Previous studies have demonstrated that the pituitary is a main target for inorganic mercury (I-Hg) deposition and accumulation within the brain. My recent study of the US population (1999–2006) has uncovered a significant, inverse relationship between chronic mercury exposure and levels of luteinizing hormone (LH). This association with LH signifies more than its presumed role as bioindicator for pituitary neurosecretion and function. LH is the only hormone with a rare and well characterized, high affinity binding site for mercury. On its catalytic beta subunit, LH has the structure to preferentially bind inorganic mercury almost irreversibly, and, by that manner, accumulate the neurotoxic element. Thus, it is likely that LH is an early and significant target of chronic mercury exposure. Moreover, due to the role of LH in immune-modulation and neurogenesis, I present LH as a central candidate to elucidate a causal mechanism for chronic mercury exposure and associated disease.

Hypothesis

The biological association between chronic mercury exposure and luteinizing hormone represents a central, causal mechanism for mercury associated disease.

Chronic mercury exposure and deposition

Mercury is a potent neurotoxin that directly impairs many areas and functions of the neuron including calcium channels [1–3], protein synthesis [4], mitochondria [4], and neurite outgrowth [5]. Both the aforementioned neurotoxicity and a human disease response to mercury exposure has been shown to be dependent on  reaching a critical threshold concentration [6]. Therefore, in cases of acute mercury poisoning, the direct neurotoxic effect of mercury in the brain may surpass this threshold and elicit a disease response.

However, in cases of chronic mercury exposure, mercury concentrations in the brain may remain beneath the critical threshold concentration and therefore a direct relationship between chronic mercury exposure and neurotoxicity is not evident, prima facie.

In toxicological studies of chronic mercury exposure in primates, organic mercury has been shown to demethylate and form inorganic mercury deposits which persist in the brain for years  [7,8]. In both primates and humans, inorganic mercury deposits preferentially target the pituitary where they accumulate [8,9].

The accumulation of inorganic mercury deposits in the body is reasoned to be detectable by changes of inorganic mercury levels in the blood [10]. In a recent human population dependent on fish, inorganic mercury accumulation in the blood has been shown to be associated with chronic mercury exposure [11]. In another recent study, I used inorganic mercury exposure as the bioindicator of chronic mercury exposure within the US population [12] and discovered a significant, inverse relationship between chronic mercury exposure and luteinizing hormone (LH).

High affinity target

As the pituitary had previously been shown to be a principle site in the brain for inorganic mercury deposition and accumulation, I had used LH as a general bioindicator for pituitary neurosecretion and function. Upon an extensive literature review of LH, I unearthed a significant and clear explanation for why LH is associated with chronic mercury exposure. Based on its unique amino acid sequence, thioredoxin is a high affinity target for inorganic mercury [13]. Due to a specific sequence of cysteine residues, free sulfur bonds will bind almost irreversibly to inorganic mercury, thioredoxin will tend to bio-accumulate mercury, and this interaction has been hypothesized to be a molecular mechanism for mercury toxicity. In 1990, evidence was presented that LH was the only hormone to share that specific amino acid sequence found in thioredoxin [14]. Furthermore, this specific sequence was found on the catalytic, beta subunit of LH. Therefore, it is logical to assume that LH, like thioredoxin, is a high affinity target for inorganic mercury. 

As such, LH will preferentially and almost irreversibly bind to inorganic mercury. This specific, high affinity binding should result in the toxico-kinetic properties of mercury bio-accumulation. As LH is secreted by the pituitary, a main site for inorganic mercury deposition and accumulation, and as it seems to be a high affinity target for inorganic mercury, it is reasonable to assume that the recently reported relationship with chronic mercury exposure represents a significant, biological association. Furthermore, understanding the unique role of LH in the body, an association with chronic mercury exposure presents LH as a strong candidate to elucidate a causal mechanism for mercury neurotoxicity and associated disease. 

The role of LH

LH is not only a high affinity target for mercury, located in the prime area of mercury deposition and accumulation, but it also regulates diverse systems whose impairment is symptomatic of mercury associated disease. LH is secreted by the anterior pituitary and mediates androgen stimulation, mitogenesis, and immune regulation [15–18]. 

Specific neuronal tracts have been shown to produce luteinizing hormone releasing hormone (LHRH) within the adult brain to modulate glial formation and the complex neuronal-macroglia networks that are crucial to brain development, plasticity, function, and the neuroimmune inflammatory response [17]. LHRH is also found on human peripheral lymphocytes, indicating a role for LH in mediating both the central and peripheral immune systems [19]. As a mitogen, LH is not only involved as a gonadotroph, but also in the birth of neurons. Recently, LH was demonstrated in both mice [20] and sheep [21] to directly induce neurogenesis in the adult hippocampus, the area of the brain associated with learning and memory. 

LH is directly involved in regulating all of the systems that are symptomatic of mercury associated disease; impaired immune response, inflammation, disruption of glia-neuronal networks, and impaired neurogenesis. Therefore, it is reasonable to assume that the biological association between chronic mercury exposure and luteinizing hormone represents a causal mechanism to delineate the pathology from chronic mercury exposure and deposition, to an impaired endocrine system and the defining characteristics of mercury associated disease.

Conclusion

Certainly it is well understood, in multiple human and animal models, that mercury exposure targets the endocrine system [36]. However, the relationship between endocrine impairment and mercury associated disease is poorly understood. This perspective posits that luteinizing hormone represents a promising, and viable candidate to provide a causal mechanism for mercury associated disease.

LH has recently been shown to be associated with chronic mercury exposure [12]. This finding, in the context of other evidence to date, indicates a biologically relevant process wherein mercury targets LH through high affinity binding at the main site for chronic mercury deposition and accumulation, the pituitary. 

As LH has essential roles in immune-modulation, inflammation, and neurogenesis, it provides all the requisite functions to explain how focal deposition and targeting of chronic mercury exposure can incur a wide variety of mercury associated disease. 

As chronic mercury exposure is rising over time, it is likely that the risks of associated disease will rise in concert. Thus, understanding the mechanisms of mercury associated disease is a crucial step in being able to prevent, diagnose, and treat what shall become a growing medical and public health concern.

As mercury is a known neurotoxin, it is important that neuroscientists focus their talents and efforts in this emergent field. Further research is necessary to investigate whether luteinizing hormone provides a causal mechanism for mercury associated disease.