Enhanced inflammatory response in neural tubes of embryos derived from diabetic mice exposed to a teratogen.
Exposure of embryos to the teratogen cyclophosphamide (CP) and maternal diabetes is linked to pathogenesis of neural tube defects during development. Maternal diabetes aggravates the teratogen-induced inflammatory reaction leading to increased risk of neural tube defects in mouse embryos. The inflammatory reaction in the developing neural tube has been characterized by the presence of activated amoeboid microglia/brain macrophages and altered expression levels of cytokines. Although there were no obvious anomalies observed in the neural tubes of embryos from CP-treated non-diabetic mice, the frequency of neural tube defects was increased significantly in embryos of CP-treated diabetic mice. Moreover, there were more activated amoeboid microglia in the forebrain of CP-treated diabetic embryos compared to that in CP-treated non-diabetic mice. The expression of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) in the fetal brain of normal and diabetic embryos was induced in the neural tubes after CP treatment. Furthermore, the mRNA expression levels of both genes were increased markedly in the neural tube of CP-treated diabetic embryos compared to that of CP-treated non-diabetic embryos as measured by quantitative real-time PCR. Immunohistochemically, more TNF-alpha- and TGF-beta1-positive cells, which included neurons and amoeboid microglia, were detected in CP-treated diabetic embryos than in CP-treated normal embryos. Maternal diabetes aggravates teratogen-induced inflammation, which is characterized in the developing neural tube by increased amoeboid microglia and enhanced expression of inflammatory cytokines. Although a definite link has yet to be elucidated, it is suggested that the increased rate of neural tube defects observed in CP-treated diabetic embryos may be due to upregulation of proinflammatory cytokines caused by maternal diabetes.
Lian
Qizhou
Q
Molecular Neurobiology Laboratory, Department of Anatomy, Faculty of Medicine, National University of Singapore, Singapore.
Dheen
S Thameem
ST
Liao
Dongmei
D
Tay
Samuel Sam Wah
SS
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000196:embryology / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009420:Nervous System / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013723:Teratogens / Q000633:toxicity*
D016207:Cytokines; D013723:Teratogens