title: Early Life Exposure to Fructose Alters Maternal, Fetal and Neonatal Hepatic Gene Expression and Leads to Sex-Dependent Changes in Lipid Metabolism in Rat Offspring.
abstract: OBJECTIVE
  Fructose consumption is associated with altered hepatic function and metabolic compromise and not surprisingly has become a focus for perinatal studies. We have previously shown that maternal fructose intake results in sex specific changes in fetal, placental and neonatal outcomes. In this follow-up study we investigated effects on maternal, fetal and neonatal hepatic fatty acid metabolism and immune modulation.
  
  
  METHODS
  Pregnant rats were randomised to either control (CON) or high-fructose (FR) diets. Fructose was given in solution and comprised 20% of total caloric intake. Blood and liver samples were collected at embryonic day 21 (E21) and postnatal day (P)10. Maternal liver samples were also collected at E21 and P10. Liver triglyceride and glycogen content was measured with standard assays. Hepatic gene expression was measured with qPCR.
  
  
  RESULTS
  Maternal fructose intake during pregnancy resulted in maternal hepatic ER stress, hepatocellular injury and increased levels of genes that favour lipogenesis. These changes were associated with a reduction in the NLRP3 inflammasome. Fetuses of mothers fed a high fructose diet displayed increased hepatic fructose transporter and reduced fructokinase mRNA levels and by 10 days of postnatal age, also have hepatic ER stress, and elevated IL1β mRNA levels. At P10, FR neonates demonstrated increased hepatic triglyceride content and particularly in males, associated changes in the expression of genes regulating beta oxidation and the NLRP3 inflammasome. Further, prenatal fructose results in sex-dependant changes in levels of key clock genes.
  
  
  CONCLUSIONS
  Maternal fructose intake results in age and sex-specific alterations in maternal fetal and neonatal free fatty acid metabolism, which may be associated in disruptions in core clock gene machinery. How these changes are associated with hepatic inflammatory processes is still unclear, although suppression of the hepatic inflammasome, as least in mothers and male neonates may point to impaired immune sensing.
authors.affiliation: Liggins Institute and Gravida: National Centre for Growth and Development, University of Auckland, Aukland, New Zealand.
authors.forename: Zoe E
authors.initials: ZE
authors.lastname: Clayton
authors.affiliation: Liggins Institute and Gravida: National Centre for Growth and Development, University of Auckland, Aukland, New Zealand.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Vickers
authors.affiliation: Liggins Institute and Gravida: National Centre for Growth and Development, University of Auckland, Aukland, New Zealand.
authors.forename: Angelica
authors.initials: A
authors.lastname: Bernal
authors.affiliation: Liggins Institute and Gravida: National Centre for Growth and Development, University of Auckland, Aukland, New Zealand.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Yap
authors.affiliation: Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada.|Department of Obstetrics and Gynaecology, McMaster University, Hamilton, Canada.|Department of Pediatrics, McMaster University, Hamilton, Canada.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Sloboda
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D005632:Fructose / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006003:Glycogen / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D013997:Time Factors
chemical_list: D056925:Circadian Rhythm Signaling Peptides and Proteins; D005230:Fatty Acids, Nonesterified; D005632:Fructose; D006003:Glycogen