As a heterogeneous reproductive disorder, polycystic
ovary syndrome
(PCOS) can be caused by genetic, diet, and environmental factors.
Bisphenol A (BPA) can induce PCOS and nonalcoholic fatty liver disease
(NAFLD) due to direct exposure; however, whether these phenotypes
persist in future unexposed generations is not currently understood.
In a previous study, we observed that transgenerational NAFLD persisted
in female medaka for five generations (F4) after exposure to an environmentally
relevant concentration (10 μg/L) of BPA. Here, we demonstrate
PCOS in the same F4 generation female medaka that developed NAFLD.
The ovaries contained immature follicles, restricted follicular progression,
and degenerated follicles, which are characteristics of PCOS. Untargeted
metabolomic analysis revealed 17 biomarkers in the ovary of BPA lineage
fish, whereas transcriptomic analysis revealed 292 genes abnormally
expressed, which were similar to human patients with PCOS. Metabolomic–transcriptomic
joint pathway analysis revealed activation of the cancerous pathway,
arginine–proline metabolism, insulin signaling, AMPK, and HOTAIR
regulatory pathways, as well as upstream regulators esr1 and tgf signaling in the ovary. The present results
suggest that ancestral BPA exposure can lead to PCOS phenotypes in
the subsequent unexposed generations and warrant further investigations
into potential health risks in future generations caused by initial
exposure to EDCs.