Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/21/2008
Publication Date: 7/1/2008
Citation: Johnson, W.T., Anderson, C.M. 2008. Cardiac Cytochrome c Oxidase Activity and Contents of Submits 1 and 4 are Altered in Offspring by Low Prenatal Intake by Rat Dams. Journal of Nutrition. 138:1269-1273
Interpretive Summary: Estimates of usual copper intakes from food indicate that up to 90% of pregnant women and up to 95% of lactating women do not meet either the estimated average requirement (EAR) or recommended dietary allowance (RDA) for copper. These results indicate that copper intakes below the EAR and RDA are not uncommon for pregnant and lactating women. Although it is not known what effect maternal copper deficiency has on human fetal heart development, studies with animals have shown that copper deficiency during pregnancy and lactation results in abnormalities in the activity of cytochrome c oxidase, a copper-containing enzyme, in hearts of the offspring. The heart in neonatal rats is not completely developed until about two weeks after birth. During this period, the activity of cytochrome c oxidase increases to satisfy the energy requirements of the developing, growing heart. Cytochrome c oxidase contains multiple protein subunits some of which are gene products of mitochondrial DNA and some of which are gene products of nuclear DNA. This study shows that low prenatal copper intake in rats causes a reduction in a subunit that is a nuclear gene product. The reduction in this subunit persists postnatally, is resistant to restoration by adequate Cu intake by the newborn and contributes to the loss of cytochrome c oxidase activity in the fully developed heart. Thus, low prenatal copper intake can alter the subunit composition of cytochrome c oxidase in the developing fetal heart in a manner that leads to persistently suppressed cytochrome c oxidase activity in neonates once their hearts become fully developed. Suppression of cytochrome c oxidase deficiency is associated with some forms of heart disease and the findings from this study suggest that copper-deficiency in pregnant and lactating women may be increasing their children's risk for developing heart disease at some time during their life time.
Technical Abstract: It has been reported previously that the offspring of rat dams consuming low dietary copper (Cu) during pregnancy and lactation experience a deficiency in cardiac cytochrome c oxidase (CCO) characterized by reduced catalytic activity and mitochondrial- and nuclear-subunit content after postnatal day 10. The present study was undertaken to determine if the cardiac CCO deficiency was caused directly by low postnatal Cu intake or whether it was a prenatal effect of low Cu intake that became manifest postnatally. Dams were fed either Cu-adequate diet (6 mg Cu/kg) or Cu-deficient diet (1 mg Cu/kg) beginning 3 weeks before conception and throughout gestation and lactation. One day following parturition, several litters from Cu-adequate dams were cross fostered to Cu-deficient dams and several litters from Cu-deficient dams were cross fostered to Cu-adequate dams. Litters that remained with their birth dams served as controls. CCO activity, the content of the mitochondrial-encoded subunit COX1, and the content of the nuclear-encoded subunit COX4 in cardiac mitochondria were reduced in the 21-day-old offspring of Cu-deficient dams. COX1 content was normal in the 21-day-old cross fostered offspring of Cu-deficient dams, but CCO activity and COX4 were reduced. Cross fostering the offspring of Cu-adeuqate dams to Cu-deficient dams did not significantly affect CCO activity, COX1 content, or COX4 content in cardiac mitochondria of 21-day old offpsring. These data indicate that low prenatal Cu intake by dams affects CCO activity in cardiac mitochondria of their offspring by causing a persistent alteration in COX4 content that leads to the assembly of a less than fully active holoenzyme.