Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease.
Maternal diet can affect fetal gene expression through epigenetic mechanisms. Wilson disease (WD), which is caused by autosomal recessive mutations in ATP7B encoding a biliary copper transporter, is characterized by excessive hepatic copper accumulation, but variability in disease severity. We tested the hypothesis that gestational supply of dietary methyl groups modifies fetal DNA methylation and expression of genes involved in methionine and lipid metabolism that are impaired prior to hepatic steatosis in the toxic milk (tx-j) mouse model of WD. Female C3H control and tx-j mice were fed control (choline 8 mmol/Kg of diet) or choline-supplemented (choline 36 mmol/Kg of diet) diets for 2 weeks throughout mating and pregnancy to gestation day 17. A second group of C3H females, half of which were used to cross foster tx-j pups, received the same diet treatments that extended during lactation to 21 d postpartum. Compared with C3H, fetal tx-j livers had significantly lower copper concentrations and significantly lower transcript levels of Cyclin D1 and genes related to methionine and lipid metabolism. Maternal choline supplementation prevented the transcriptional deficits in fetal tx-j liver for multiple genes related to cell growth and metabolism. Global DNA methylation was increased by 17% in tx-j fetal livers after maternal choline treatment (P<0.05). Maternal dietary choline rescued the lower body weight of 21 d tx-j mice. Our results suggest that WD pathogenesis is modified by maternal in utero factors, including dietary choline.
Department of Internal Medicine; Division of Gastroenterology and Hepatology; University of California Davis; Davis, CA USA.
Valentina
V
Medici
Department of Internal Medicine; Division of Gastroenterology and Hepatology; University of California Davis; Davis, CA USA.
Noreene M
NM
Shibata
Research Service; Veterans Affairs Nebraska-Western Iowa Health Care System; Omaha, NE USA.
Kusum K
KK
Kharbanda
Department of Medical Microbiology and Immunology; Genome Center; MIND Institute; University of California Davis; Davis, CA USA.
Mohammad S
MS
Islam
Department of Nutrition; University of California Davis; Davis, CA USA.
Carl L
CL
Keen
Department of Public Health Sciences; Division of Biostatistics; University of California Davis; Davis, CA USA.
Kyoungmi
K
Kim
Department of Pathology; UCLA/Harbor Medical Center; Torrance, CA USA.
Brittany
B
Tillman
Department of Pathology; UCLA/Harbor Medical Center; Torrance, CA USA.
Samuel W
SW
French
Department of Internal Medicine; Division of Gastroenterology and Hepatology; University of California Davis; Davis, CA USA.
Charles H
CH
Halsted
Department of Medical Microbiology and Immunology; Genome Center; MIND Institute; University of California Davis; Davis, CA USA.
Janine M
JM
LaSalle
D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D002794:Choline / Q000008:administration & dosage / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D019175:DNA Methylation; D004032:Diet; D005260:Female; D005333:Fetus / Q000378:metabolism*; D015870:Gene Expression; D006527:Hepatolenticular Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008431:Maternal-Fetal Exchange; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D011247:Pregnancy
D019938:Cyclin D1; D003300:Copper; D008715:Methionine; D002794:Choline
CyclinD1; DNA methylation; S-adenosylmethionine; choline; copper; fetus; liver