Cardiac abnormalities induced by zinc deficiency are associated with alterations in the expression of genes regulated by the zinc-finger transcription factor GATA-4.
Zinc (Zn) deficiency during pregnancy results in a wide variety of developmental abnormalities. The objective of this study was to determine if expression of cardiac developmental genes regulated by Zn-finger transcription factors could be modulated during dietary Zn deficiency. Rats were fed 0.5 (low Zn) or 90 (controls) microg Zn/g diet throughout pregnancy. Fetal development was examined and RNA isolated at gestation day (GD) 13 and 20. Cardiac abnormalities were detected at GD 20 in 82% of fetuses from dams fed low Zn diets compared with only 2% in controls. Cardiac developmental gene expression regulated by the Zn-finger transcription factor, GATA-4, was measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). In GD 13 and 20 hearts, two genes critical for heart development, alpha-myosin heavy chain (alpha-MHC) and cardiac troponin I (cTnI), were down-regulated in Zn-deficient fetuses. Expression of alpha-MHC was 66 and 40% lower at GD 13 and 20, respectively, in fetuses from dams fed low Zn diets compared with fetuses from control dams (p<0.05). Fetal cardiac TnI RNA levels were reduced 40 and 45% at GD 13 and 20 in the Zn-deficient group compared with controls (p<0.05). Fetal cardiac transcript levels of GATA-4 and MHox, a gene regulated by a helix-loop-helix transcription factor, whose expressions are not Zn-dependent, were unaffected by diet. These data indicated that alterations in gene regulation might be an underlying mechanism of cardiac abnormalities. Dysfunction of other Zn-dependent transcription factors may be an integral part of the extensive teratogenesis associated with Zn deficiency.
Duffy
J Y
JY
Pediatric Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA. jodie.duffy@cchmc.org
Overmann
G J
GJ
Keen
C L
CL
Clegg
M S
MS
Daston
G P
GP
D000015:Abnormalities, Multiple; D000818:Animals; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000502:physiology*; D004587:Electrophoresis, Agar Gel; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D050991:GATA4 Transcription Factor; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000187:drug effects*; D006330:Heart Defects, Congenital / Q000209:etiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D018995:Myosin Heavy Chains / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014336:Troponin / Q000378:metabolism; D024723:Ventricular Myosins / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000172:deficiency*; D016335:Zinc Fingers
D017931:DNA Primers; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D018398:Homeodomain Proteins; C489936:Prrx1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D014336:Troponin; D012313:RNA; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains; D015032:Zinc