| Title: | MDR-1 function protects oocyte mitochondria against the transgenerational effects of nitrogen mustard exposure |
| Author(s): | Clark H; Pereira Vera B; Zhang Z; Brayboy LM; |
| Address: | "Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA; Brown University Providence, RI USA. Electronic address: Haley_Clark@alumni.brown.edu. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University 185 Meeting Street, Providence, RI 02912, USA; Brown University Providence, RI USA. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA; Brown University Providence, RI USA. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA; Alpert Medical School of Brown University, 222 Richmond Street Providence, RI 02903, USA; Department of Molecular Biology, Cell Biology and Biochemistry, Brown University 185 Meeting Street, Providence, RI 02912, USA; Brown University Providence, RI USA. Electronic address: Lynae_Brayboy@brown.edu" |
| DOI: | 10.1016/j.reprotox.2020.10.010 |
| ISSN/ISBN: | 1873-1708 (Electronic) 0890-6238 (Linking) |
| Abstract: | "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" |
| Keywords: | "ATP Binding Cassette Transporter, Subfamily B/*genetics Animals Chemical Warfare Agents/*toxicity Female Loss of Function Mutation Male Maternal-Fetal Exchange Mechlorethamine/*toxicity Membrane Potential, Mitochondrial/drug effects Mice Mitochondria/*dru;" |
| Notes: | "MedlineClark, Haley Pereira Vera, Barbara Zhang, Zijing Brayboy, Lynae M eng P20 GM121298/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2020/11/10 Reprod Toxicol. 2020 Dec; 98:252-259. doi: 10.1016/j.reprotox.2020.10.010. Epub 2020 Oct 23" |
