Abstract
The onset of puberty is the result of complex neuroendocrine interactions within hypothalamic region of the brain, as well as from genetic and environmental influences. These interactions ultimately result in the increased synthesis and release of luteinizing hormone-releasing hormone (LHRH). Manganese (Mn) is an essential environmental element known for years to be involved in numerous mammalian physiological processes, including growth and reproductive function. Studies in recent years have shown the ability of Mn to cross the blood–brain barrier and act within the hypothalamus to influence the timing of puberty. This review will depict research showing the molecular and physiological actions of Mn in the control of prepubertal LHRH and discuss the potential for the element to cause either helpful or harmful outcomes on the developmental process depending upon the age and accumulation of Mn within the hypothalamus.
Introduction
The time at which puberty begins is the culmination of a series of events within the hypothalamus that results in the increased pulsatile release of luteinizing hormone-releasing hormone (LHRH) secretion. This change in LHRH release is associated with the gradual removal of inhibitory inputs such as gamma aminobutyric acid (Terasawa & Hernandez 2001), as well as the development of an increased responsiveness to excitatory inputs such as excitatory amino acids, insulin-like growth factor-1 (IGF-1) and kisspeptin (KP). These excitatory components are major contributors to the increased secretion of LHRH and drive the pubertal process in rats (Urbanski & Ojeda 1987, Hiney et al. 1996, Navarro et al. 2004a,b), monkeys (Gay & Plant 1987, Wilson 1998, Shahab et al. 2005) and humans (Juul et al. 1994, Seminara et al. 2003). This pubertal increase in LHRH secretion is associated with the active participation of both neurons and glial cells of which their functions are further influenced by peripheral metabolic signals, genetic and environmental influences.
With regard to influences by environmental substances, manganese (Mn) is an essential nutrient that is abundantly present in water, food, air and soil and required for many normal mammalian physiological processes, including growth and reproduction (Greger 1999, Keen et al. 1999, Griffiths et al. 2007). In laboratory animals, deficiencies of Mn are associated with impaired development and reproduction (Boyer et al. 1942, Smith et al. 1944), thus, further suggesting this element plays a role in reproductive function. It is well known that Mn crosses the blood–brain barrier by binding to transport systems such as transferrin and divalent metal transporter-1 (Aschner & Aschner 1990, Aschner 2000, Garcia et al. 2006) and therefore, enters the hypothalamus through the cerebral vasculature and the cerebral spinal fluid. Importantly, Mn crosses into the brain four times more efficiently in infant and young rats because of an incompletely developed blood–brain barrier (Mena 1974, Dorman et al. 2000), and their inability to fully eliminate the element (Fechter 1999, Takeda et al. 1999, Aschner 2000); thus, allowing Mn to accumulate in the hypothalamus (Deskin et al. 1980, Pine et al. 2005). Furthermore, the young are generally found to be more sensitive to the element (Environmental Protection Agency 2003). Based on this collective information, it was suspected that Mn may play a role in pubertal onset. In this regard, this review will describe animal research showing the neuroendocrine effects and mechanisms of action of Mn on pubertal processes and discuss how these actions have the potential to be both beneficial and harmful.
Neuroendocrine actions of Mn on puberty
Mn effects on female development
Initial experiments assessed the ability of Mn to stimulate critical hypothalamic actions associated with the onset of puberty (Pine et al. 2005). It was first revealed that a single acute injection of Mn into the third ventricle of the brain of 30-day-old female rats caused a dose-responsive increase in the serum levels of luteinizing hormone (LH) released from the pituitary (Fig. 1). To more closely evaluate this apparent hypothalamic effect, the medial basal hypothalamus (MBH) was removed from immature animals and incubated in vitro in order to determine whether Mn could induce LHRH release directly. In this regard, Mn induced a dose-dependent increase in the release of the LHRH peptide (Fig. 2). Finally, the hypothalamic site of Mn action was confirmed by the lack of the element to stimulate LH from pituitaries incubated in vitro, and by the in vivo blockade of LHRH receptors on the pituitary gland with acyline, an LHRH antagonist (Fig. 3). Importantly, a mechanistic study (Lee et al. 2007) demonstrated that Mn activates hypothalamic soluble guanylyl cyclase (sGC), resulting in increased release of both cyclic guanosine monophosphate (cGMP) and LHRH from the same hypothalamic tissue (Fig. 4). Subsequently, this study further showed that a nitric oxide (NO) synthase inhibitor was ineffective at blocking the Mn-induced LHRH release with a low dose of 50 µM. Furthermore, although capable of stimulating LHRH, this dose did not induce total nitrite, a marker for NO production. Hence, these results indicate that Mn-induced LHRH release following its activation of sGC, was not a result of NO synthase/NO stimulation. Other investigators similarly revealed Mn supplementation did not activate NO synthase/NO in the hypothalamus of birds (Xie et al. 2014).
