Transcriptomic changes upon epoxiconazole exposure in a human stem cell-based model of developmental toxicity.

Area of Science:

• Endocrinology
• Developmental Toxicology
• Molecular Biology

Background:

• Conazole fungicides, like epoxiconazole, inhibit fungal sterol 14α-demethylase (CYP51A1).
• This enzyme is conserved in humans and crucial for steroid hormone biosynthesis.
• Epoxiconazole's endocrine-disrupting effects are known in rodents, but molecular mechanisms in humans are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms of epoxiconazole's developmental toxicity using a human stem cell model.
• To assess the impact of epoxiconazole on the steroid biosynthesis pathway in early human development.

Main Methods:

• Utilized a human stem cell-based in vitro model (3D embryoid body cultures differentiating into cardiomyocytes).
• Employed global transcriptome analysis via RNA sequencing to study gene expression changes.
• Confirmed deregulation of the steroid biosynthesis pathway and CYP51A1 expression.

Main Results:

• Epoxiconazole significantly deregulated the steroid biosynthesis pathway, including CYP51A1, in the human stem cell model.
• Most genes in the steroid biosynthesis pathway were upregulated, suggesting a compensatory response.
• Data indicate epoxiconazole primarily decreases cholesterol biosynthesis.

Conclusions:

• Epoxiconazole has the potential to impair human embryonic development by inhibiting the steroid biosynthesis pathway.
• This mechanism suggests conazole fungicides targeting CYP51A1 may pose risks as human developmental toxicants.
• Highlights the need for further investigation into conazole fungicide safety during development.