MDR-1 function protects oocyte mitochondria against the transgenerational effects of nitrogen mustard exposure
| Autor: | Lynae M. Brayboy, Zijing Zhang, Barbara Pereira Vera, Haley Clark |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
ATP Binding Cassette Transporter Subfamily B Offspring 010501 environmental sciences Mitochondrion Toxicology medicine.disease_cause 01 natural sciences Andrology 03 medical and health sciences chemistry.chemical_compound Mice Loss of Function Mutation Pregnancy medicine Animals Chemical Warfare Agents Mechlorethamine Maternal-Fetal Exchange 030304 developmental biology 0105 earth and related environmental sciences chemistry.chemical_classification Membrane Potential Mitochondrial 0303 health sciences Reactive oxygen species Germinal vesicle Chemistry Wild type Oocyte Nitrogen mustard Mitochondria medicine.anatomical_structure Prenatal Exposure Delayed Effects Oocytes Female Reactive Oxygen Species Oxidative stress |
| Zdroj: | Reproductive toxicology (Elmsford, N.Y.). 98 |
| ISSN: | 1873-1708 |
| Popis: | Oocytes are vulnerable to alkylating agents like nitrogen mustard (NM), which can cause mitochondrial dysfunction associated with increased oxidative stress. Because mitochondria are maternally inherited, NM exposure affects oocyte mitochondrial physiology and compromises future progeny. Multidrug resistance transporters (MDRs) are transmembrane proteins that efflux such cytotoxic substances; MDR-1 is expressed in oocyte plasma and mitochondrial membranes and protects against oxidative stress. Our objective was to investigate how loss of MDR-1 can modulate oocyte response to NM transgenerationally. Wild Type (WT) and Mdr1a mutant female mice were injected intraperitoneally with sterile saline (control) or 0.1 mg/kg NM. 48 h post-injection, females were either sacrificed for F0 studies or mated with control males to yield F1 pups. After weaning, F1 females were sacrificed or mated to yield F2 pups. Germinal vesicle oocytes were assessed for mitochondrial membrane potential and reactive oxygen species (ROS) levels. NM exposed oocytes of both genotypes exhibited significantly higher ROS than controls in F0 and F1. NM F2 oocytes of neither genotype exhibited significantly higher ROS, though variation in Mdr1a mutants led to an upward trend. NM oocytes of both genotypes exhibited significantly disrupted mitochondrial membrane potential in F0. WT regained normalcy by F1 whereas Mdr1a mutants were unable to by F2. Our data suggest that Mdr1a mutants exhibit transgenerational mitochondrial dysfunction following toxic challenge that persists, implying that MDR-1 protects against toxicant-induced mitochondrial stress. Women without functional MDR-1 exposed to environmental toxicants could therefore be at risk for passing on compromised mitochondria to future offspring. |
| Databáze: | OpenAIRE |
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