The effect of third ventricular administration of MnCl2 on LH release during the late juvenile phase of developing female rats. Each concentration point indicates basal LH levels vs stimulated levels. The animals that received the saline and the 1.0 µg dose of MnCl2 showed no significant changes in LH secretion when compared to basal levels. However, animals that received 2.5, 5 and 25 µg doses of Mn showed marked increases in LH secretion when compared to their respective basal levels. Each bar represents mean ± s.e.m. The number of samples is depicted within each panel. *P < 0.05; **P < 0.01 vs basal. Adapted, with permission, from Pine MD, Lee B, Dearth RK, Hiney JK & Dees WL 2005 Manganese acts centrally to stimulate luteinizing hormone secretion: a potential influence on female pubertal development. Toxicological Sciences 85 880–885. Copyright 2005 Oxford University Press.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
The effect of MnCl2 on LHRH release from the medial basal hypothalamus in vitro. Each concentration point indicates basal LHRH levels vs stimulated levels. Tissues incubated in buffer containing 50 µM and 250 µM concentrations of MnCl2 showed significant increases in LHRH secretion when compared to their respective basal levels. Values represent mean ± s.e.m. The number of samples is depicted within each panel. *P < 0.05; **P < 0.02. Adapted, with permission, from Pine MD, Lee B, Dearth RK, Hiney JK & Dees WL 2005 Manganese acts centrally to stimulate luteinizing hormone secretion: a potential influence on female pubertal development. Toxicological Sciences 85 880–885. Copyright 2005 Oxford University Press.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
The effect of pretreatment with the LHRH receptor antagonist acyline, on MnCl2-stimulated LH release. Acyline-treated animals showed no significant change in LH release after third ventricular administration of MnCl2 as compared to basal levels. Animals not pretreated with acyline exhibited a four-fold increase in LH as compared to basal levels (**P < 0.01). Each bar represents the mean ± s.e.m. N = 4 for saline treated; N-6 for acyline treated. Adapted, with permission, from Pine MD, Lee B, Dearth RK, Hiney JK & Dees WL 2005 Manganese acts centrally to stimulate luteinizing hormone secretion: a potential influence on female pubertal development. Toxicological Sciences 85 880–885. Copyright 2005 Oxford University Press.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
MnCl2 stimulates cyclic guanosine monophosphate (cGMP) and luteinizing hormone-releasing hormone (LHRH) release in vitro. Open bar represents basal cGMP and LHRH release. Filled bars represent cGMP and LHRH released following addition of 50 µM MnCl2 into the medium. Note that MnCl2 stimulated both cGMP (A) and LHRH (B) secreted from the same median eminence tissue incubates. *P < 0.05 and **P < 0.01 vs basal levels. Each bar resents the mean (± s.e.m.). N = 8 for both A and B. Adapted, with permission, from Lee B, Hiney JK, Pine MD, Srivastava VK & Dees WL 2007 Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action. Journal of Physiology 578 765–772. Copyright 2007 The Physiological Society.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
Another series of studies assessed whether chronic, low-dose Mn exposure could sustain elevated serum levels of puberty-related hormones and alter the time of pubertal onset. In this regard, immature female rats received a supplemental dose of Mn (10 mg/kg of MnCl2) by gavage from day 12 until tissues were collected on day 29, or in some cases, until vaginal opening (VO) occurred. Results from this study (Pine et al. 2005) revealed that Mn accumulated in the hypothalamus (P < 0.05), an action that was associated with increased (P < 0.05) serum levels of LH, follicle-stimulating hormone (FSH) and estradiol, as well as causing an earlier (P < 0.001) day of VO (Mn treated: 32.8 ± 0.21) when compared to controls (saline treated: 34.3 ± 0.22). These results show that Mn is capable of enhancing puberty-related hormone secretions, and thus, may facilitate the normal onset of puberty. Furthermore, the results indicate the possibility that Mn may contribute to precocious puberty if an individual is exposed to low, but elevated levels of the element too early in development.
