Hypospadias and Intake of Nutrients Related to One-Carbon Metabolism

California Research Division, March of Dimes Foundation, Oakland, California, USA.
The Journal of urology (Impact Factor: 4.47). 12/2008; 181(1):315-21; discussion 321. DOI: 10.1016/j.juro.2008.09.041
Source: PubMed


We examined whether hypospadias is associated with maternal intake of folic acid containing vitamin/mineral supplements or dietary intake of nutrients related to one-carbon metabolism (folate, choline, vitamins B12 and B6, thiamine, riboflavin, methionine and zinc).
The study included births from October 1997 to December 2003 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews. Analyses included 915 cases with second or third degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 2,266 male, liveborn, nonmalformed controls. All ORs and 95% CIs were estimated from logistic regression models that included several potential confounders. Nutrient based analyses also included energy intake.
Hypospadias risk was not associated with supplement use (adjusted ORs were 1.2, 95% CI 0.9-1.6 for intake beginning in the month before or the first month of pregnancy and 1.1, 95% CI 0.8-1.4 for intake beginning in the second or third month, relative to no intake). Among women who took supplements reduced hypospadias risk was associated with higher dietary intakes of choline, methionine and vitamin B12. The respective ORs (CIs) for the highest vs lowest quartiles were 0.7 (0.5-1.1), 0.6 (0.4-0.9) and 0.7 (0.5-1.0). Among women who did not take supplements increased risk of hypospadias was associated with higher vitamin B12 intake. The OR (CI) for the highest vs lowest quartile was 3.1 (1.1-9.0).
This study suggests an association of hypospadias with intake of certain nutrients related to one-carbon metabolism.

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    • "We found an association between increased level of propionylcarnitine and the risk of hypospadias in newborns. The presented results support the hypothesis that there is a link between maternal intake of certain nutrients involved in the metabolism of methyl groups and the risk of hypospadias [5]. Some experimental evidence exists in favor of the ameliorative effects of vitamin B12 on teratogen–induced congenital anomalies in rodents [13, 14]. "
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    ABSTRACT: Of interest is if factors like maternal diet can influence the risk of hypospadias-affected pregnancy. Increased propionylcarnitine (C3) is regarded as a biomarker of vitamin B12 deficiency. The retrospective study was undertaken to determine whether increased propionylcarnitine and low methionine in newborns are associated with hypospadias. 41 newborns with hypospadias and 90 control newborns without congenital anomalies were investigated. Whole blood propionylcarnitine and methionine concentrations were measured using tandem mass spectrometry. The mean concentration of propionylcarnitine was higher in newborns with hypospadias compared with newborns without congenital anomalies (p = 0.026). The mean methionine level in cases was insignificantly lower than in controls. There appears to be an association between decreased vitamin B12, as indexed by an increase of propionylcarnitine, and hypospadias in the investigated group of patients.
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    • "MTHFR and OCM play key roles in physiologic processes by regulating the channeling of onecarbon units between the DNA cycle (nucleotide synthesis) and the methylation cycle (Frankenburg, 2007; Krebs et al., 2009; Laanpere et al., 2010). Dysfunction of the OCM cycle has been linked to neural tube defects (van der Put et al., 2001; Zhang et al., 2008) and autism (Pasca et al., 2009), and may contribute to the pathogenesis of other disorders, including leukemia (de Jonge et al., 2009; Wiemels et al., 2001), dementia (Kim et al., 2008; Kronenberg et al., 2009), colorectal cancer (Kim, 1999; Levine et al., 2010), cardiovascular disease (Smulders and Stehouwer, 2005) and congenital abnormalities (Carmichael et al., 2009; Wani et al., 2008). Given MTHFR's essential role in brain function and neurodevelopment (del Rio Garcia et al., 2009; Ueland et al., 2001), and that family and twin studies have demonstrated considerable shared genetic variance between psychiatric disorders (Cardno et al., 2002; Lichtenstein et al., 2009; McGuffin et al., 2003; Van Snellenberg and de Candia, 2009), it is reasonable to hypothesize that genetic variation in MTHFR may contribute to the shared genetic vulnerability of common psychiatric disorders. "
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