Reduction in Valproic Acid–Induced Neural Tube Defects by Maternal Immune Stimulation: Role of Apoptosis

Abstract

Teratogenic deregulation of apoptosis during development is a possible mechanism for birth defects. Administration of valproic acid (VA) during first trimester of pregnancy causes neural tube defects (NTDs). Nonspecific stimulation of the mother’s immune system has been shown to reduce various teratogen-induced fetal malformations including NTDs in rodents. This present study investigated the role of reduced apoptosis by maternal immune stimulation in prevention of VA-induced NTDs in CD-1 mice. Prevention of VA-induced NTDs by nonspecific maternal immune stimulation using IFNγ was employed to evaluate the role of reduced apoptosis by IFNγ in this protective mechanism. Apoptosis was quantified using flow cytometry. Terminal Transferase dUTP Nick End Labeling assay was used to localize the apoptosis. Increased apoptosis, suggesting involvement in VA teratogenicity, was observed along the neural tube in both normal and abnormal embryos from VA-exposed dams. Increased apoptosis in normal VA-exposed embryos suggests that VA may alter other cellular processes such as cell proliferation and differentiation in addition to apoptosis. Apoptotic levels in embryos with closed neural tubes from IFNγ + VA dams were similar to controls indicating resistance to VA-induced apoptosis and protection against teratogenicity of VA. In IFNγ + VA exposed embryos with open neural tubes, maternal immune stimulation failed to regulate apoptosis resulting in an NTD. Overall, these results suggest that VA alters several biological processes including apoptosis in the developing embryos to induce fetal malformations. Resistance to VA-induced apoptosis in embryos resulting from maternal immune stimulation may be involved in protective mechanism.

Congenital malformation and autism spectrum disorder: Insight from a rat model of autism spectrum disorder

“…Other mechanisms implicated in valproate-induced defects are altered cell proliferation, differentiation and apoptosis,[ 47 ] DNA damage and the consequent increase of embryonic p27(KIP1) and caspase-3 expression,[ 48 ] epigenetic modifications during early organogenesis expression,[ 49 ] and histone deacetylase inhibition. [ 50 ]…”

Levels of PAH–DNA adducts in cord blood and cord tissue and the risk of fetal neural tube defects in a Chinese population

“…Studies have shown that the formation of DNA adducts induced by PAHs can increase Ser-15 phosphorylation of p53 tumor suppressor levels, which is associated with the induction of the apoptotic pathways (Nicol et al, 1995, Topinka et al, 2008). Animal studies have indicated that NTDs induced by in utero valproic acid exposure was mediated by apoptosis (Mallela and Hrubec, 2012, Tung and Winn, 2011). PAH exposure has also been associated with epigenetic alterations.…”

Micronutrient imbalance and common phenotypes in neural tube defects

“…Excess ZnO induced an increase in apoptosis in mouse and chick embryos and in chick the increase in apoptosis occurred in both the cranial and trunk regions (Figure 1‐yellow) (Yan et al, 2021). In addition to the environmental cases, we highlighted in this review that an increase in apoptosis is also a known factor into the etiology of NTDs in mice resulting from (a) induction of diabetes by STZ (Figure 1‐purple), (b) folate dysregulation by MTX (Figure 1‐blue), and (c) treatment with the antiepileptic drug VPA (Figure 1‐gray) (Gu et al, 2015; Mallela & Hrubec, 2012; Tung & Winn, 2011; X. Wang et al, 2014). The increase in apoptotic cells may represent a common phenotypic node that each of these different etiologies manifests, resulting in failure of the neural tube to close.…”