Mn effects on male development
As in females, the central administration of Mn dose dependently stimulated the secretion of LH in males, an action blocked by the prior administration of the LHRH receptor antagonist (Lee et al. 2006). Furthermore, the element likewise stimulated the release of LHRH from male hypothalami incubated in vitro. The chronic ingestion of Mn also affected puberty-related events in males (Lee et al. 2006) and revealed specific gender differences when compared with females (Pine et al. 2005, Lee et al. 2006). In this study, the diets of male pups were supplemented with 10 or 25 mg/kg of MnCl2 from day 15 until they were 48 or 55 days old. While the 10 mg/kg dose did not produce significant effects, the 25 mg/kg dose caused marked increases in prepubertal LH, FSH and testosterone by 55 days. There was also a concomitant increase in daily sperm production and efficiency of spermatogenesis at 55 days, indicating a Mn-induced acceleration of spermatogenesis that was positively associated with increases in the puberty-related hormones. Specifically, LH acts on spermatogeneis by stimulating Leydig cell production of testosterone, and furthermore, FSH and testosterone are capable of stimulating all phases of spermatogenesis (Simoni et al. 1999). These observations support the results presented above showing that Mn-treated male rats mature at an accelerated rate when compared to age-matched control animals. Interestingly, gender differences were observed, in that immature males appear less sensitive to the hypothalamic influences of Mn than females. While a greater dose of Mn was required for males, it is noteworthy that the dose was still much lower than doses known to produce neurotoxicological effects in adult rats and primates (Newland 1999). The reason for the higher minimum dose effect in males could be due to differences in metabolism, since males clear Mn faster than females (Zheng et al. 2000, Oulhote et al. 2014).
Mn regulation of specific puberty-related genes and proteins in the hypothalamus
Chronic Mn administration on the LHRH gene
Previously we described the Mn action to activate the sGC-cGMP-protein kinase G (PKG) pathway to induce LHRH secretion from the nerve terminals in the MBH (Lee et al. 2007). Development of the glial–neuronal communication network in the MBH is necessary for LHRH secretion. In this regard, chronic Mn treatment caused an increase in Igf1 mRNA in the MBH at 22 and 29 days of age, along with a concomitant increase in IGF1 receptor content (Hiney et al. 2011). Mn induction of this growth factor gene in the MBH during early juvenile development and prior to pubertal onset indicates that this heavy metal can promote the maturation of the glial-neuronal neurosecretory activity in the hypothalamic area responsible for LHRH secretion. Importantly, the secretion of LHRH from nerve terminals in the MBH must be sustained in order to drive the pubertal process. Thus, identifying factors capable of stimulating Lhrh gene expression and synthesis prior to the peptides release is critical for understanding the mechanisms that control and/or alter the onset of puberty. In this regard, Mn administration markedly increased Lhrh gene expression in the preoptic area (POA)/rostral hypothalamic area (RHA) of the prepubertal female rat brain (Hiney et al. 2011, Srivastava et al. 2013). The Mn-induced increase in Lhrh gene expression in the hypothalamus has also been shown in birds (Xie et al. 2014). This elevation in LHRH synthesis and release is associated with the increased levels of puberty-related hormones as mentioned previously.
Chronic Mn administration affects regulation of the Kiss-1/Kisspeptin system
In recent years, genes first associated with tumor suppression (Lee et al. 1996, Ohtaki et al. 2001) have now been linked to events leading to the onset of puberty. Such a gene is Kiss-1, which increases in the hypothalamus as puberty approaches (Navarro et al. 2004a, Shahab et al. 2005). This gene encodes the kisspeptin (KP) family of peptides, which act through specific G protein receptors (GPR54) on LHRH neurons (Messager et al. 2005), resulting in the stimulation of LHRH neuronal activity (Thompson et al. 2004, Keen et al. 2008). Hence, the Kiss-1/KP system is considered critical for pubertal development in every species studied, including humans (de Roux et al. 2003, Seminara et al. 2003, Navarro et al. 2004b, Smith et al. 2007). Because of the relationship between Kiss-1 and LHRH, it was important to determine if Mn could upregulate Kiss-1 expression similar to the prepubertal increase noted above for Lhrh. In this regard, rats treated with Mn revealed increased Kiss-1 gene expression within the POA/RHA (Srivastava et al. 2013). Importantly, the RHA brain region includes the anteroventral periventricular (AVPV) nucleus, the specific region containing the Kiss-1-expressing neurons that provide the critical inputs to most LHRH neurons located in the adjacent POA (Lehman et al. 2010). The ability for chronic Mn exposure to induce the Kiss-1 gene is important and thus, opened up the question as to whether this element may influence potential genes upstream to Kiss-1.
