Effect Of Polyunsaturated Fatty Acids On Neural Tube Defects And Spontaneous Abortion And Its Mechanism

Neural tube defects(NTD)and spontaneous abortion are diseases occurred during the process of embryo development.NTD is a congential malformation resulting from failure of neural tube to close.The most important pathogenesis for NTD is abonormal folate-homocysteine(Hcy)metabolism induced by folate deficiency.In addition,inositol metabolism pathway and inflammation are also involved in the development of NTD.The main causes of spontaneous abortion involve chromosome abnormality,infection,immunity,inflammation,endocrine and folate-Hcy metabolism.Polyunsaturated fatty acid(PUFA)is important structure component of nervous system.Eicosanoids TXA2 and PGI2(their stable metabolites are TXB2 and 6-keto-PGF1?,respectively)generated from PUFA can modulate nutrion transfer from mother to fetus via placenta.PUFA can also modulate folate-Hcy metabolim and inflammation.Based on these previous findings,we hypothesized:PUFA intake can prevent NTD and spontaneous abortion by modulating eicosanoids metabolism,folate-Hcy metabolism and inflammation as well as making up for the deficiency of PUFA.In the present study,we assessed the association between PUFA and NTD as well as spontaneous abortion by case-control studies in Chinese,and further evaluated the effect of PUFA intake of pregnant mouse on the rate of NTD and abortion in embryos and its potential mechanisms.The main results are as follows:(1)The results of case-control study in Chinese indicated that the low content of C18:2n-6,C18:3n-6,C20:3n-6.C18:3n-3,C20:3n-3,C20:5n-3 and C22:5n-3 and the high ratios of C20:4n-6/C20:5n-3 and TXB2/6-keto-PGF1? in placenta were risk factors of NTD.(2)In a case-control study in Chinese,we found that essential fatty acid C18:3n-3 in decidual and villous tissues of placenta,total n-3 PUFA in decidual tissue,and essential fatty acid C18:2n-6 in villous tissue were all significantly lower in women with early spontaneous abortion than in healthy pregnant women.These results indicated that lack of those PUFA mentioned above is associated with the occurance of early spontaneous abortion.The ratio of C20:4n-6/C20:5n-3 in villous tissue was signifantly higher,but PGI2(eicosanoid generated from C20:4n-6)as well as HEPE,LTB5 and TXB3(3 kinds of eicosanoids generated from C20:5n-3)in villous tissue were significantly lower in women with early spontaneous abortion than in healthy pregnant women.These results indicated that abnormal eicosanoids metabolism is a pontential risk factor for early spontaneous abortion.In addition,the low content of lysophosphatide in decidual and villous tissues and the low content of diacylglycerol in villous tissue are also associated with the occurance of spontaneous abortion.(3)Animal study found that PUFA intake of pregnant mouse can prevent NTD and abortion induced by sodium valproate(VPA)in embryos,and the prevention effect of n-3 PUFA is better than n-6 PUFA.PUFA intake significantly alleviate the increasing effect of VPA on TXB2 and 6-keto-PGF1?synthesis in placenta,and n-3 PUFA significantly reduced the the ratio of TXB2/6-keto-PGF1? in placenta,indicating that the prevention effect of PUFA against NTD and abortion may be attributed to its modulation on placental eicosanoids metabolism.(4)Animal study indicated that intraperitoneal injection of VPA in pregnant mouse inhibited the mRNA and protein expression level of several genes involved in folate-Hcy metabolism(DHFR,MTRR,CSE,GAMT and CBS)in liver of pregnant mouse.However,VPA injection in pregnant mouse led to the overexpression of genes involved in folate-Hcy metabolism(DHFR,MTRR,CSE,GAMT,CBS and MTHFR)in embryos.n-3 PUFA or n-6 PUFA intake of pregnant mouse all alleviated the disturbance of folate-Hcy metabolism induced by VPA,and the alleviation effect of n-3 PUFA is better than n-6 PUFA.This result well explained the reason why n-3 PUFA and n-6 PUFA can prevent VPA-induced NTD and abortion,and why the prevention effect of n-3 PUFA is better than n-6 PUFA.In addition,VPA significantly reduced the level of C18:2n-6,C20:4n-6 and C22:6n-3 in liver of pregnant mouse,and dietary intake of n-3 PUFA and n-6 PUFA can effectively make up for the deficiency of these PUFA induced by VPA.This may be another one mechanism for the prenvetion effect of PUFA against NTD and abortion.In conclusion,case-control studies indicated that PUFA insufficiency and abnormal eicosanoids metabolism were pontential risk factors of NTD and spontaneous abortion.Animal study showed that dietary n-3 PUFA or n-6 PUFA intake can signicantly reduce the rate of NTD and abortion in embryos,and the reduction effect of n-3 PUFA is better than n-6 PUFA.Animal studies indicated that PUFA intake can prevent NTD and abortion by modulating eicosanoids metabolism and folate-Hcy metabolism and making up for the deficiency of PUFA.