Maternal Diet Supplementation with Methyl Donors and Increased Parity Affect the Incidence of Craniofacial Defects in the Offspring of Twisted gastrulation Mutant Mice

Abstract

Diets rich in methyl-donating compounds, including folate, can provide protection against neural tube defects, but their role in preventing craniofacial defects is less clear. Mice deficient in Twisted gastrulation (TWSG1), an extracellular modulator of bone morphogenetic protein signaling, manifest both midline facial defects and jaw defects, allowing study of the effects of methyl donors on various craniofacial defects in an experimentally tractable animal model. The goal of this study was to examine the effects of maternal dietary supplementation with methyl donors on the incidence and type of craniofacial defects among Twsg1 2/2 offspring. Nulliparous and primiparous female mice were fed an NIH31 standard diet (control) or a methyl donor supplemented (MDS) diet (folate, vitamin B-12, betaine, and choline). Observed defects in the pups were divided into those derived mostly from the first branchial arch (BA1) (micrognathia, agnathia, cleft palate) and midline facial defects in the holoprosencephaly spectrum (cyclopia, proboscis, and anterior truncation). In the first pregnancy, offspring of mice fed the MDS diet had lower incidence of BA1-derived defects (12.8% in MDS vs. 32.5% in control; P = 0.02) but similar incidence of midline facial defects (6.4% in MDS vs. 5.2% in control; P = 1.0). Increased maternal parity was independently associated with increased incidence of craniofacial defects after adjusting for diet (from 37.7 to 59.5% in control, P = 0.04 and from 19.1 to 45.3% in MDS, P = 0.045). In conclusion, methyl donor supplementation shows protective effects against jaw defects, but not midline facial defects, and increased parity can be a risk factor for some craniofacial defects.

Genistein inhibits DNA methylation and increases expression of tumor suppressor genes in human breast cancer cells

“…A recent study (Lubecka-Pietruszewska et al, 2013) showed that folic acid lead to down regulation of PTEN and APC which may be linked to the increased DNA methylation detected within their promoter regions. It may be explained by that folic acid as a methyl donor can directly increase the methylation (Billington et al, 2013). Another study has found that there was no significant change in the SERPINB5 expression when 50 mM of genistein was given to treat LNCap prostate cancer cell line (Merchant et al, 2011).…”

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

“…Several methyl donor diets were tested for their ability to rescue craniofacial defects in twisted gastrulation mutants [Billington et al, 2013]: these mutants have jaw defects (micrognathia and agnathia) with or without midline defects characteristic of holoprosence-phaly. The defects occur with incomplete penetrance (40% rate for all defects combined) on the C57BL/6 back-ground when dams are fed a control diet.…”

“…Since neural crest cells are the source of cranial mesenchyme, protective effect of diet on branchial arch development was interpreted as a beneficial action particularly on neural crest cells. Because the midline defects were unresponsive to methyl donor diet, the authors speculate that they arise from an independent pathological process [Billington et al, 2013]. Their model suggests that different structures are differentially sensitive to folic acid and methyl donor supplementation, with greater response in craniofacial and less in neural structures.…”

Folate Deficiency during Early-Mid Pregnancy Affects the Skeletal Muscle Transcriptome of Piglets from a Reciprocal Cross

“…Many studies have demonstrated a link between folate deficiency during early pregnancy and developmental abnormalities, such as neural tube defects [10], abnormal embryonic development [11,12], and tumor formation [13]. For these reasons, dietary folate supplementation is routinely recommended during early pregnancy in human [14].…”