Transgenerational Inheritance of Increased Fat Depot Size, Stem Cell Reprogramming, and Hepatic Steatosis Elicited by Prenatal Exposure to the Obesogen Tributyltin in Mice
Raquel Chamorro-García,1 Margaret Sahu,1 Rachelle J. Abbey,1 Jhyme Laude,1 Nhieu Pham,1 and Bruce Blumberg1,2
1Department of Developmental and Cell Biology, and 2Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, California, USA
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.
Discussion: 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.
Key words: adipogenesis, endocrine disruption, MSCs, NAFLD, nonalcoholic fatty liver disease, obesogen, PPARγ, TBT, transgenerational, tributyltin.
Environ Health Perspect 121:359–366 (2013). http://dx.doi.org/10.1289/ehp.1205701 [Online 15 January 2013]
Address correspondence to B. Blumberg, UC Irvine, 2011 BioSci 3, Irvine, CA 92697-2300 USA. Telephone: (949) 824-8573. E-mail: firstname.lastname@example.org
Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205701).
We thank A. Janesick and M. Skinner for advice and comments on the manuscript, and T.F. Schilling and members of his laboratory for use of, and assistance with, his Zeiss Axioplan II microscope.
This research was supported by National Institutes of Health grants ES-015849 and ES-015849-01S1 to B.B.
B.B. is a named inventor on U.S. patents 5,861,274; 6,200,802; 6,815,168; and 7,250,273 related to PPARγ (peroxisome proliferator activated receptor γ). The other authors declare they have no actual or potential competing financial interests.
Received 2 July 2012; Accepted 11 January 2013; Online 15 January 2013.
Recent Advance Publications
- Long Term Exposure to PM10 and NO2 in Association with Lung Volume and Airway Resistance in the MAAS Birth Cohort
- Retinal Microvascular Responses to Short-Term Changes in Particulate Air Pollution in Healthy Adults
- Short-term Associations between Fine and Coarse Particulate Matter and Hospitalizations in Southern Europe: Results from the MED-PARTICLES Project
- Perinatal Air Pollutant Exposures and Autism Spectrum Disorder in the Children of Nurses’ Health Study II Participants
- Prenatal Nitrate Intake from Drinking Water and Selected Birth Defects in Offspring of Participants in the National Birth Defects Prevention Study
- Current Perspectives on the Use of Alternative Species in Human Health and Ecological Hazard Assessments
- Instruments for Assessing Risk of Bias and Other Methodological Criteria of Published Animal Studies: A Systematic Review