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Maternal mood during pregnancy, methyl nutrient metabolism, and serotonin transporter

University of British Columbia

Depression occurs in 15% of pregnant women and 1/3 are taking selective serotonin reuptake inhibitors (SSRIs) as antidepressants. The neurotransmitter, serotonin, plays a critical role in modulating stress responses and early brain development. Serotonin transporter (SLC6A4) regulates extracellular serotonin levels, and an insertion/deletion variant in the promoter (5HTTLPR) is associated with depression. Maternal mood and SSRIs may program newborns’ behaviour later in life. The underlying molecular mechanism for developmental programming may involve DNA methylation, which requires methyl nutrients as enzymatic cofactors. While low methyl nutrient status (folate and vitamin B₁₂) and a genetic variant in methylenetetrahydrofolate reductase (MTHFR C677T) have been associated with depression in adults, the role of methyl nutrient metabolism in depression during pregnancy remains unclear. Furthermore, little is known about the combined roles of methyl nutrient status and depression in the epigenetic regulation of SLC6A4. The experiments in this thesis explored whether disturbances in methyl nutrient metabolism and depressed mood during the 3rd trimester of pregnancy affect SLC6A4 methylation and expression in mothers and their newborns. Maternal folate status was positively associated with maternal SLC6A4 methylation at CpGs 1, 4, and 8 (P<0.05). Maternal 3rd trimester mood was inversely associated with SLC6A4 CpG 10 methylation in both mothers and newborns (P<0.05). Methylation at SLC6A4 CpG 8 was lower in newborns with mothers with the MTHFR 677TT genotype, and methylation at CpGs 6 and 10 were lower in newborns with the MTHFR 677TT genotype (P<0.05). Maternal SLC6A4 mRNA level was positively associated with mean maternal methylation and methylation at CpGs 5, 7, 8, and 10 (P<0.05). Yet, newborn SLC6A4 mRNA level was negatively associated with newborn methylation at CpGs 4 and 7 (P<0.05). Homozygosity for the minor allele for MTHFR C677T and 5-HTTLPR insertion/deletion variants in mothers were not associated with maternal mood (P>0.05). These results provide evidence to suggest that maternal mood during pregnancy and methyl nutrient metabolism may program SLC6A4 gene expression through DNA methylation in both mothers and their newborns. Mood during pregnancy and disturbances in methyl nutrient metabolism could set up life-long health consequences in the development of the offspring.

Text

2011-07-04

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/35857

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/