Transgenerational Transcriptomic and DNA Methylome Profiling of Mouse Fetal Testicular Germline and Somatic Cells after Exposure of Pregnant Mothers to Tributyltin, a Potent Obesogen

Metabolites

Keiko Shioda¹  Junko Odajima¹  Toshi Shioda²  Bruce Blumberg³ 

[1] Center for Cancer Research, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA;Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA;Department of Developmental and Cell Biology, University of California, Irvine, CA 92697-2300, USA;

关键词: transgenerational;    obesity;    obesogen;    diet-induced obesity;    tributyltin;    RNA-seq;   

DOI  :  10.3390/metabo12020095

来源: DOAJ

【 摘 要 】

Obesogens such as tributyltin (TBT) are xenobiotic compounds that promote obesity, in part by distorting the normal balance of lipid metabolism. The obesogenic effects of TBT can be observed in directly exposed (F1 and F2 generations) and also subsequent generations (F3 and beyond) that were never exposed. To address the effects of TBT exposure on germ cells, we exposed pregnant transgenic OG2 mouse dams (F0), which specifically express EGFP in germline cells, to an environmentally relevant dose of TBT or DMSO throughout gestation through drinking water. When fed with a high-fat diet, F3 male offspring of TBT-exposed F0 dams (TBT-F3) accumulated much more body fat than did DMSO-F3 males. TBT-F3 males also lost more body fluid and lean compositions than did DMSO-F3 males. Expression of genes involved in transcriptional regulation or mesenchymal differentiation was up-regulated in somatic cells of TBT-F1 (but not TBT-F3) E18.5 fetal testes, and promoter-associated CpG islands were hyper-methylated in TBT-F1 somatic cells. Global mRNA expression of protein-coding genes in F1 or F3 fetal testicular cells was unaffected by F0 exposure to TBT; however, expression of a subset of endogenous retroviruses was significantly affected in F1 and F3. We infer that TBT may directly target testicular somatic cells in F1 testes to irreversibly affect epigenetic suppression of endogenous retroviruses in both germline and somatic cells.

【 授权许可】

Unknown