Low levels of Cd2+ combined with procymidone may cause ovarian damage in mice via unfolded protein response

Abstract As no study about the combined effect of low levels of Cd 2+ with procymidone (PCM) on organs and organisms, we investigated their actions on mouse‐ovary in vivo and in vitro. Four‐week mice were treated with corn oil for the control group, corn oil + 0.0045 mg/L Cd 2+ (CdCl 2 was dissolved in ultrapure water and freely consumed by mice) for Cd 2+ group, 50 mg/kg/d PCM (suspended in corn oil and administered orally to mice) for PCM group, and 50 mg/kg/d PCM + 0.0015 (0.0045 and 0.0135) mg/L Cd 2+ for L+ (M+ and H+) PCM group for 21 days. For in vitro experiment, the cultured ovaries were treated with acetone for the control group, 0.1% acetone + 8.4 μg/L Cd 2+ for the Cd 2+ group, 0.63 mg/L PCM (dissolved in acetone) for the PCM‐group, and 0.63 mg/L PCM + 2.8 (8.4 and 25.2) μg/L Cd 2+ for L+ (M+ and H+) PCM group for 7 days. Mouse body weight in each treatment group, the weight and volume of ovaries in all PCM groups were lower than the control. Both in vivo and in vitro, all‐stage follicle numbers were lower in M+PCM and H+PCM groups, whereas the atretic follicles and CASPASE3/8 were higher; meanwhile, lower estradiol and progesterone and higher unfolded protein response (UPR) members in all PCM groups. L+, M+, and H+PCM groups had further ovarian damage and stronger UPR than PCM groups, as did M+PCM groups over Cd 2+ groups. It is hypothesized low‐level PCM and Cd 2+ may mutually promote each other's triggered UPR and exacerbate ovarian damage.