Signaling by mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, is regulated by growth factors, amino acids and cellular energy levels (Wullschleger et al. 2004, Avruch et al. 2009), but is also considered a modulator of puberty through its regulation of Kiss-1. The downregulation of mTOR in the POA/RHA region caused decreases in both Kiss-1 and Lhrh gene expressions (Roa et al. 2009). Recently, it was shown that exposure to low but elevated levels of Mn caused increased prepubertal gene expressions of both mTOR and Kiss-1 (Srivastava et al. 2013), followed by the increased translation to their respective proteins (Srivastava et al. 2016). Since Mn causes early puberty (Pine et al. 2005, Lee et al. 2006), we assessed the potential for everolimus (EV), an mTOR inhibitor (Fox et al. 2010), to block the advanced VO that occurs in Mn-treated animals. As expected, the Mn supplementation advanced (P < 0.05) the day of VO when compared to the saline-treated animals (P < 0.05; Mn −32.5 ± 0.6 vs saline −34.6 ± 0.6 days of age). Conversely, the administration of the mTOR inhibitor, EV, blocked the action of Mn to induce precocious puberty. In this regard, VO in these animals was observed at 35.2 ± 0.4 days of age, which was similar to the saline-treated animals. These data clearly demonstrate that blockade of the mTOR/KP/LHRH system with this mTOR inhibitor negated Mn-induced early VO; thus, further implicating the effect of Mn on mTOR (Srivastava et al. 2016).
Because Akt and ras homologue enriched in brain (Rheb) are upstream pathway components associated with mTOR induction (Wullschleger et al. 2004), the same tissues as above were used to show that the expression of both of these proteins were also increased following chronic Mn administration (Srivastava et al. 2016). It is important to note that when activated, Rheb binds directly to mTOR (Avruch et al. 2009), an interaction that is essential for activation of the mTOR complex 1. This complex is a nutrient-responsive mediator regulating cell growth (Kim et al. 2002, 2003, Loewith et al. 2002) and involved in the activation of puberty at the hypothalamic level (Roa et al. 2009). Collectively, these results clearly show that exposure to Mn can precociously induce the expressions of Akt, Rheb, mTOR and Kiss-1/KP in the prepubertal POA/RHA, and importantly, that these increases are associated with the increased expression of the LHRH gene in this same brain region. They further demonstrate a role for Kiss-1/KP in the regulation of LHRH gene expression, an action supported by the fact that LHRH neurons express the KP receptor, GPR54 (Messager et al. 2005).
Identification of the Mn-induced upstream signaling pathway
We identified the IGF1 peptide, which is capable of activating hypothalamic Akt signaling (Cardona-Gomez et al. 2002, Hiney et al. 2010), as a potential upstream target that could be influenced by Mn. Figure 5 shows that Mn induced a dose-dependent release of hypothalamic IGF1 in vitro, demonstrating that Mn can influence IGF1 synthesis in the hypothalamus. Furthermore, an injection of the element directly into the brain third ventricle increased the synthesis of phosphorylated IGF1 receptor (IGF1R) and Akt within the POA/RHA nucleus (Fig. 6). Importantly, the induction of both of these proteins by Mn was blocked by JB-1, an IGF1R antagonist (Srivastava et al. 2016). These results clearly show that Mn can induce IGF1R activated Akt; thus demonstrating an upstream action of Mn to regulate Akt. Previous studies, although not associated with Mn, have revealed events downstream from Akt showing that activation of this transduction signal can induce phosphorylation of (TSC2), an action that inhibits TSC2 activity (Inoki et al. 2002, Manning et al. 2002) and thus, leads to the activation of Rheb and mTOR (Inoki et al. 2003, Long et al. 2005). Recent results (Srivastava et al. 2016) revealed that Mn utilizes this pathway, since in addition to the Mn induction of Akt, the element also stimulated increases in phosphorylation of tuberous sclerosis complex 2 (TSC2), which removes the inhibitory tone on Rheb protein allowing its levels to increase (Fig. 7). Furthermore, the activations of TSC2 and Rheb were accompanied by increased mTOR and KP protein expressions (Fig. 8). Thus, these data strongly suggest that Mn acts, at least in part, through an IGF1/Akt/mTOR pathway within the POA/RHA to induce prepubertal KP synthesis (Fig. 9).
