Prolactin changes as a consequence of chemical exposure: de Burbure and Bernard respond.

We appreciate the letter from Alessio and Lucchini concerning the number and variety of toxicants able to affect serum prolactin levels. Reflecting on the wide variability of the currently available data, we would like to make two additional points.

The first point concerns the usefulness of serum prolactin as a potential indicator of neurotoxicity for populations at risk. This biomarker indeed appears to be influenced by a large number of both organic and inorganic chemicals, which have seemingly little in common in terms of mechanistic action (e.g., heavy metals, pesticides, styrene, polychlorinated biphenyls). Moreover, one chemical--cadmium, for example--can have a biphasic dose-dependent effect on serum prolactin (Lafuente et al. 2003), an effect we did not observe in our study (de Burbure et al. 2006) because of low exposure levels; this dose-dependent effect is reminiscent of the biphasic effects of lead on glutamate neurotransmission shown to be dependent on glycine receptor affinity (Marchioro et al. 1996).

As proposed by Alessio and Lucchini in their letter, these data reflect the complexity of the control of prolactin secretion, which is modulated not only by dopamine but also by several other neurotransmitters. These neurotransmitters include serotonin, [gamma]-aminobutyric acid (GABA) [as demonstrated by the hyperprolactinemia developed by GAB[A.sub.B1] knock-out mice (Catalano et al. 2005)], glycine, and glutamate (Fitsanakis and Aschner, 2005; Nagy et al. 2005). In view of these neurotransmitters, serum prolactin--albeit sensitive--appears to be a rather nonspecific biomarker for monitoring populations at risk; therefore, serum prolactin will likely remain a predominantly useful tool in the field of research until the multiple facets of controlling prolactin secretion are unveiled.

Another important issue to keep in mind concerns the biological significance of all of the modifications we observed in our study (de Burbure et al. 2006). Despite their statistical significance, are the observed small changes in serum prolactin at all clinically relevant? To what extent do the variations in serum prolactin induced by the various neurotoxicants correlate with changes in brain function? Because prolactin has a large number of potential determinants, probably with different mechanisms of action, it is a rather delicate intellectual exercise to give a correct interpretation of the observed changes in terms of the possible development of neurotoxicity.

Although the lack of specificity of prolactin reduces the immediate usefulness of these dopaminergic biomarkers, the question of the potential clinical impact of the small but significant changes in terms of neurotoxicity (de Burbure et al. 2006) certainly remains an important question that further research will have to address.

Claire de Burbure

Alfred Bernard

School of Public Health

Catholic University of Louvain

Brussels, Belgium

E-mail: [e-mail]

REFERENCES

Catalano PN, Bonaventura MM, Silveyra P, Bettler B, Libertun C, Lux-Lantos VA. 2005. GAB[A.sub.B1] knockout mice reveal alterations in prolactin levels, gonadotropic axis, and reproductive function. Neuroendocrinology 82(5-6):294-305.

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.

Fitsanakis VA, Aschner M. 2005. The importance of glutamate, glycine, and gamma-aminobutyric acid transport and regulation in manganese, mercury and lead neurotoxicity. Toxicol Appl Pharmacol 204(3):343-354.

Lafuente A, Cano P, Esquifino A. 2003. Are cadmium effects on plasma gonadotropins, prolactin, ACTH, GH and TSH levels, dose-dependent? Biometals 16(2):243-250.

Marchioro M, Swanson KL, Aracava Y, Albuquerque EX. 1996. Glycine and calcium-dependent effects of lead on N-methyl-D-aspartate receptor function in rat hippocampal neurons. J Pharmacol Exp Ther 279(1):143-153.

Nagy GM, Bodnar I, Banky Z, Halasz B. 2005. Control of prolactin secretion by excitatory amino acids. Endocrine 28(3):303-308.