Sex and Ceruloplasmin Modulate the Response to Copper Exposure in Healthy Individuals

By Mendez, Marco A.; Araya, Magdalena et al. | Environmental Health Perspectives, December 2004 | Go to article overview

Sex and Ceruloplasmin Modulate the Response to Copper Exposure in Healthy Individuals


Mendez, Marco A., Araya, Magdalena, Olivares, Manuel, Pizarro, Fernando, Gonzalez, Mauricio, Environmental Health Perspectives


Previous studies indicated that sex might influence the response to copper exposure. Ceruloplasmin (Cp) is an indicator of Cu status, but it is not dear whether and how it reflects changes of Cu status among healthy individuals. In this study, 82 apparently healthy women and men were chosen from 800 individuals because their Cp values belonged to the higher and lower 10% of the group Cp distribution curve. Before and after receiving a supplement of 10 mg Cu/day (upper limit of daily intake) for 2 months, we performed blood and urinary biochemical measurement of potential Cu markers. We used principal component analysis and linear discriminant analysis to identify blood and/or urinary Cu indicators that showed a differential response to copper. Results showed that Cp values in serum represent a reliable indicator to differentiate subgroups within the normal population in their response to Cu exposure. The response depends on Cp values and on sex, such that women with higher and men with lower Cp values exhibit the greatest response. Key words: copper exposure, discriminant analysis, healthy individuals, principal component analysis. Environ Health Perspect 112:1654-1657 (2004). doi:10.1289/ehp.7134 available via http://dx.doi.org/[Online 17 August 2004]

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Copper is required for the function of several cuproenzymes; therefore, its presence is essential for different physiological functions (Linder 1991). Cu, however, is able to generate free radicals and oxidize cellular components through its redox activity (Aust et al. 1985). These conflicting properties demand a close regulation of the metal at the organism level. Effects associated with severe lack or excess Cu are well described in genetic conditions, such as Menkes disease (Chelly et al. 1993; Mercer et al. 1993; Tanzi et al. 1993; Vulpe et al. 1993) and Wilson's disease (Bull et al. 1993; Tanzi et al. 1996). In contrast, much less is known about relevant biological effects associated with situations when no excess or deficit of Cu is present (Davis 2003; Hambidge 2003). It is well known that serum ceruloplasmin (Cp) and Cu values are higher in young children and increase during even mild inflammatory/infectious processes, but their relationships to Cu intake and markers of Cu status are not clear, and available data suggest that they modify only when exposure changes by several orders of magnitude (Maya et al. 2003b, 2003c). It is still not clear whether marginal or moderate changes in Cu exposure may result in adverse effects to human health because there are no sensitive indicators of marginal changes in Cu status and because early functionally relevant responses are not well defined.

With the aim of improving our understanding about the early effects of Cu on human health, we have conducted a series of studies on asymptomatic adults undergoing controlled Cu exposure. This varied between approximately 3 and 10 times the customary dietary intake. Clinical trials showed that nausea is the earliest and most frequent response, and we used the generated data to calculate the dose-response curve to acute Cu exposure (Araya et al. 2003a, 2003b, 2003c; Olivares et al. 2001; Pizarro et al. 2001). A community survey in which participants ingested between 0.9 and 10 mg Cu/day for 2 months [the concentration defined as tolerable daily intake (TDI) of Cu ingestion for humans; Araya et al. (2003c)] allowed us to describe the full range of responses to Cu exposure, showing that there are more gastrointestinal responses (mainly nausea) with increasing Cu exposure (Cu concentration in water) and that these responses diminish with time, suggesting adaptation (Maya et al. 2004). In all of these studies, the statistical analyses suggested that the variable sex influenced the results.

No changes in biochemical blood parameters were detected in a previous study in which healthy participants were exposed to up to 6 mg Cu/L water, which represented as much as 14 mg Cu/day on occasional days depending on the volume of fluids ingested (Araya et al. …

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