title: Transgenerational inheritance of increased fat depot size, stem cell reprogramming, and hepatic steatosis elicited by prenatal exposure to the obesogen tributyltin in mice.
abstract: BACKGROUND
  We have previously shown that exposure to tributyltin (TBT) modulates critical steps of adipogenesis through RXR/PPARγ and that prenatal TBT exposure predisposes multipotent mesenchymal stem cells (MSCs) to become adipocytes by epigenetic imprinting into the memory of the MSC compartment.
  
  
  OBJECTIVE
  We tested whether the effects of prenatal TBT exposure were heritable in F2 and F3 generations.
  
  
  METHODS
  We exposed C57BL/6J female mice (F0) to DMSO vehicle, the pharmaceutical obesogen rosiglitazone (ROSI), or TBT (5.42, 54.2, or 542 nM) throughout pregnancy via the drinking water. F1 offspring were bred to yield F2, and F2 mice were bred to produce F3. F1 animals were exposed in utero and F2 mice were potentially exposed as germ cells in the F1, but F3 animals were never exposed to the chemicals. We analyzed the effects of these exposures on fat depot weights, adipocyte number, adipocyte size, MSC programming, hepatic lipid accumulation, and hepatic gene expression in all three generations.
  
  
  CONCLUSIONS
  Prenatal TBT exposure increased most white adipose tissue (WAT) depot weights, adipocyte size, and adipocyte number, and reprogrammed MSCs toward the adipocyte lineage at the expense of bone in all three generations. Prenatal TBT exposure led to hepatic lipid accumulation and up-regulated hepatic expression of genes involved in lipid storage/transport, lipogenesis, and lipolysis in all three subsequent generations.
  
  
  CONCLUSIONS
  Prenatal TBT exposure produced transgenerational effects on fat depots and induced a phenotype resembling nonalcoholic fatty liver disease through at least the F3 generation. These results show that early-life obesogen exposure can have lasting effects.
authors: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697-2300, USA.
authors: Raquel
authors: R
authors: Chamorro-García
authors: Margaret
authors: M
authors: Sahu
authors: Rachelle J
authors: RJ
authors: Abbey
authors: Jhyme
authors: J
authors: Laude
authors: Nhieu
authors: N
authors: Pham
authors: Bruce
authors: B
authors: Blumberg
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000273:Adipose Tissue; D000818:Animals; D019070:Cell Lineage; D060766:Drinking Water; D005234:Fatty Liver / Q000139:chemically induced*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology*; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D060766:Drinking Water; D014220:Trialkyltin Compounds; C011559:tributyltin