We read with great interest the article by de Burbure et al. (2006) on health effects in children who live near nonferrous smelters in France, the Czech Republic, and Poland. We were especially interested in the inverse relationship found between levels of urinary mercury and serum prolactin. We found a similar result in an Italian multicenter crosssectional survey with adult subjects (Alessio et al. 2002) using a different statistical approach based on regression analysis with mixed linear models. We found that serum prolactin decreased as a function of both urinary mercury and occupational exposure to inorganic mercury (Lucchini et al. 2003). In another study (Carta et al. 2003), our group observed the opposite behavior of prolactin in adult individuals with a high dietary intake of mercury-contaminated tuna. In that study, serum prolactin was positively associated with urinary and blood mercury. Our interpretation of this dual behavior was that prolactin may be differently affected by inorganic and organic mercury based on the interference with different neurotransmitters implicated in the regulation of prolactin secretion (Carta et al. 2003).
The article by de Burbure et al. (2006) stimulates futher consideration of the observed effects on serum prolactin after exposure to various metals and other chemical substances. In fact, prolactin can be increased by exposure to lead (Govoni et al. 1987; Lucchini et al. 2000), organic mercury (Carta et al. 2003), and manganese (Ellingsen et al. 2003; Smargiassi and Mutti 1999; Takser et al. 2004), but it can be decreased by exposure to inorganic mercury (de Burbure et al. 2006; Lucchini et al. 2003; Ramalingam et al. 2003), alluminum (Alessio et al. 1989), and cadmium (Calderoni et al. 2005; de Burbure et al. 2006). Subjects exposed to chemicals such as styrene (Bergamaschi et al. 1996; Luderer et al. 2004; Umemura et al. 2005), perchloroethylene (Beliles 2002; Ferroni 1992), and anesthetic gases (Lucchini et al. 1996; (Marana et al. 2003) have shown an increase of serum prolactin, whereas polychlorinated biphenyls (De Krey et al. 1994) and the pesticide lutheinate [U.S. Environmental Protection Agency (EPA) 2002] are known to decrease serum prolactin.
Possible mechanisms, other than direct effects at the cellular level, may be related to different neurotransmitters involved in the modulation of prolactin secretion. For example, the dopaminergic and serotoninergic systems, respectively, are involved in the physiologic regulation of this hormone as a tonic inhibitor and as an excitatory modulator. Different chemicals may interfere with these two systems, resulting in different outcomes regarding serum prolactin. Recent studies have shown that the same chemical may even cause different effects on prolactin depending on the exposure doses (Lafuente et al. 2003).
We would like to know why this neuroendocrine hormone is affected differently by exposure to different chemicals. This is important because of the possible use of prolactin, as described by de Burbure et al. (2006), as a sensitive indicator of early effects in toxicologic research and risk assessment (Mutti and Smargiassi 1998). Negative studies have also been published on the association of prolactin with the exposure to neurotoxicants (Myers et al. 2003; Roels et al. 1992). Therefore, it is vital to assess the causes of the variability that may limit the reproducibility of these tests. Further research should focus on multiple exposure to different chemicals, which may help to explain the lack of association.
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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, -aminobutyric acid (GABA) [as demonstrated by the hyperprolactinemia developed by GABAB1 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.
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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.
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