Nitrogen mustard exposure perturbs oocyte mitochondrial physiology and alters reproductive outcomes

Abstract

Nitrogen mustard (NM) is an alkylating chemical warfare agent, and its derivatives are used in chemotherapy. Alkylating agents can cause mitochondrial damage, so exposed females may transmit damaged genomes to their children, since mitochondria are maternally inherited and oocytes are not thought to undergo mitophagy (Boudoures et al. [1]). The objective of this study is to investigate NM's effects on oocyte mitochondria to understand risks facing female soldiers, cancer patients, and their children. Mice were injected intraperitoneally with NM, monitored for reproductive outcomes, and ovaries and oocytes were isolated for analysis. Escalating doses of NM increased oxidative stress in parental and F1 generation oocytes, suggesting that mitochondrial damage by NM is enhanced by mitochondrial superoxide. NM-treated ovaries in vitro exhibited smaller mitochondrial volume, more electron-dense and multivesicular structures, and lower birth weight litters. These results demonstrate that females must be protected from alkylating agents for their health, and the health of their offspring.

Keywords: Chemotherapy; Mitochondria; Mitophagy; Nitrogen mustard; Oocyte; Ovary; Oxidative stress.