A Tiered Female Ovarian Toxicity Screening Identifies Toxic Effects of Checkpoint Kinase 1 Inhibitors on Murine Growing Follicles.

Toxicological Sciences : an Official Journal of the Society of Toxicology
Jingshan XuShuo Xiao

Abstract

Ovarian toxicity (ovotoxicity) is one of the major side effects of pharmaceutical compounds for women at or before reproductive age. The current gold standard for screening of compounds' ovotoxicity largely relies on preclinical investigations using whole animals. However, in vivo models are time-consuming, costly, and harmful to animals. Here, we developed a 3-tiered ovotoxicity screening approach starting from encapsulated in vitro follicle growth (eIVFG) and screened for the potential ovotoxicity of 8 preclinical compounds from AstraZeneca (AZ). Results from Tiers 1 to 2 screenings using eIVFG showed that the first 7 tested AZ compounds, AZ-A, -B, -C, -D, -E, -F, and -G, had no effect on examined mouse follicle and oocyte reproductive outcomes, including follicle survival and development, 17β-estradiol secretion, ovulation, and oocyte meiotic maturation. However, AZ-H, a preclinical compound targeting the checkpoint kinase 1 inhibitor to potentiate the anticancer effects of DNA-damaging agents, significantly promoted granulosa cell apoptosis and the entire growing follicle atresia at clinically relevant concentrations of 1 and 10 μM. The more targeted explorations in Tier 2 revealed that the ovotoxic effect of AZ-H primarily...Continue Reading

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