TNF‐α Protects Embryos Exposed to Developmental Toxicants

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Abstract
BACKGROUND:  Tumor necrosis factor α (ΤNF‐α) has been implicated in mediating post‐implantation embryo loss or the embryonic maldevelopment induced by development toxicants or maternal metabolic imbalances. In order to clarify the role of TNF‐α further, a comparative study was performed in TNF‐α knockout and TNF‐α positive mice, exposed to a reference teratogen, cyclophosphamide (CP).METHODS:  Cyclophosphamide was injected on day 12 of pregnancy and 18‐day fetuses were examined for external structural anomalies. Apoptosis and cell proliferation were measured by TdT‐mediated biotin–dUTP nick‐end labeling and 5′‐bromo‐2′‐deoxyuridine incorporation, respectively, in the brain (an organ, sensitive to the teratogen) of embryos 24 hr after CP injection. NF‐κB DNA‐binding activity by electrophoretic mobility shift assay (EMSA) and the expression of RelA (an NF‐κB subunit) and IκBα proteins by Western blot analysis were assessed in the brain of embryos tested 24 and 48 hr after CP treatment.RESULTS:  Surprisingly, the proportion of fetuses with craniofacial, trunk and severe limb reduction anomalies were significantly higher in TNF‐α–/– females, than in TNF‐α+/+ mice. Excessive apoptosis and suppression of cell proliferation was found in the brain, and they were more prominent in TNF‐α–/– than TNF‐α+/+ embryos, when examined 24 hr after CP injection. Finally, CP‐induced suppression of NF‐κB DNA‐binding activity was found to be enhanced in the brain of TNF‐α–/– embryos, and the restoration of NF‐κB DNA‐binding activity was compromised.CONCLUSION:  This work demonstrates for the first time that TNF‐α may act as a protector of embryos exposed to teratogenic stress. One possible mechanism may be restoration of NF‐κB activity in embryonic cells surviving the teratogenic insult.

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