MnCl2 stimulates insulin-like growth factor 1 (IGF1) release from hypothalamic fragments of prepubertal female rats. Thirty-day-old female rats were killed and a tissue fragment containing the preoptic area/medial basal hypothalmic (POA/MBH) region of each animal was excised and incubated in medium. Open bar represents tissue exposed to medium only, striped bar represents tissues exposed to the different concentrations of MnCl2. Note that the 1mM dose did not stimulate IGF1 over medium only controls, but that the 10 mM and the 20 mM doses of MnCl2 stimulated increases in IGF1 release over the controls and those exposed to 1 mM. The respective bars illustrate the mean (± s.e.m.) of an N of 8–10 animals/group. *P < 0.05; **P < 0.01 vs medium only. Adapted, with permission, from Srivastava VK, Hiney JK & Dees WL 2016 Manganese stimulated kisspeptin is mediated by the IGF-1/akt/mammalian target of rapamycin pathway in the prepubertal female rat. Endocrinology 157 3233–3241. Copyright 2016 the Endocrine Society.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
Effect of acute Mn exposure on insulin-like growth factor 1 receptor (IGF1R) and Akt protein expressions in the preoptic area/rostral hypothalamic area (POA/RHA) of prepubertal female rats. Animals were exposed via a third ventricular injection of MnCl2 (10 µg/3µL) or saline and IGF1R and Akt proteins were assessed in the POA/RHA tissue fragment 4 h post injection (A) Densitometric quantitation of all bands from two immunoblots evaluating phosphorylated (p)-IGF1R normalized to total IGF1R protein. (B) Densitometric quantitation of all bands from two immunoblots evaluating p-Akt normalized to total Akt protein. Note that Mn stimulated an increase in the phosphorylation of IGF1R and then Akt when compared to the respective saline-treated animals. The bars illustrate the mean (± s.e.m.) of an N of 8 per group. *P < 0.05; **P < 0.01 vs saline-treated animals. Adapted, with permission, from Srivastava VK, Hiney JK & Dees WL 2016 Manganese stimulated kisspeptin is mediated by the IGF-1/akt/mammalian target of rapamycin pathway in the prepubertal female rat. Endocrinology 157 3233–3241. Copyright 2016 the Endocrine Society.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
Effect of acute Mn exposure on tuberous sclerosis complex 2 (TSC2) and ras homologue enriched in brain (Rheb) protein expressions in the preoptic area/rostral hypothalamic area (POA/RHA) of prepubertal female rats. TSC2 and Rheb protein levels were measured from the same tissue samples as in Fig. 6. (A) Densitometric quantitation of all bands from two immunoblots evaluating p-TSC2 normalized to total TSC2 protein. Central administration of Mn induced a marked increase in p-TSC2 protein synthesis when compared to the saline-treated animals. (B) Densitometric quantitation of all bands from two blots evaluating Rheb protein expression normalized to ß-actin protein. Rheb protein synthesis also markedly increased when compared to the saline treated animals, demonstrating that activation of phosphorylation of TSC2 (seen in panel A) removes the inhibitory tone on Rheb causing the increase in synthesis of this protein. The respective bars illustrate the mean (± s.e.m.) of an N of 8 per group. *P < 0.05; **P < 0.01 vs saline treated animals. Adapted, with permission, from Srivastava VK, Hiney JK & Dees WL 2016 Manganese stimulated kisspeptin is mediated by the IGF-1/akt/mammalian target of rapamycin pathway in the prepubertal female rat. Endocrinology 157 3233–3241. Copyright 2016 the Endocrine Society.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
