Detection of DNA damage in oocytes of small ovarian follicles following phosphoramide mustard exposures of cultured rodent ovaries in vitro

Petrillo, Stephanie; Desmeules, Patrice; Truong, To‐Quyen; Devine, Patrick J.

doi:10.1016/j.taap.2011.03.012

Cited by 83 publications

(90 citation statements)

References 66 publications

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“…Moreover, the toxic metabolite, phosphoramide mustard (PM) of cyclophosphamide has been shown to be active ovotoxic in vivo 35 and in vitro 36 and may cause DNA double-strand breaks in oocytes, which could lead to permanent changes in gamete health and increased risk for fertility problems or unhealthy offspring. 37 In addition, chloroacetaldehyde (CAA), which is produced by the sidechain oxidation of ifosfamide in renal tubular cells, 38 is responsible for severe glutathione (GSH) depletion and malondialdehyde (MDA) accumulation.…”

Section: Discussionmentioning

confidence: 99%

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

Helal

2016

Renal Failure

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This study was designed to investigate whether the treatment with the N-acetyl-L-cysteine prior to the administration of chemotherapy drug would prevent from nephrotoxicity and the loss of reproductive performance induced from chemotherapy treatment. Female rats were divided into five equal groups of six each: 1/control group; 2/rats i.p administered saline solution; 3/rats i.p administered holoxan (50 mg/kg b.wt); 4/rats i.p administered N-acetyl-L-cysteine (160 mg/kg b.wt); 5/rats i.p administered holoxan and N-acetyl-L-cysteine at the same doses. After medications, females rats were allowed to mate with males and the pregnant rats were sacrificed on day 18 of gestation. Premating treatment with holoxan showed reduction (p50.05) in reproductive performance. Whereas administration of N-acetyl-L-cysteine prior to treatment with holoxan and then concurrently with it modulated significantly fertility index, progesterone level, decreasing postimplantation loss, resorbed fetuses and improved fetal growth. Additionally, holoxan elevated the renal nicotinamide dinucleotide phosphate (NADPH) oxidase activity, oxidative stress, renal functions and caused histological changes in renal tissue. N-Acetyl-L-cysteine treatment reduced (p50.05) renal tissue NADPH oxidase, nitric oxide, malondialdehyde and improved super oxide dismutase (SOD) depletion, elevated levels phosphate, total protein and calcium as well as prevented renal histological damages. N-Acetyl-L-cysteine can confer protection against nitrosative and oxidative stresses in renal tissue induced by holoxan by suppressing NADPH oxidase activation, malondialdehyde, nitric oxide and restoring SOD activity which led to the reduction of reactive oxygen species production and subsequently might effectively improve the gonadal hormone disturbance and reproductive functions. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

Helal

2016

Renal Failure

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“…According to the previous studies, chemotherapeutic drugs significantly increased follicle atresia predominantly within 72 h after the treatment and the number of atretic follicle quickly returned to the basal level within one week after the treatment. Subsequently, the degenerative follicles were removed from the ovary within a 3-day period [32], [44]. This should be the reason of the discordance in the observed numbers of follicle loss versus atresia.…”

Section: Discussionmentioning

confidence: 99%

Amniotic Fluid Stem Cells Prevent Follicle Atresia and Rescue Fertility of Mice with Premature Ovarian Failure Induced by Chemotherapy

