Journal
ARCHIVES OF TOXICOLOGY
Volume 93, Issue 6, Pages 1665-1677Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-019-02449-y
Keywords
Theca cells; Tributyltin; Cholesterol; Retinoid X receptor; Steroidogenesis; Luteinization
Categories
Funding
- National Institute of Environmental Health Sciences [1K22ES026208, R01ES027863]
- National Cancer Institute of the National Institute of Health [K08CA218460]
- Michigan State University (MSU) General Funds
- AgBioResearch
- United States Department of Agriculture (USDA) National Institute of Food and Agriculture
- Environmental and Integrative Toxicological Sciences (EITS) of the Institute for Integrative Toxicology at MSU
- MSU Office of the Vice President for Research and Graduate Studies
- College of Graduate Studies
- College of Human Medicine
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Tributyltin (TBT), an organotin chemical used as a catalyst and biocide, can stimulate cholesterol efflux in non-steroidogenic cells. Since cholesterol is the first limiting step for sex hormone production, we hypothesized that TBT disrupts intracellular cholesterol transport and impairs steroidogenesis in ovarian theca cells. We investigated TBT's effect on cholesterol trafficking, luteinization, and steroidogenesis in theca cells of five species (human, sheep, cow, pig, and mice). Primary theca cells were exposed to an environmentally relevant dose of TBT (1 or 10ng/ml) and/or retinoid X receptor (RXR) antagonist. The expression of RXR alpha in sheep theca cells was knocked down using shRNA. Steroidogenic enzymes, cholesterol transport factors, and nuclear receptors were measured by RT-qPCR and Western blotting, and intracellular cholesterol, progesterone, and testosterone secretion by ELISA. TBT upregulated StAR and ABCA1 in ovine cells, and SREBF1 mRNA in theca cells. TBT also reduced intracellular cholesterol and upregulated ABCA1 protein expression but did not alter testosterone or progesterone production. RXR antagonist and RXR alpha knockdown demonstrates that TBT's effect is partially through RXR. TBT's effect on ABCA1 and StAR expression was recapitulated in all five species. TBT, at an environmentally relevant dose, stimulates theca cell cholesterol extracellular efflux via the RXR pathway, triggers a compensatory upregulation of StAR that regulates cholesterol transfer into the mitochondria and SREBF1 for de novo cholesterol synthesis. Similar results were obtained in all five species evaluated (human, sheep, cow, pig, and mice) and are supportive of TBT's conserved mechanism of action across mammalian species.
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