Olaparib induces craniofacial cartilage malformations in zebrafish embryos through DNA damage, oxidative stress, and Wnt dysregulation
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Assessing Teratogenic Changes in a Zebrafish Model of Fetal Alcohol Exposure
Published on: March 20, 2012
Min Huang1, Nannan Wang2, Xianhua Zhang1
1The Affiliated Stomatological Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Oral Diseases, Jiangxi Provincial Clinical Research Center for Oral Diseases, Nanchang, Jiangxi 330006, PR China.
Abstract:
Pharmaceutical residues in aquatic environments are a growing concern. Global surveillance has detected these residues in nearly a quarter of the world's rivers, with anticancer drugs drawing particular attention due to their high bioactivity. Olaparib (Ola), a poly(ADP-ribose) polymerase (PARP) inhibitor, is widely used to treat breast and ovarian cancers, but its developmental toxicity to aquatic vertebrates remains unclear. We exposed zebrafish embryos to Ola (5-15 mg/L) from 6 to 120 h post-fertilization (hpf). Ola exposure caused dose-dependent craniofacial cartilage malformations and behavioral abnormalities. Mechanistically, Ola induced DNA damage (Comet assay) and mitochondrial depolarization (JC-10), as well as oxidative stress evidenced by elevated reactive oxygen species (ROS) levels and impaired antioxidant defenses. Ola exposure impaired cranial neural crest cell (CNCC) migration, as shown by reduced sox10:GFP⁺ fluorescence and altered expression of pax3a, dlx2a, and dlx5a. It also reduced chondrogenic differentiation, with lower expression of sox9a and col2a1, and increased apoptosis, as indicated by more TUNEL-positive cells. Ola also altered Wnt/β‑catenin pathway gene expression. Pharmacological rescue experiments showed that the antioxidant astaxanthin (60 μg/L) and the Wnt inhibitor C59 (3.79 μg/L) both attenuated craniofacial malformations. Together, these results indicate that Ola induces DNA damage and oxidative stress, impairs CNCC function, and disrupts Wnt signaling, leading to craniofacial cartilage deformities. This study underscores the developmental toxicity of PARP inhibitors as emerging environmental contaminants and offers insights into the mechanisms underlying craniofacial cartilage malformations.
Insights
Olaparib, a cancer drug, causes developmental defects in zebrafish by damaging DNA and increasing oxidative stress. These effects impair neural crest cell development and Wnt signaling, leading to craniofacial deformities in aquatic vertebrates.
Area of Science:
- Environmental Toxicology
- Developmental Biology
- Pharmacology
Background:
- Pharmaceutical residues, including anticancer drugs like Olaparib (PARP inhibitor), are detected in global river systems.
- The developmental toxicity of Olaparib to aquatic vertebrates is not well understood, posing a potential environmental risk.
Purpose of the Study:
- To investigate the developmental toxicity of Olaparib in zebrafish embryos.
- To elucidate the underlying molecular mechanisms of Olaparib-induced developmental abnormalities.
Main Methods:
- Zebrafish embryos were exposed to Olaparib (5-15 mg/L) from 6 to 120 hours post-fertilization.
- Assessed craniofacial morphology, behavior, DNA damage (Comet assay), mitochondrial function (JC-10), oxidative stress (ROS), neural crest cell migration (sox10:GFP), gene expression (pax3a, dlx2a, dlx5a, sox9a, col2a1), apoptosis (TUNEL), and Wnt/β-catenin signaling.
- Pharmacological rescue experiments were conducted using astaxanthin and C59.
Main Results:
- Olaparib exposure caused dose-dependent craniofacial cartilage malformations and behavioral issues.
- Mechanisms included induced DNA damage, mitochondrial depolarization, elevated oxidative stress, impaired antioxidant defenses, reduced cranial neural crest cell migration, and disrupted chondrogenic differentiation.
- Olaparib altered Wnt/β-catenin pathway gene expression, and astaxanthin/C59 partially rescued the malformations.
Conclusions:
- Olaparib exhibits developmental toxicity in zebrafish, inducing craniofacial deformities through DNA damage, oxidative stress, impaired neural crest cell function, and Wnt signaling disruption.
- PARP inhibitors represent emerging environmental contaminants with significant developmental risks to aquatic life.
- This study provides crucial insights into the ecotoxicological impact of Olaparib and the mechanisms of craniofacial development disruption.
