H2AX and folate deficiency: The study of pathogenesis of NTDs has demonstrated that the E3 ligase mouse double minute 2 homolog (Mdm2) colocalized with γ-H2AX is recruited to the sites of DSBs in mouse embryonic stem cells (mESCs) after exposure to methotrexate (a folate antagonist [16]), which might contribute to NTDs induced by folate deficiency [113].