Diverse ability of maternal immune stimulation to reduce birth defects in mice exposed to teratogens: a review

Hrubec, Terry C.; Prater, M. Renée; Mallela, M. K.; Gogal, Robert M.; Guo, Tai L.; Holladay, Steven D.

doi:10.1017/s204017441100078x

Cited by 5 publications

(7 citation statements)

References 62 publications

(101 reference statements)

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“…It has been experimentally demonstrated that maternal immune stimulation can reduce the incidence of diabetic craniofacial embryopathy 60,61 . Furthermore, birth defects in mice exposed to teratogens can be reduced by select immunostimulatory treatments, such as immune modulation of cytokines before or during pregnancy 62,63 . Studies have shown that several acute phase reactive protein and complement components, such as C1q and C3a, increase in maternal blood circulation during normal pregnancy 64 …”

Section: Discussionmentioning

confidence: 99%

Complement factors and alpha‐fetoprotein as biomarkers for noninvasive prenatal diagnosis of neural tube defects

Dong

Liú

et al. 2020

Annals of the New York Academy of Sciences

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Neural tube defects (NTDs) are serious congenital malformations. In this study, we aimed to identify more specific and sensitive maternal serum biomarkers for noninvasive NTD screenings. We collected serum from 37 pregnant women carrying fetuses with NTDs and 38 pregnant women carrying normal fetuses. Isobaric tags for relative and absolute quantitation were conducted for differential proteomic analysis, and an enzyme-linked immunosorbent assay was used to validate the results. We then used a support vector machine (SVM) classifier to establish a disease prediction model for NTD diagnosis. We identified 113 differentially expressed proteins; of these, 23 were either upor downregulated 1.5-fold or more, including five complement proteins (C1QA, C1S, C1R, C9, and C3); C3 and C9 were downregulated significantly in NTD groups. The accuracy rate of the SVM model of the complement factors (including C1QA, C1S, and C3) was 62.5%, with 60% sensitivity and 67% specificity, while the accuracy rate of the SVM model of alpha-fetoprotein (AFP, an established biomarker for NTDs) was 62.5%, with 75% sensitivity and 50% specificity. Combination of the complement factor and AFP data resulted in the SVM model accuracy of 75%, and receiver operating characteristic curve analysis showed 75% sensitivity and 75% specificity. These data suggest that a disease prediction model based on combined complement factor and AFP data could serve as a more accurate method of noninvasive prenatal NTD diagnosis.

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Section: Discussionmentioning

confidence: 99%

Complement factors and alpha‐fetoprotein as biomarkers for noninvasive prenatal diagnosis of neural tube defects

Dong

Liú

et al. 2020

Annals of the New York Academy of Sciences

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“…VPA‐induced open NT is associated with increased apoptosis localized to the midline of the NT in GD9 mouse embryos (Hrubec et al, ; Tung & Winn, ). Active pStat3 is required for the induction of the antiapoptotic protein (Fukada, Hibi, & Yamanaka, ) and previously VPA has been shown to downregulate Bcl2 protein expression by approximately three‐fold in both VPA‐treated open NT and closed NT embryos in comparison to control embryos (Dawson et al, ).…”

Section: Discussionmentioning

confidence: 99%

Gestational exposure to valproic acid upregulates total Stat3 protein expression while downregulating phosphorylated Stat3 in CD‐1 mouse embryos with neural tube defects

Shafique

Winn

2020

Birth Defects Research

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Valproic acid (VPA), a widely prescribed antiepileptic drug and an effective treatment for psychiatric disorders, is teratogenic causing neural tube defects (NTDs) and other defects in the exposed embryo. Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that is activated via tyrosine phosphorylation. Stat3, as well as its active form (pYStat3), is expressed during neural tube closure in murine development. This study investigated the effects of in utero VPA exposure on embryonic Stat3 mRNA and protein expression during the critical period of neural tube closure in CD‐1 mouse embryos. Following the exposure of CD‐1 pregnant mice to the teratogenic dose of 400 mg/kg VPA or saline on gestational day (GD) 9, embryos were harvested at 1, 3, 6, or 24 hr and on GD13. Stat3 mRNA levels remained unchanged at all time points. Total Stat3 protein levels were significantly (p < .05) increased in GD9 embryos at 1 and 6 hr post‐exposure and in GD13 exposed nonexencephalic and exencephalic embryo heads. In contrast, phosphorylated Stat3 levels were significantly (p < .05) downregulated in GD9 embryos at the 3 and 6 hr time points with an overall trend of downregulation in the GD10 and GD13 groups. Total and phosphorylated Stat3 protein levels remained unchanged in nuclear extracts of the exposed nonexencephalic and exencephalic GD13 embryo heads. The reported significant downregulation of phosphorylated Stat3 levels suggests its possible role in VPA‐induced NTDs in mouse embryos.

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“…Nonspecific stimulation of the maternal immune system in mice reduces a wide variety of teratogen‐induced fetal malformations (Hrubec et al., ). Many different immunologically active agents and stimulation regimes have proved effective in reducing fetal malformations.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, many maternal cytokines can cross the placenta and reach the embryos. It is possible that increased levels of maternal cytokines resulting from immune stimulation prevent teratogenic effects on normal morphogenic processes such as cell proliferation and apoptosis in the embryo (Hrubec et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…Failure of the neural tube to close during development results in exencephaly, anencephaly, and spina bifida. Nonspecific stimulation of maternal immune system in mice reduces a wide variety of fetal malformations induced by various physical and chemical agents, and also diseases such as diabetes mellitus (Nomura et al., ; Toder et al., ; Holladay et al., ; Prater et al., ; Punareewattana and Holladay ; Laudermilch et al., ; Khaksary et al., ; Latorre et al., ; Hrubec et al., ). Maternal immune stimulation with IFNγ reduces the incidence of valproic acid (VA) induced NTDs in late gestational fetuses (Hrubec et al., ).…”

Section: Introductionmentioning

confidence: 99%

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

Mallela

Hrubec

2012

Birth Defects Research Pt B

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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.

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Diverse ability of maternal immune stimulation to reduce birth defects in mice exposed to teratogens: a review

Cited by 5 publications

References 62 publications

Complement factors and alpha‐fetoprotein as biomarkers for noninvasive prenatal diagnosis of neural tube defects

Complement factors and alpha‐fetoprotein as biomarkers for noninvasive prenatal diagnosis of neural tube defects

Gestational exposure to valproic acid upregulates total Stat3 protein expression while downregulating phosphorylated Stat3 in CD‐1 mouse embryos with neural tube defects

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

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