title: Disturbed one-carbon metabolism causing adverse reproductive outcomes in mice is associated with altered expression of apolipoprotein AI and inflammatory mediators PPARα, interferon-γ, and interleukin-10.
abstract: Low dietary choline or deficiency of methylenetetrahydrofolate reductase (Mthfr) leads to hyperhomocysteinemia (Hhcy) and adverse reproductive outcomes. Homocysteine reduces synthesis of ApoAI, the major lipoprotein in HDL-cholesterol; ApoAI is regulated by PPARα and has antiinflammatory properties. Our aim was to determine whether pregnancy complications due to genetic or nutritional deficiencies in 1-carbon metabolism could relate to dysregulation of ApoAI and inflammatory mediators. We fed pregnant mice, with or without a deficiency of Mthfr, control or choline-deficient (ChDD) diets for 10-12 wk and examined levels of ApoAI, PPARα, IFNγ, and IL-10. ApoAI mRNA was reduced in livers of Mthfr(+/-) mice and ApoAI protein was reduced due to Mthfr deficiency or choline deficiency in liver and plasma. Placental ApoAI protein was also reduced due to Mthfr genotype or choline-deficient diet and in developmentally delayed embryos. Reduced liver PPARα expression (mRNA and protein) was observed in ChDD-fed mice and was associated with increased methylation of a CpG dinucleotide in its promoter. Hepatic IFNγ increased due to genotype, and placental IFNγ was higher in Mthfr(+/-) ChDD-fed dams compared to Mthfr(+/+) mice fed ChDD or Mthfr(+/-) mice fed CD. IL-10 was reduced in livers of ChDD-fed mice. We propose that a deficiency of dietary choline or Mthfr leads to Hhcy and reduced expression of maternal ApoAI, with reduced ApoAI transfer to embryo. Disturbances in 1-carbon metabolism also reduce maternal PPARα expression, possibly through promoter hypermethylation, and increase IFNγ and decrease IL-10 levels. This disturbance of the T helper (Th1) (IFNγ):Th2 (IL-10) ratio and the increase in inflammatory mediators may contribute to pregnancy complications.
authors.affiliation: Department of Human Genetics, McGill University, Montreal Children's Hospital Research Institute, Montreal, QC, Canada.
authors.forename: Leonie G
authors.initials: LG
authors.lastname: Mikael
authors.forename: Jill
authors.initials: J
authors.lastname: Pancer
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002796:Choline Deficiency / Q000150:complications / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D006710:Homocysteine / Q000097:blood / Q000378:metabolism; D006712:Homocystinuria / Q000150:complications / Q000235:genetics / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000150:complications / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009128:Muscle Spasticity / Q000150:complications / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011618:Psychotic Disorders / Q000150:complications / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D047493:PPAR alpha; D012333:RNA, Messenger; D006710:Homocysteine; D016753:Interleukin-10; D007371:Interferon-gamma; D042965:Methylenetetrahydrofolate Reductase (NADPH2)