Manganese as a Potential Confounder of Serum Prolactin
Referencing: Renal and Neurologic Effects of Cadmium, Lead, Mercury, and Arsenic in Children: Evidence of Early Effects and Multiple Interactions at Environmental Exposure Levels
de Burbure et al. (2006) elegantly demonstrated that dopaminergic markers in the serum, namely prolactin and homovanillic acid, are affected in children exposed to cadmium, lead, mercury, and arsenic. These findings, at low environmental exposure levels, reinforce the potential of these metals to perturb dopaminergic function and optimal development.
In spite of the strengths of the article, de Burbure et al. (2006) overlooked an important potential confounder. Specifically, the authors should consider the possibility that manganese confounded their data; if so, the data set should be reexamined. A strong relationship between manganese exposure and serum prolactin levels has been raised in multiple studies. Although prolactin levels serve as a direct measurement of monoamines or their metabolites in peripheral tissues (e.g., blood platelets, plasma, urine), plasma prolactin is also an indirect indicator of dopaminergic functioning, a target for excessive exposure to manganese (Mutti and Smargiassi 1998; Smargiassi and Mutti 1999). A concordance between neurocognitive deficits and manganese exposure also exists, including a recent study in children exposed to water manganese concentrations exceeding 300 µg/L (Wasserman et al. 2006). A significant and positive correlation between blood manganese concentrations and prolactin levels in cord blood has also been established (Tasker et al. 2004). Other examples abound, although negative relationships between manganese and prolactin have also been reported (Roels et al. 1992).
The potential that exposure to manganese contributed to or confounded the effects of the four metals on serum prolactin levels in the cohorts studied by de Burbue et al. (2006) should be considered. If samples are available for additional analysis, correlations between manganese exposure and prolactin would be beneficial and welcomed by various health forums as the debate on safe manganese exposure levels and sensitive health effect biomarkers continues.
The author receives funding support from the National Institutes of Health, the Department of Defense, and Afton Chemicals for manganese research.
Michael Aschner
Department of Pediatrics
Vanderbilt University Medical Center
Nashville, Tennessee
E-mail: michael.aschner@vanderbilt.edu
References
de Burbure C, Buchet JP, Leroyer A, Nisse C, Haguenoer JM, Mutti A, et al. 2006. Renal and neurologic effects of cadmium, lead, mercury, and arsenic in children: evidence of early effects and multiple interactions at environmental exposure levels. Environ Health Perspect 114: 584–590.
Mutti A, Smargiassi A. 1998. Selective vulnerability of dopaminergic systems to industrial chemicals: risk assessment of related neuroendocrine changes. Toxicol Ind Health 14:311–323.
Roels HA, Ghyselen P, Buchet JP, Ceulemans E, Lauwerys R. 1992. Assessment of the permissible exposure level to manganese in workers exposed to manganese dioxide dust. Br J Ind Med 49:25–34.
Smargiassi A, Mutti A. 1999. Peripheral biomarkers and exposure to manganese. Neurotoxicology 20: 401–406.
Tasker L, Mergler D, de Grosbois S, Smargiassi A, Lafond J. 2004. Blood manganese content at birth and cord serum prolactin levels. Neurotoxicol Teratol 26: 811–815.
Wasserman GA, Liu X, Parvez F, Ahsan H, Levy D, Factor-Litvak P, et al. 2006. Water manganese exposure and children's intellectual function in Araihazar, Bangladesh. Environ Health Perspect 114:124–129.
Potential Confounder: Bernard and de Burbure Respond
We thank Aschner for his positive comments and interesting suggestion regarding a possible influence of manganese on serum prolactin levels. We fully acknowledge that the four elements we studied (De Burbure et al. 2006) are probably not the only determinants of serum prolactin levels, especially because variations in blood or urinary levels explained only a few percent of the total variance. Other factors, including perhaps some other metals, most probably also contribute to modulate dopaminergic function and serum prolactin levels. Because the epidemiologic evidence suggesting a link between manganese and serum prolactin in children is recent, we did not measure this metal in our study. However, if we had measured blood manganese in the children in our study, it is far from certain that this factor would have emerged as a significant determinant, possibly confounding the relationships between neurologic markers and blood or urinary levels of cadmium, mercury, and lead.
In the recent study by Wasserman et al. (2006), neurocognitive deficits were indeed not related to blood concentrations of manganese. As to the correlation between blood manganese at birth and cord blood prolactin levels reported by Takser et al. (2004), this association was not adjusted for possible exposure to lead, an indisputable confounder in this sort of study. This being said, we agree of course with Aschner that exposure to manganese should be considered in future studies investigating the developmental effects of heavy metals in the environment.
The authors declare they have no competing financial interests.
Alfred Bernard
Claire de Burbure
Unit of Toxicology
School of Public Health
Catholic University of Louvain
Brussels, Belgium
E-mail: bernard@toxi.ucl.ac.be
References
de Burbure C, Buchet JP, Leroyer A, Nisse C, Haguenoer JM, Mutti A, et al. 2006. Renal and neurologic effects of cadmium, lead, mercury, and arsenic in children: evidence of early effects and multiple interactions at environmental exposure levels. Environ Health Perspect 114: 584–590.
Takser L, Mergler D, de Grosbois S, Smargiassi A, Lafond J. 2004. Blood manganese content at birth and cord serum prolactin levels. Neurotoxicol Teratol 26: 811–815.
Wasserman GA, Liu X, Parvez F, Ahsan H, Levy D, Factor-Litvak P, et al. 2006. Water manganese exposure and children's intellectual function in Araihazar, Bangladesh. Environ Health Perspect 114:124–129.