Epi-mutations for spermatogenic defects by maternal exposure to di(2-ethylhexyl) phthalate

Area of Science:

• Reproductive toxicology
• Epigenetics
• Developmental biology

Background:

• Environmental factors during fetal development can cause epigenomic modifications in germ cells, potentially affecting future generations.
• Maternal exposure to di(2-ethylhexyl) phthalate (DEHP) is known to cause male reproductive defects in subsequent generations of mice, but the underlying mechanisms are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms by which maternal di(2-ethylhexyl) phthalate (DEHP) exposure impairs spermatogenesis in offspring.
• To identify specific genes and epigenetic changes involved in DEHP-induced reproductive defects.

Main Methods:

• Mice were exposed to di(2-ethylhexyl) phthalate (DEHP) during gestation.
• DNA methylation status of spermatogenesis-related genes in fetal testicular germ cells and adult spermatogonia was analyzed.
• Gene expression levels of affected genes were quantified.
• Reporter assays were used to confirm the effect of promoter methylation on gene expression.

Main Results:

• Maternal DEHP exposure led to DNA hypermethylation of spermatogenesis-related gene promoters in fetal testicular germ cells of F1 mice.
• Hypermethylation of specific genes, including Hist1h2ba, Sycp1, and Taf7l, persisted from fetal stages to adult spermatogonia.
• This persistent hypermethylation resulted in the downregulation of these crucial spermatogenesis genes.
• Forced methylation of these gene promoters in a reporter assay confirmed gene silencing.

Conclusions:

• Maternal DEHP exposure induces persistent DNA hypermethylation of key spermatogenesis genes (Hist1h2ba, Sycp1, Taf7l) in germ cells.
• This epigenetic modification leads to gene downregulation and subsequent defects in spermatogenesis in the F1 generation.
• The findings elucidate a mechanism for transgenerational reproductive toxicity caused by environmental chemicals.