4-Phenylbutyric acid may prevent mouse ovarian and uterine damage due to procymidone-induced alteration of circRNA Scar and circZc3h4 levels by controlling excessive unfolded protein response

Abstract

Procymidone (PCM) below the no-observed-adverse-effect-level (NOAEL) has previously been proven to induce ovarian and uterine damage in adolescent mice due to its raised circRNA Scar, decreased circZc3h4, and overactivated unfolded protein response (UPR). Also, 4-phenylbutyric acid (4-PBA) inhibits histone deacetylase and endoplasmic reticulum stress, reduces UPR, improves metabolism, and ensures homeostasis within the endoplasmic reticulum. In this study, 20, 40 and 80 mM of 4-PBA were utilized respectively to intervene the damage caused by 1.0 × 10−5 M PCM to ovaries and uterus in vitro culture. Besides, 100 mg/kg /d 4-PBA was intraperitoneally injected to female adolescent mice before, during and after oral administration of 100 mg/kg /d PCM for prevention and cure to observe tissue changes in the ovaries and uteri, and levels of circRNA Scar, circZc3h4 and UPR members. Our findings demonstrated that in vitro experiments, all doses of 4-PBA could inhibit ovarian and uterine damage caused by PCM, and the effect of 80 mM was especially noticeable. In the in vivo experiments, the best results were obtained when PCM was given with simultaneous 4-PBA intervention, i.e., minimal ovarian and uterine damage. Both in vivo and in vitro, 4-PBA in the ovary and uterus resulted in decreased circRNA Scar levels, increased circZc3h4 abundance, and moderately elevated levels of UPR members. So, it is suggested that 4-PBA moderately activates UPR, partially or completely antagonizing the elevated circRNA Scar and decreased circZc3h4 and consequently preventing PCM-induced ovarian and uterine damage effectively in adolescent mice.