Influence of the menstrual cycle and sex hormones on the response to genotoxic stress in human cells

Although the menstrual cycle and sex hormones have been shown to influence the molecular response to drugs and chemicals, this phenomenon is still insufficiently examined. In this study, the effects of the menstrual cycle and sex hormones on the genotoxic stress response were investigated, with the focus on the activation of poly(ADP-ribose) polymerases (PARPs). Peripheral blood mononuclear cells (PBMCs) were isolated from blood collected from naturally cycling female donors (n=10) at three phases of their menstrual cycle: (I) early follicular, (II) late follicular/ovulatory, and (III) mid-luteal, as well as from age-matched males (n=6). PBMCs were treated with the DNA-damaging agent hydrogen peroxide (H 2 O 2 ) in the presence or absence of the PARP inhibitor olaparib. In female-derived cells, phase I showed the lowest level of DNA strand breaks (SBs) and the highest cell survival following H 2 O 2 exposure. Of note, cell death positively correlated with plasma progesterone levels. Simultaneously, the menstrual cycle had no clear effect on PAR formation or the inhibitory properties of olaparib. Females showed generally lower levels of DNA SBs and higher PAR accumulation than males. Moreover, sex hormones (17β-estradiol, progesterone, or testosterone) showed a moderate dose- and cell type-specific modulation of genotoxic stress in in vitro experiments on several cell lines. Together, this pilot study shows the potential impact of the menstrual cycle and sex hormones on the molecular genotoxic stress response and calls for deeper exploration of their role in toxicological and pharmacological studies.