标题：Transgenerational Inheritance of Increased Fat Depot Size, Stem Cell Reprogramming, and Hepatic Steatosis Elicited by Prenatal Exposure to the Obesogen Tributyltin in Mice
摘要：a c k g r o u n d: We have previously shown that exposure to tributyltin (TBT) modulates critical steps of adipo genesis through RXR/PPARγand that prenatal TBT exposure predisposes multi-potent mesen chymal stem cells (MSCs) to become adipocytes by epigenetic imprinting into the memory of the MSC compartment.oB j e c t i v e: We tested whether the effects of prenatal TBT exposure were heritable in F2 and F3 generations.Me t h o d s: We exposed C57BL/6J female mice (F0) to DMSO vehicle, the pharmaceutical obeso-gen 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, adipo cyte number, adipocyte size, MSC programming, hepatic lipid accumulation, and hepatic gene expression in all three generations.di sc us si o n: 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 accumula-tion and up-regulated hepatic expression of genes involved in lipid storage/transport, lipogenesis, and lipolysis in all three subsequent generations.co n c l u s i o n s: Prenatal TBT exposure produced transgenerational effects on fat depots and induced a phenotype resembling non alcoholic fatty liver disease through at least the F3 generation. These results show that early-life obesogen exposure can have lasting effects
