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Cisplatin-DNA adduct formation in rat spermatozoa and its effect on fetal development
S B Hooser1, W C van Dijk-Knijnenburg, I D Waalkens-Berendsen
1TNO Nutrition and Food Research Institute, Toxicology Division, Zeist, The Netherlands. hooser@addl.purdue.edu
Abstract:
Exposure of males to some genotoxic chemicals causes DNA damage in spermatozoa resulting in embryotoxicity and developmental defects in their offspring. This study demonstrates that cisplatin-DNA adducts could be measured in spermatozoa following treatment with the antineoplastic drug, cisplatin. The formation of spermatozoa cisplatin-DNA adducts showed dose and time-dependent increases both in vitro, and in vivo up to 168 h (7 days) after dosing. Treatment of rats with 10 mg cisplatin/kg resulted in spermatozoa Pt-GG adduct levels of approximately 1.0 fmol/microg DNA. When cisplatin-treated male rats were bred to untreated females 6-24 h after cisplatin administration, no adverse developmental effects or decreases in body weight were seen in the offspring although there was a trend towards increased early embryo mortality.
Insights
Exposure to cisplatin, a cancer drug, can damage sperm DNA. This study measured cisplatin-DNA adducts in sperm, showing dose and time-dependent increases, with a trend towards early embryo mortality in offspring.
Area of Science:
- Toxicology
- Reproductive Biology
- Genetics
Background:
- Genotoxic chemical exposure in males can lead to sperm DNA damage.
- This damage may cause embryotoxicity and developmental issues in offspring.
- Cisplatin is an antineoplastic drug with known genotoxic potential.
Purpose of the Study:
- To determine if cisplatin-DNA adducts can be measured in spermatozoa.
- To investigate the dose and time-dependent formation of these adducts.
- To assess the developmental effects on offspring after paternal cisplatin exposure.
Main Methods:
- In vitro and in vivo experiments were conducted.
- Rats were treated with varying doses of cisplatin.
- Spermatozoa were analyzed for cisplatin-DNA adducts (Pt-GG) using quantitative methods.
- Offspring developmental parameters were evaluated after breeding treated males with untreated females.
Main Results:
- Cisplatin-DNA adducts were successfully measured in spermatozoa.
- Adduct formation increased with cisplatin dose and time post-treatment (up to 7 days).
- A dose of 10 mg/kg cisplatin resulted in approximately 1.0 fmol/microg DNA adducts.
- Offspring showed no adverse developmental effects or reduced body weight, but a trend towards increased early embryo mortality was observed.
Conclusions:
- Spermatozoa can retain cisplatin-DNA adducts following drug exposure.
- Paternal exposure to cisplatin at the tested dose did not cause significant developmental defects in offspring.
- A potential trend towards increased early embryo mortality warrants further investigation.
