Superfund Research Program
Sensitive Genotypes to Arsenic as a Model Environmental Teratogen
Project Leader: Richard H. Finnell (Baylor College of Medicine)
Grant Number: P42ES004917
Funding Period: 2000-2008
Final Progress Reports
The second most common of all structural birth defects, neural tube defects (NTDs), affect approximately 2.6/1000 births worldwide and 1/1000 births in the United States, causing serious physical disability and death. Arsenite and arsenate are suspect reproductive toxicants and are possibly teratogens in humans; however, epidemiological studies have fallen short of a conclusive association. Arsenate injected intraperitoneally (IP) to gravid laboratory rodents (mouse, rat, and hamster) during neural tube closure induces NTDs. In order to establish the teratogenic risk conferred by ingestion, the most common environmental exposure route, Dr. Finnell evaluated the teratogenicity of oral exposure during neural tube closure to 4.8, 9.6, and14.4 mg/kg (sodium arsenate) in an inbred mouse strain, LM/Bc/Fnn, that does not exhibit spontaneous neural tube malformations. Dams (20 per treatment group) were weighed daily, and evaluated for signs of maternal toxicity. Fetuses were evaluated for soft tissue and skeletal malformations. There was no evidence of maternal toxicity and the number of live fetuses affected with an NTD was 0 (0.0%), 1 (0.5%), 7 (4.0%), and 15 (8.2%) in animals treated with 0 (water treated control), 4.8, 9.6, and 14.4 mg/kg sodium arsenate, respectively. The results exhibited a positive linear trend (p< 0.0001). There was also evidence for linear trends in the relationships between the dose of arsenate and anomalies involving several components of the axial skeleton (sternebral, p< 0.0003; rib, p< 0.0002; vertebral, p< 0.0001; and calvarial, p< 0.0001). In Finnell's model system, maternal oral treatment with arsenate caused exencephaly and significantly increased the axial skeletal variations and malformations in the offspring exposed in utero, without evidence of maternal toxicity.
Dr. Finnell also evaluated the teratogenicity of maternal IP exposure to 9.6 mg/kg of sodium arsenate during neural tube closure in LM/Bc/Fnn mice. Arsenate exposure caused a rate of nearly 100% NTDs (100%, p<0.0001). Embryos were fixed and the anterior neural tube evaluated via electron microscopy for mitochondrial morphology with the assistance of the Image Analysis Core facility. Arsenate-exposed anterior neural tube tissue displayed mitochondrial morphological alterations characterized by disorganized cristae and the mechanisms of these effects were also investigated.