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Here we report that disrupting folate metabolism by the hypomorphic Mtrr mutation in mice causes morphological and functional defects in their placentas that correspond with early- and late-onset fetal growth restriction. Remarkably, Mtrr heterozygous males initiate inheritance of similar placenta phenotypes and fetal growth defects in their wildtype grandprogeny. An integrated genome-wide approach shows placental transcriptional change and epigenetic instability is caused by an intrinsic or ancestral Mtrr mutation, affecting genes important for placenta development and function (e.g., pregnancy specific glycoprotein (Psg)/Ceacams). Crucially, we establish a functional association between mouse placenta transcript levels and fetal size and identify a human PSG gene variant linked to birthweight. This study provides molecular insight into how folate metabolism influences placental development and attributes a potential multigenerational epigenetic mechanism to unexplained cases of fetal growth defects. Overall design: RNA-seq from E10.5 mouse placentas to assess the intrinsic and ancestral effect of an Mtrrgt allele impairing folate metabolismENAvitamin B9 metabolism, folate metabolic process, atypia, Ideal, Desired Family Sizes, 249 grams, FET GROWTH RET 750-999G, placenta (Spanish, Family Sizes, RNA-seq., Intrauterine Growth Retardation, vitamin M metabolism, One-Person Households, Poor fetal growth state, Average Family Sizes, Pregnancies, FET GROWTH RETARD <500G, unspecified, PREGN, One Person Household, exact), 750-1, Household Heads, 999 grams, FET GROWTH RETARD WTNOS, Head of Household, FET GRWTH RET 1250-1499G, 1, 2, Survey, Whole Transcriptome Shotgun Sequencing, Ideal Family Size, intrauterine Growth restriction, atypical, IUGR, fetal SGA, placenta, Intrauterine, Family and Household, FET GRWTH RET 1000-1249G, Intrauterine growth retardation, FET GRWTH RET 1500-1749G, Fetal growth retardation NOS (disorder), Fetal growth retardation (disorder), Expected Family Sizes, fetal growth restriction, 500-1, fetal growth retardation, 500+ grams, Family Size, Family Life Survey, Fetal growth retardation NOS, Poor fetal growth, FGR - Fetal growth retardation, 胎座 (Japanese, portion of placenta tissue (exact), Family Life, Households, intrauterine Growth retardation, fetus small for gestational Age, 250-1, Completed Family Sizes, Average, 500-749 grams, Normal, vitamin B9 metabolic process, 000-1, 000-2, Fetal Growth Restriction, Fetal growth retardation, One-Person, FET GRWTH RET 1750-1999G, Family, Desired Family Size, eutherian placenta, Family Characteristic, Desired, Generations, fetal Growth retardation, less than 500 grams, placentas (exact, foetal Growth retardation, aberrant, plural), Placentas, foetal SGA, One-Person Household, defective, Family Demography, Expected Family Size, folic acid metabolism, Household and Family, Expected, unspecified [weight], Intrauterine Growth Restriction, Fetal Growth Retardation, Household, placentae (exact, FGR, Completed Family Size, foetal small for gestational Age, NOS, Ideal Family Sizes, Average Family Size, Couples, Demography, Growth Retardation, carrying of young, FET GROWTH RET 500-749G, fetal small for gestational Age, Gestation, FET GROWTH RET 2500+G, allantoic placenta, Microsomic baby, Family Demographies, Family Life Surveys, IUGR - Intrauterine growth retardation, foetal growth retardation, folate metabolism, vitamin M metabolic process, foetus small for gestational Age, 750-999 grams, Placentomes, Microsomia, Household Head, Placentome, Foetal growth retardation, FET GRWTH RET 2000-2499G, 749 grams, 499 grams, Completed, Placentomavitamin B9 metabolism, folate metabolic process, atypia, Ideal, Desired Family Sizes, 249 grams, FET GROWTH RET 750-999G, placenta (Spanish, Family Sizes, RNA-seq., Intrauterine Growth Retardation, vitamin M metabolism, One-Person Households, Poor fetal growth state, Average Family Sizes, Pregnancies, FET GROWTH RETARD <500G, unspecified, PREGN, One Person Household, exact), 750-1, Household Heads, 999 grams, FET GROWTH RETARD WTNOS, Head of Household, FET GRWTH RET 1250-1499G, 1, 2, Survey, Whole Transcriptome Shotgun Sequencing, Ideal Family Size, intrauterine Growth restriction, atypical, IUGR, fetal SGA, placenta, Intrauterine, Family and Household, FET GRWTH RET 1000-1249G, Intrauterine growth retardation, FET GRWTH RET 1500-1749G, Fetal growth retardation NOS (disorder), Fetal growth retardation (disorder), Expected Family Sizes, fetal growth restriction, 500-1, fetal growth retardation, 500+ grams, Family Size, Family Life Survey, Fetal growth retardation NOS, Poor fetal growth, FGR - Fetal growth retardation, 胎座 (Japanese, portion of placenta tissue (exact), Family Life, Households, intrauterine Growth retardation, fetus small for gestational Age, 250-1, Completed Family Sizes, Average, 500-749 grams, Normal, vitamin B9 metabolic process, 000-1, 000-2, Fetal Growth Restriction, Fetal growth retardation, One-Person, FET GRWTH RET 1750-1999G, Family, Desired Family Size, eutherian placenta, Family Characteristic, Desired, Generations, fetal Growth retardation, less than 500 grams, placentas (exact, foetal Growth retardation, aberrant, plural), Placentas, foetal SGA, One-Person Household, defective, Family Demography, Expected Family Size, folic acid metabolism, Household and Family, Expected, unspecified [weight], Intrauterine Growth Restriction, Fetal Growth Retardation, Household, placentae (exact, FGR, Completed Family Size, foetal small for gestational Age, NOS, Ideal Family Sizes, Average Family Size, Couples, Demography, Growth Retardation, carrying of young, FET GROWTH RET 500-749G, fetal small for gestational Age, Gestation, FET GROWTH RET 2500+G, allantoic placenta, Microsomic baby, Family Demographies, Family Life Surveys, IUGR - Intrauterine growth retardation, foetal growth retardation, folate metabolism, vitamin M metabolic process, foetus small for gestational Age, 750-999 grams, Placentomes, Microsomia, Household Head, Placentome, Foetal growth retardation, FET GRWTH RET 2000-2499G, 749 grams, 499 grams, Completed, PlacentomafalsePlacenta insufficiency caused by abnormal folate metabolism linked to fetal growth restriction across gestation and generations [RNA-Seq]Placenta insufficiency caused by abnormal folate metabolism linked to fetal growth restriction across gestation and generations [RNA-Seq]2025-09-242023-06-09PRJNA976334GSE2334811009037440923