Genomic and Hormonal Biomarkers of Phthalate-Induced Male Rat Reproductive Developmental Toxicity Part II: A Targeted...

Area of Science:

• Endocrinology
• Developmental Toxicology
• Molecular Biology

Background:

• Diortho-phthalate esters disrupt male reproductive development by reducing fetal testosterone production (T Prod).
• Gene expression in fetal rat testes is altered by phthalate exposure in a dose-dependent manner.

Purpose of the Study:

• Expand the range of tested compounds (phthalates, alternatives, pesticides, drugs) that reduce fetal T Prod.
• Correlate reductions in T Prod with changes in testis mRNA expression.
• Investigate the molecular pathways affected by T Prod-disrupting chemicals.

Main Methods:

• Assessed the impact of various chemicals on fetal rat testis testosterone production.
• Analyzed changes in mRNA expression for specific gene clusters related to steroidogenesis and cholesterol metabolism.
• Examined the effects on peroxisome proliferator-activated receptor (PPAR) pathways in the fetal liver.

Main Results:

• Phthalate esters disrupting T Prod also reduced mRNA expression for genes in sterol transport, hormone synthesis, and cholesterol metabolism.
• Phthalates minimally affected fetal liver PPAR pathway genes, unlike specific PPAR agonists.
• A novel adverse outcome pathway involving down-regulation of fetal endocrine and cholesterol metabolism genes was identified for T Prod-disrupting phthalates.

Conclusions:

• Phthalates disrupting T Prod act through a distinct pathway affecting fetal endocrine function and cholesterol metabolism.
• Gene expression and T Prod reductions in utero can establish relative potency factors for predicting adverse reproductive effects.
• This study provides a framework for quantitative risk assessment of phthalates and related compounds on male reproductive development.