14 antigen increased in the BMI≥25 group. Glycated albumin peptides
increased in fetal plasma in the BMI≥25 group, as did placental levels
of Vitamin-D binding protein. Liver transcripts of vitamin D receptor
increased in the BMI≥25 group. Liver triglycerides increased with BMI
in female fetuses only.
Conclusion: During pregnancy, high BMI mothers are pro-inflammatory
and here we show that such a pro-inflammatory environment is reflected
in the fetus. The latter is expected to be a significant contributor to
offspring disease predisposition and may explain why children from
mothers with high BMI are more likely to develop non-alcoholic fatty
liver disease, obesity, metabolic disorders and altered neurodevelopment.
Reduced vitamin D signalling in the fetal organs suggests that vitamin
D supplementation during pregnancy may ameliorate negative outcomes
in children at risk.