Journal
TOXICOLOGICAL SCIENCES
Volume 182, Issue 2, Pages 195-214Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfab053
Keywords
in utero phthalate; AOP; fetal testis gene expression; testosterone production; PPAR pathway; cholesterol metabolism
Categories
Funding
- National Toxicology Program at the National Institute of Environmental Health Sciences
- U.S. Environmental Protection Agency [RW-75-92285501-1]
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This study showed that diortho-phthalate esters disrupting T Prod also reduced the expression of genes related to hormone synthesis and cholesterol metabolism, while having little effect on genes in the PPAR pathway in the fetal liver. Thus, the mechanism of action of these chemicals involves down-regulation of genes involved in hormone function and cholesterol synthesis.
Previously, we demonstrated that exposure to some diortho-phthalate esters during sexual differentiation disrupts male reproductive development by reducing fetal rat testis testosterone production (T Prod) and gene expression in a dose-related manner. The objectives of the current project were to expand the number of test compounds that might reduce fetal T Prod, including phthalates, phthalate alternatives, pesticides, and drugs, and to compare reductions in T Prod with altered testis mRNA expression. We found that PEs that disrupt T Prod also reduced expression of a unique cluster of mRNAs for about 35 genes related to sterol transport, testosterone and insulin-like hormone 3 hormone syntheses, and lipoprotein signaling and cholesterol synthesis. However, phthalates had little or no effect on mRNA expression of genes in peroxisome proliferator-activated receptor (PPAR) pathways in the fetal liver, whereas the 3 PPAR agonists induced the expression of mRNA for multiple fetal liver PPAR pathway genes without reducing testis T Prod. In summary, phthalates that disrupt T Prod act via a novel adverse outcome pathway including down regulation of mRNA for genes involved in fetal endocrine function and cholesterol synthesis and metabolism. This profile was not displayed by PEs that did not reduce T Prod, PPAR agonists or the other chemicals. Reductions in fetal testis gene expression and T Prod in utero can be used to establish relative potency factors that can be used quantitatively to predict the doses of individual PEs and mixtures of phthalates that produce adverse reproductive tract effects in male offspring.
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