Effect of acute Mn exposure on mammalian target of rapamycin (mTOR) and kisspeptin (KP) protein expressions in the preoptic area/rostral hypothalamic area (POA/RHA) of prepubertal female rats. Protein levels of mTOR and KP were assessed from the same tissue samples as in Fig. 6. (A) Densitometric quantitation of all bands from two immunoblots evaluating p-mTOR normalized to total mTOR protein. Note that phosphorylation of mTOR protein was significantly increased following central administration of Mn when compared to the animals that received saline. (B) Densitometric quantitation of all bands from two immunoblots evaluating KP protein expression normalized to ß-actin protein. Central Mn administration also increased KP protein expression when compared to saline-treated animals. The respective bars illustrate the mean (± s.e.m.) of an N of 8 per group. *P < 0.05 vs saline controls. Adapted, with permission, from Srivastava VK, Hiney JK & Dees WL 2016 Manganese stimulated kisspeptin is mediated by the IGF-1/akt/mammalian target of rapamycin pathway in the prepubertal female rat. Endocrinology 157 3233–3241. Copyright 2016 the Endocrine Society.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
Mn control of KP synthesis within the POA/RHA. Stimulation of IGF1 by Mn induces phosphorylation of the IGF1R. This action results in the up-regulation of Akt to induce phosphorylation of TSC2 causing the removal of the inhibitory tone on Rheb. Activation of Rheb stimulates mTOR and ultimately, KP protein synthesis. IGF1, insulin-like growth factor 1; IGF1R, IGF1 receptor; KP, kisspeptin; Mn, manganese; mTOR C1, mammalian target of rapamycin complex 1; POA/RHA, preoptic area/rostral hypothalamic area; Rheb, ras homologue enriched in brain; TSC2, tuberous sclerosis complex 2.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
Overall benefits and consequences associated with prepubertal Mn intake
Over many years, it has been well documented that Mn can be both beneficial and harmful. The prepubertal actions of Mn are in agreement with this overall observation, and thus, because the effects of Mn at this critical time of development are relevant, they are worthy of further discussion. It is important to note that the supplemental dose of Mn used in the chronic studies are within the upper end of the estimated range of levels considered safe for children (Institute of Medicine 2001, Environmental Protection Agency 2003), but about 10–20 times below the amounts used for studying some of its neurotoxic effects (Gray & Laskey 1980, Laskey et al. 1982, Newland 1999, Moreno et al. 2009). We suggest, therefore, that Mn is beneficial in this regard and may contribute to the normal onset of puberty; however, a potential also exists for an increased risk of precocious pubertal development if exposed to low but elevated levels of the element during the juvenile or early adolescent years. It should be noted that central precocious puberty is a serious disorder that is initiated when the LHRH secretory system is activated prematurely, thus resulting in hormonal changes that resemble those that occur at the time of normal puberty, just too early. Several facts support the potential ability of Mn to elicit precocious development. Once taken into the body, the element accumulates in key areas of the prepubertal hypothalamus responsible for regulating the synthesis and release of LHRH (Pine et al. 2005, Lee et al. 2006). It up-regulates an upstream pathway involved in the control of LHRH neuronal activity (Srivastava et al. 2016), and subsequently, induces secretion of puberty-related hormones that are associated with advanced puberty in both sexes (Pine et al. 2005, Lee et al. 2006). The fact that females appear more sensitive to the element (Pine et al. 2005, Lee et al. 2006) is of potential importance as evidence indicates a trend for increased precocious puberty cases in females (Herman-Giddings et al. 1997, Parent et al. 2003). In boys, less than 10% of the cases are idiopathic, whereas in girls, over 95% of precocious puberty cases have no identifiable cause with puberty appearing normal, except for being early (Rosenfield 2002). Generally, it is thought that any substance that can act within the hypothalamus to induce LHRH secretion could be an underlying cause of this condition. Mn may be considered such a candidate, since it can induce pathways that are normally involved in controlling the LHRH system at the time of puberty. Overall, the evidence presented herein supports the notion that Mn can be beneficial, but also potentially harmful if the element accumulates in the hypothalamus at too young an age.
