Transgenerational inheritance of increased fat depot size, stem cell reprogramming, and hepatic steatosis elicited by prenatal exposure to the obesogen tributyltin in mice

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. We tested...

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Published in:	Environmental health perspectives Vol. 121; no. 3; pp. 359 - 366
Main Authors:	Chamorro-García, Raquel, Sahu, Margaret, Abbey, Rachelle J, Laude, Jhyme, Pham, Nhieu, Blumberg, Bruce
Format:	Journal Article
Language:	English
Published:	United States National Institute of Environmental Health Sciences 01-03-2013
Subjects:	Adipocytes Adipocytes - cytology Adipocytes - drug effects Adipose Tissue Animal experimentation Animals Antifouling substances Body fat Bones Cell Lineage Chemicals Disease Drinking Water Environmentally induced diseases Epigenetics Exposure Fatty Liver - chemically induced Female Females Gene expression Health aspects Hypotheses Laboratories Laboratory animals Lipids Liver Male Metabolism Mice Mice, Inbred C57BL Nutrition research Obesity Offspring Pregnancy Prenatal exposure Prenatal Exposure Delayed Effects Prenatal influences Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Risk factors Rodents Stem cells Stem Cells - cytology Studies Trialkyltin Compounds - toxicity Tributylin Tributyltin
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Summary:	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. We tested whether the effects of prenatal TBT exposure were heritable in F2 and F3 generations. 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0091-6765 1552-9924
DOI:	10.1289/ehp.1205701