et al. 2014

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Chemotherapy used to treat cancer may cause irreversible premature ovarian failure (POF). Of late, amniotic fluid stem cells (AFSCs) provide a novel source for regenerative medicine because of their primitive stage, low immunogenicity, and easy accessibility. In this study, we isolated AFSCs from transgenic mice that ubiquitously express enhanced green fluorescence protein (EGFP). These AFSCs exhibited morphologies, immunophenotypes, and mesoderm trilineage differentiation potentials similar to mesenchymal stem cells (MSCs). Further, AFSCs proliferated faster than MSCs and expressed OCT4, a marker for pluripotency. To investigate their potential in recovering fertility in POF model, AFSCs were transplanted into the ovaries of mice with POF six weeks post induction using chemotherapeutic drugs, busulfan and cyclophosphamide. AFSCs could rescue the reproductive ability of mice with POF by preventing follicle atresia and sustaining the healthy follicles. Notably, the transplanted AFSCs did not differentiate into granulosa and germline cells in vivo. After one month, the decreased numbers of transplanted AFSCs accompanied with the reduced beneficial effects indicated that the therapeutic efficacy were directly from AFSCs. These findings demonstrated the therapeutic effects of AFSCs and suggested the promise of AFSCs for treating infertility and POF caused by chemotherapy.

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“…ATM phosphorylates histone H2AX (γH2AX) which leads, within seconds, to recruitment of DNA repair molecules to the site of DSBs (Sedelnikova et al , 2002; Svetlova et al , 2010), thus γH2AX has become a gold standard marker for localizing DSBs. DNA DSB's pose a serious threat to both cell viability and genome stability if left unrepaired or repaired incorrectly, and could potentially lead to permanent damage with resulting negative consequences for gamete health (Petrillo et al , 2011; Summers et al , 2011). Two major pathways can repair DNA DSB's: Non-Homologous End Joining (NHEJ) (Chiruvella et al , 2012) and Homologous Recombination (HR) (Scully et al , 1997).…”

Section: Introductionmentioning

confidence: 99%

Enhanced susceptibility of ovaries from obese mice to 7,12-dimethylbenz[a]anthracene-induced DNA damage

Ganesan

Nteeba

Keating

2014

Toxicology and Applied Pharmacology

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7,12-dimethylbenz[a]anthracene (DMBA) depletes ovarian follicles and induces DNA damage in extra-ovarian tissues, thus, we investigated ovarian DMBA-induced DNA damage. Additionally, since obesity is associated with increased offspring birth defect incidence, we hypothesized that a DMBA-induced DNA damage response (DDR) is compromised in ovaries from obese females. Wild type (lean) non agouti (a/a) and KK.Cg-Ay/J heterozygote (obese) mice were dosed with sesame oil or DMBA (1mg/kg; intraperitoneal injection) at 18 wks of age, for 14 days. Total ovarian RNA and protein were isolated and abundance of Ataxia telangiectasia mutated (Atm), X-ray repair complementing defective repair in chinese hamster cells 6 (Xrcc6), Breast cancer type 1 (Brca1), Rad 51 homolog (Rad51), Poly [ADP-ribose] polymerase 1 (Parp1) and Protein kinase, DNA-activated, catalytic polypeptide (Prkdc) were quantified by RT-PCR or Western blot. Phosphorylated histone H2AX (γH2AX) level was determined by Western blotting. Obesity decreased (P < 0.05) basal protein abundance of PRKDC and BRCA1 proteins but increased (P < 0.05) γH2AX and PARP1 proteins. Ovarian ATM, XRCC6, PRKDC, RAD51 and PARP1 proteins were increased (P < 0.05) by DMBA exposure in lean mice. A blunted DMBA-induced increase (P < 0.05) in XRCC6, PRKDC, RAD51 and BRCA1 was observed in ovaries from obese mice, relative to lean counterparts. Taken together, DMBA exposure induced γH2AX as well as the ovarian DDR, supporting that DMBA causes ovarian DNA damage. Additionally, ovarian DDR was partially attenuated in obese females raising concern that obesity may be an additive factor during chemical-induced ovotoxicity.

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Detection of DNA damage in oocytes of small ovarian follicles following phosphoramide mustard exposures of cultured rodent ovaries in vitro

Cited by 83 publications

References 66 publications

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

Amniotic Fluid Stem Cells Prevent Follicle Atresia and Rescue Fertility of Mice with Premature Ovarian Failure Induced by Chemotherapy

Enhanced susceptibility of ovaries from obese mice to 7,12-dimethylbenz[a]anthracene-induced DNA damage

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