Conclusions
Deriving a better understanding of endogenous neuroendocrine factors, as well as genetic and environmental influences controlling or altering the onset of puberty is important. Evidence in recent years suggests that Mn, a naturally occurring environmental nutrient, may play an early role in pubertal development. In this review, we have described the actions of Mn to regulate prepubertal LHRH release from the nerve terminals in the MBH, as well as more recent studies describing an action of Mn with regard to synthesis of the peptide by neurons in the POA/RHA brain region. Specifically, Mn is capable of stimulating LHRH release from the nerve terminals in the MBH, an action due to the element inducing the sGC-cGMP-PKG pathway that facilitates secretion of the peptide. Subsequent research revealed that chronic Mn administration acted within the hypothalamus to cause increased secretion of pituitary gonadotropins in both prepubertal male and female rats, resulting in increased signs of testicular and ovarian function, respectively. While the increased secretion of prepubertal LHRH is critical at puberty, new synthesis of the peptide is needed to keep up with the release. Importantly, prepubertal Mn administration was shown to be associated with an increased expression of the Lhrh gene. Because the majority of LHRH neurons in the rat are located in the POA/RHA brain region, and because KP is synthesized within the RHA and is known to directly influence LHRH neuronal activity, the effect of Mn on KP synthesis in this area of the brain was also investigated. In this regard, Mn was shown to activate an IGF1/Akt/mTOR pathway resulting in increased prepubertal KP synthesis within the POA/RHA. This upstream action of Mn to promote KP synthesis is important considering the critical facilitative role that KP plays in the control of LHRH at puberty. A schematic drawing demonstrating the hypothalamic actions of Mn on prepubertal LHRH is shown in Fig. 10. These prepubertal actions suggest Mn may represent an environmental element that is beneficial to the timing of normal puberty. However, they additionally suggest that should Mn accumulate in the hypothalamus too early in life, it may be harmful by potentially promoting precocious pubertal development. Epidemiological research in children and experimental studies in primates will be useful in further addressing this important issue regarding interactions between environmental and genetic influences on the neuroendocrine control of pubertal development.
Hypothalamic actions of manganese (Mn) in the control of prepubertal luteinizing hormone-releasing hormone (LHRH) in the rat. Note that in the POA/RHA region, Mn induces IGF-1 secretion from neurons and glia to stimulate KP synthesis. Once released, KP binds its GPR54 receptors on LHRH neurons causing increased neuronal activity. LHRH neuronal dendrites travel caudally into the MBH where they release the peptide from their terminals directly into the hypophyseal portal vessels within the median eminence. In addition, Mn also acts downstream within the MBH to facilitate LHRH release from the nerve terminals by directly activating the soluble guanosine cyclase/cyclic guanosine monophosphate/protein kinase G pathway discussed earlier. GPR54, G protein receptor 54; IGF1, insulin-like growth factor 1; KP, kisspeptin; MBH, medial basal hypothalamus; POA/RHA, preoptic area/rostral hypothalamic area.
Citation: Journal of Endocrinology 235, 1; 10.1530/JOE-17-0237
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work was supported by the NIEHS grant ESO13143 (to WLD).
References
Aschner M 2000 Manganese: brain transport and emerging research needs. Environmental Health Perspectives 108 429–432. (doi:10.1289/ehp.00108s3429)
Aschner M & Aschner JL 1990 Manganese transport across the blood brain barrier: relationship to iron homeostasis. Brain Research Bulletin 24 857–860. (doi:10.1016/0361-9230(90)90152-P)
Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A & Dai N 2009 Amino acid regulation of TOR complex 1. American Journal of Physiology: Endocrinology and Metabolism 296 592–602. (doi:10.1152/ajpendo.90645.2008)
Boyer PH, Shaw JH & Philips PH 1942 Studies on manganese deficiency in the rat. Journal of Biological Chemistry 143 417–425.
Cardona-Gomez GP, Mendez P & Garcia-Segura LM 2002 Synergistic interaction of estradiol and insulin-like growth factor-1 in the activation of P13K/Akt signaling in the adult rat hypothalamus. Molecular Brain Research 107 80–88. (doi:10.1016/S0169-328X(02)00449-7)
Deskin R, Bursain SJ & Edens FW 1980 Neurochemical alterations induced by manganese chloride in neonatal rats. Neurotoxicology 2 65–73.
