Abstract
Highlights
- The effects of fluoride on the transcriptome and metabolome in the mice brain of two generations were studied.
- Fluoride mainly affected metabolites and genes in neuronal development and synaptic vesicle transport in two generations.
- Integrative analysis revealed that fluoride effectively disturbed choline and arachidonic acid metabolism in different ways for two generations.
Fluoride could cause developmental neurotoxicity and significantly affect the intelligence quotient (IQ) of children. However, the systematic mechanism of neuronal damage caused by excessive fluoride administration in offspring is largely unknown. Here, we present a comprehensive integrative transcriptome and metabolome analysis to study the mechanism of developmental neurotoxicity caused by chronic fluoride exposure. Comparing the different doses of fluoride treatments in two generations revealed the exclusive signature of metabolism pathways and gene expression profiles. In particular, neuronal development and synaptic ion transport are significantly altered at the gene expression and metabolite accumulation levels for both generations, which could act as messengers and enhancers of fluoride-induced systemic neuronal injury. Choline and arachidonic acid metabolism, which highlighted in the integrative analysis, exhibited different regulatory patterns between the two generations, particularly for synaptic vesicle formation and inflammatory factor transport. It may suggest that choline and arachidonic acid metabolism play important roles in developmental neurotoxic responses for offspring mice. Our study provides comprehensive insights into the metabolomic and transcriptomic regulation of fluoride stress responses in the mechanistic explanation of fluoride-induced developmental neurotoxicity.
Keywords
Excerpt:
5. Conclusion
First, fluoride exposure during pregnancy and lactation may cause neurodevelopmental disorders in the offspring mice, including abnormal expression of genes related to synaptic function, and aneurotransmitters’ accumulation; the magnitude and spectrum of response to fluoride exposure in parents and offspring are significantly different.
Second, in mice exposed to fluoride during gestation and lactation, metabolic accumulation of choline and arachidonic acid and their derivatives are the most important marker related to developmental neurotoxicity. This scenario is reported here for the first time.
Our study shows the correlation and difference between two generations of gene expression and metabolite accumulation in fluoride-exposed mice during pregnancy and lactation. We also found that choline and arachidonic acid metabolism pathways played the central role in neurodevelopmental disorders caused by fluoride uptake, and that further experiments need to be conducted to explore the regulatory mechanisms.
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