Endocrine Abstracts

Background: Maternal B12 deficiency is linked with adverse metabolic disorders in infants. B12 has a potential epigenetic role which could influence placental dysfunction and fetal metabolism. Adipokines such as leptin and adiponectin play a major role in placental development by regulating lipid metabolism. Alterations in in-utero programming develop risk to obesity and metabolic diseases in offspring. B12 deficiency in mothers has been linked with higher cord triglyceride and lower HDL levels. Here, we aim to assess the adaptation of placental adipokine promoter methylation due to low B12 and determine the consequences of these epigenetic changes on gene expression and lipid metabolism.

Methods: Human placental explants (derived from 10 healthy pregnant women) and BeWo trophoblastic cell line were cultured for 7 days in CMRL or custom-made Ham’s F12 media, respectively, supplemented with sufficient (500nM-Control) or low B12 concentrations (25pM-low B12). Expression of lipid metabolism genes was detected using qRT-PCR. CpG methylation was measured using pyrosequencing.

Results: Placental explants and BeWo cells deficient in B12 demonstrated increased gene expression of nuclear transcription factors regulating fatty-acid (FA) synthesis (SREBF1), adipogenesis (PPARγ, CEBPα) and significantly altered the gene expressions of FA (FASN, ACACA, ACLY, ELOVL6), triglycerides biosynthesis (AGPAT2, GPAM, SCD, DGAT1, DGAT2) and FA oxidation (LDLR, ACADM, ACADS, ACSL1, SLC25A20) compared to control (P<0.05). Low B12 showed significant hypomethylation of specific CpG sites in the leptin promoter and an increase in gene expression. However, we found that the adiponectin gene was not expressed, and there were only slightly elevated methylated CpG sites in the adiponectin promoter region.

Conclusion: Our novel data highlights that low B12 has a key role in altering lipid metabolism which might be via leptin gene promoter methylation in placenta. Thus, indicating maternal B12 deficiency during placental development could lead to metabolic defects such as dyslipidaemia in infants.