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Arsenic-induced neural tube defects in mice: alterations in cell cycle gene expression
B J Wlodarczyk1, G D Bennett, J A Calvin
1Department of Veterinary Anatomy and Public Health, Texas A & M University, College Station 77843-4458, USA.
Abstract:
The potential of arsenic to cause neural tube defects (NTD) in the human population remains a topic of controversy. While clearly toxic, the lack of well-defined human epidemiologic studies on this subject has made it difficult to fully understand the effects arsenic may have on the developing human neural tube. In the absence of good clinical data, we have tried to develop a murine model where hypotheses about the reproductive toxicity of arsenate can be tested. For these studies a murine strain (LM/Bc) that has proven to be susceptible to arsenic-induced NTD was use. Because cellular proliferation is vital for normal neural tube closure (NTC) to occur, in the present study we investigated whether an acute arsenate treatment could alter the expression of several cell cycle genes during murine neurulation. Pregnant LM/Bc dams were injected intraperitoneally on gestation day (GD) 7:12 (day:hour) and 8:12 with 40 mg/kg of arsenate, a treatment that causes exencephaly in 90 to 100% of the exposed fetuses. Neural tubes were then isolated from both control and arsenic treated embryos at GD 9:00, 9:12, 10:00, and 10:12, which encompasses all the stages of neurulation for this murine strain. Using the molecular techniques of in situ transcription and antisense RNA amplification (RT/aRNA) the expression pattern for bc1-2, p53, wee-1, and wnt-1 was analyzed at each of these time points. In the neural tubes isolated from control embryos, the expression of all four genes was significantly altered as neurulation progressed, demonstrating their developmental regulation. Following arsenate treatment, however, there was a significant upregulation in the expression of bc1-2 and p53 at gestational day 9:0, compared to their control values. The heightened expression of both of these genes suggests that arsenic inhibits cell proliferation, rather than inducing apoptosis, which delayed NTC and ultimately led to the neural tube defects observed in exposed embryos.
Insights
Arsenic exposure during pregnancy can cause neural tube defects (NTDs) by inhibiting cell proliferation, not by inducing cell death. This study used a mouse model to investigate arsenic
Area of Science:
- Developmental toxicology
- Neuroscience
- Molecular biology
Background:
- Arsenic's potential to cause neural tube defects (NTDs) in humans is controversial due to limited epidemiologic data.
- Cellular proliferation is crucial for normal neural tube closure (NTC).
Purpose of the Study:
- To investigate the effects of acute arsenate exposure on cell cycle gene expression during murine neurulation.
- To elucidate the mechanism by which arsenic may cause NTDs.
Main Methods:
- A murine model (LM/Bc strain) susceptible to arsenic-induced NTDs was used.
- Pregnant dams received arsenate injections on specific gestational days.
- Neural tubes from control and treated embryos were analyzed for gene expression (bcl-2, p53, wee-1, wnt-1) using RT/aRNA.
Main Results:
- Arsenate treatment significantly upregulated bcl-2 and p53 expression in neural tubes at gestational day 9:0.
- Developmental regulation of bcl-2, p53, wee-1, and wnt-1 was observed in control embryos.
- Heightened bcl-2 and p53 expression suggests arsenic inhibits cell proliferation.
Conclusions:
- Arsenic exposure during critical developmental periods inhibits cell proliferation, leading to delayed neural tube closure and NTDs.
- The findings suggest a mechanism for arsenic-induced reproductive toxicity.
- Further research is needed to fully understand arsenic's impact on human neural tube development.