Nitrogen mustard exposure perturbs oocyte mitochondrial physiology and alters reproductive outcomes

•Molecular and longitudinal effects of NM exposure are transmitted to F1 generation, but not to the F2 generation.•Primary nitrogen mustard exposure increases reactive oxygen species, but does not change ATP abundance.•Maternal nitrogen mustard exposure prior to pregnancy resulted in lowered birth w...

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Published in:Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2018-12, Vol.82, p.80-87
Main Authors: Brayboy, Lynae M., Clark, Haley, Knapik, Laura O., Schnirman, Ruby E., Wessel, Gary M.
Format: Article
Language:English
Subjects:
Animals
Chemical Warfare Agents - toxicity
Chemotherapy
Female
Mechlorethamine - toxicity
Mice
Microscopy, Electron
Mitochondria
Mitochondria - drug effects
Mitochondria - physiology
Mitochondria - ultrastructure
Mitophagy
Nitrogen mustard
Oocyte
Oocytes - drug effects
Oocytes - physiology
Oocytes - ultrastructure
Ovary
Oxidative stress
Reproduction
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Summary:•Molecular and longitudinal effects of NM exposure are transmitted to F1 generation, but not to the F2 generation.•Primary nitrogen mustard exposure increases reactive oxygen species, but does not change ATP abundance.•Maternal nitrogen mustard exposure prior to pregnancy resulted in lowered birth weights in PND3 pups. 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.
ISSN:0890-6238
1873-1708
DOI:10.1016/j.reprotox.2018.10.002