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) mug 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. (C) 2004 Wiley-Liss, Inc.