TNF-α protects embryos exposed to developmental toxicants

被引:56
作者
Torchinsky, A [1 ]
Shepshelovich, J [1 ]
Orenstein, H [1 ]
Zaslavsky, Z [1 ]
Savion, S [1 ]
Carp, H [1 ]
Fein, A [1 ]
Toder, V [1 ]
机构
[1] Tel Aviv Univ, Sackler Sch Med, Dept Embryol & Teratol, IL-69978 Tel Aviv, Israel
关键词
birth defects; embryo; NF-kappa B; teratogenesis; tumor necrosis factor alpha;
D O I
10.1034/j.1600-0897.2003.01174.x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) 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-alpha further, a comparative study was performed in TNF-alpha knockout and TNF-alpha 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-kappaB DNA-binding activity by electrophoretic mobility shift assay (EMSA) and the expression of RelA (an NF-kappaB subunit) and IkappaBalpha 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-alpha(-/-) females, than in TNF-alpha(+/+) mice. Excessive apoptosis and suppression of cell proliferation was found in the brain, and they were more prominent in TNF-alpha(-/-) than TNF-alpha(+ /+) embryos, when examined 24 hr after CP injection. Finally, CP-induced suppression of NF-kappaB DNA-binding activity was found to be enhanced in the brain of TNF-alpha(-/-) embryos, and the restoration of NF-kappaB DNA-binding activity was compromised. CONCLUSION: This work demonstrates for the first time that TNF-alpha may act as a protector of embryos exposed to teratogenic stress. One possible mechanism may be restoration of NF-kappaB activity in embryonic cells surviving the teratogenic insult.
引用
收藏
页码:159 / 168
页数:10
相关论文
共 44 条
[1]   Apoptosis and nuclear factor-κB:: A tale of association and dissociation [J].
Aggarwal, BB .
BIOCHEMICAL PHARMACOLOGY, 2000, 60 (08) :1033-1039
[2]  
[Anonymous], DRUG TOXICITY EMBRYO
[3]   TNFα promotes proliferation of oligodendrocyte progenitors and remyelination [J].
Arnett, HA ;
Mason, J ;
Marino, M ;
Suzuki, K ;
Matsushima, GK ;
Ting, JPY .
NATURE NEUROSCIENCE, 2001, 4 (11) :1116-1122
[4]   Control of apoptosis by Rel/NF-κB transcription factors [J].
Barkett, M ;
Gilmore, TD .
ONCOGENE, 1999, 18 (49) :6910-6924
[5]   Signal transduction by tumor necrosis factor and its relatives [J].
Baud, V ;
Karin, M .
TRENDS IN CELL BIOLOGY, 2001, 11 (09) :372-377
[6]   THE BIOLOGY OF CACHECTIN/TNF - A PRIMARY MEDIATOR OF THE HOST RESPONSE [J].
BEUTLER, B ;
CERAMI, A .
ANNUAL REVIEW OF IMMUNOLOGY, 1989, 7 :625-655
[7]  
Bradham CA, 1998, AM J PHYSIOL-GASTR L, V275, pG387, DOI 10.1152/ajpgi.1998.275.3.G387
[8]   New insights into the role of nuclear factor-κB in cell growth regulation [J].
Chen, F ;
Castranova, V ;
Shi, XL .
AMERICAN JOURNAL OF PATHOLOGY, 2001, 159 (02) :387-397
[9]   Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality [J].
Doi, TS ;
Marino, MW ;
Takahashi, T ;
Yoshida, T ;
Sakakura, T ;
Old, LJ ;
Obata, Y .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (06) :2994-2999
[10]  
Gorivodsky M, 1998, J IMMUNOL, V160, P4280