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A Paternal Methylation Error in the Congenital Hydrocephalic Texas (H-Tx) Rat Is Partially Rescued with Natural
Naila Naz1, Ghazaleh Moshkdanian1, Salma Miyan1
1Division of Neuroscience, Faculty of Biology, Medicine and Health, The University of Manchester, 3.540 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
Insights
Germline folate metabolism errors and reduced DNA methylation in male H-Tx rats contribute to hydrocephalus. Folate supplementation partially restored methylation, suggesting maternal supplementation alone may not fully prevent this neurological disorder.
Area of Science:
- Reproductive biology
- Developmental neuroscience
- Biochemistry
Background:
- Folate deficiencies and abnormal methylation are linked to birth defects and neurological conditions.
- Reduced 10-formyl tetrahydrofolate dehydrogenase (FDH) in hydrocephalic Texas (H-Tx) rats correlates with decreased DNA methylation.
- The H-Tx rat model exhibits hydrocephalus, a complex neurological disorder.
Purpose of the Study:
- To investigate folate metabolism and methylation errors in sexually mature, unaffected H-Tx rats.
- To determine if germline methylation defects in male H-Tx rats contribute to hydrocephalus inheritance.
- To assess the impact of folate supplementation on methylation in H-Tx rats.
Main Methods:
- Comparison of normal Sprague Dawley (SD) rats with untreated (uH-Tx) and folate-treated (TrH-Tx) H-Tx rats.
- Analysis of testicular structural abnormalities, DNA methylation (5-methylcytosine, 5-hydroxymethylcytosine), and protein expression (FDH, FRα, DNA-methyltransferase-1).
- Evaluation of tissue folate levels and cell death, particularly in sperm.
Main Results:
- uH-Tx rats showed testicular structural abnormalities, decreased DNA methylation, increased demethylation, and sperm cell death.
- FDH and FRα protein expression increased in uH-Tx males; 5-methylcytosine was significantly reduced.
- Folate treatment partially restored 5-methylcytosine and DNA-methyltransferase-1 expression, but tissue folate levels remained unchanged.
Conclusions:
- Unaffected adult male H-Tx rats exhibit germline methylation errors, specifically in the testes and sperm.
- Reduced testicular methylation is partially reversible with folate supplementation.
- Maternal folate supplementation alone may be insufficient to completely eradicate hydrocephalus in H-Tx offspring.
Abstract:
Folate deficiencies, folate imbalance and associated abnormal methylation are associated with birth defects, developmental delays, neurological conditions and diseases. In the hydrocephalic Texas (H-Tx) rat, 10-formyl tetrahydrofolate dehydrogenase (FDH) is reduced or absent from the CSF and the nuclei of cells in the brain and liver and this is correlated with decreased DNA methylation. In the present study, we tested whether impaired folate metabolism or methylation exists in sexually mature, unaffected H-Tx rats, which may explain the propagation of hydrocephalus in their offspring. We compared normal Sprague Dawley (SD, n = 6) rats with untreated H-Tx (uH-Tx, n = 6 and folate-treated H-Tx (TrH-Tx, n = 4). Structural abnormalities were observed in the testis of uH-Tx rats, with decreased methylation, increased demethylation, and cell death, particularly of sperm. FDH and FRα protein expression was increased in uH-Tx males but not in folate-treated males but tissue folate levels were unchanged. 5-Methylcytosine was significantly reduced in untreated and partially restored in treated individuals, while 5-hydroxymethylcytosine was not significantly changed. Similarly, a decrease in DNA-methyltransferase-1 expression in uH-Tx rats was partially reversed with treatment. The data expose a significant germline methylation error in unaffected adult male H-Tx rats from which hydrocephalic offspring are obtained. Reduced methylation in the testis and sperm was partially recovered by treatment with folate supplements leading us to conclude that this neurological disorder may not be completely eradicated by maternal supplementation alone.
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