de Roux N, Genin E, Carel J, Matsuda F, Chaussin J & Milgron E 2003 Hypogonadotropic hypogonadism due to loss of function of the KiSS 1- derived peptide receptor GPR54. PNAS 100 10972–10976. (doi:10.1073/pnas.1834399100)
Dorman DC, Struve MF,, Vitarella D, Byerly FL, Goetz J & Miller R 2000 Neurotoxicity of manganese chloride in neonatal and adult CD rat following subchronic (21-day) high dose oral exposure. Journal of Applied Toxicology 20 179–187. (doi:10.1002/(SICI)1099-1263(200005/06)20:3<179::AID-JAT631>3.0.CO;2-C)
Environmental Protection Agency 2003 Health effects support document for manganese. EPA Report EPA 822-R-03-003. Washington DC, USA: EPA. (available at: https://www.epa.gov/sites/production/files/2014-09/documents/support_cc1_magnese_healtheffects_0.pdf)
Fechter LD 1999 Distribution of manganese in development. Neurotoxicology 20 197–201.
Fox JH, Connor T, Chopra V, Dorsey K, Kama JA, Bleckmann D, Betschart C, Hoyer D, Frentzel S & Difiglia M et al. 2010 The mTOR kinase inhibitor Everolimus decreases S6 knase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington’s disease. Molecular Neurodegeneration 5 26–38. (doi:10.1186/1750-1326-5-26)
Garcia SJ, Gellein K, Syversen T & Aschner M 2006 A manganese-enhanced diet alters brain metals and transporters in the developing rat. Toxicological Sciences 92 516–525. (doi:10.1093/toxsci/kfl017)
Gay VL & Plant TM 1987 N-methyl-D,L-aspartate elicits hypothalamic gonadotropin-releasing hormone release in prepubertal male rhesus monkeys (Macaca mulatta). Endocrinology 120 2289.S–2296.S. (doi:10.1210/endo-120-6-2289)
Gray LE & Laskey JW 1980 Multivariate analysis of the effects of manganese on the reproductive physiology and behavior of the male house mouse. Journal of Toxicology and Environmental Health 6 861–867. (doi:10.1080/15287398009529904)
Greger JL 1999 Nutrition versus toxicology of manganese in humans: evaluation of potential biomarkers. Neurotoxicology 20 205–212.
Griffiths LM, Loeffler SH, Socha MT, Tomlinson DJ & Johnson AB 2007 Effects of supplementing complexed zinc, manganese, copper and cobalt on lactation and reproductive performance of intensively grazed lactating dairy cattle on the South Island of New Zealand. Animal Feed Science and Technology 137 69–83. (doi:10.1016/j.anifeedsci.2006.10.006)
Herman-Giddings PA, Slora E, Wasserman RC, Bourdony CJ, Bhapkar MV & Koch GG 1997 Secondary sexual characteristics and menses in young girls seen in office practice: a study from a pediatric office setting network. Pediatrics 88 505–512. (doi:10.1542/peds.99.4.505)
Hiney JK, Srivastava VK, Nyberg CL, Ojeda SR & Dees WL 1996 Insulin-like growth factor-1 (IGF-1) of peripheral origin acts centrally to accelerate the initiation of female puberty. Endocrinology 137 3717–3721. (doi:10.1210/endo.137.9.8756538)
Hiney JK, Srivastava VK & Dees WL 2010 Insulin-like growth factor-1 stimulates hypothalamic Kiss-1 gene expression by activating Akt: effect of alcohol. Neuroscience 166 625–632. (doi:10.1016/j.neuroscience.2009.12.030)
Hiney JK, Srivastava VK & Dees WL 2011 Manganese induces IGF-1 and cyclooxygenase-2 gene expressions in the basal hypothalamus during prepubertal female development. Toxicological Sciences 121 389–396. (doi:10.1093/toxsci/kfr057)
Inoki K, Li Y, Zhu T, Wu J & Guan KL 2002 TSC2 is phosphorylated and inhibited by akt and suppresses mTOR signaling. Nature Cell Biology 4 648–657. (doi:10.1038/ncb839)
Inoki K, Zhu T & Guan KL 2003 TSC2 mediates cellular energy response to control cell growth and survival. Cell 115 577–590. (doi:10.1016/S0092-8674(03)00929-2)
Institute of Medicine 2001 Manganese. In Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium and zinc, ch 10, pp 394–419. Washington DC, USA: National Academy Press. (available at: https://www.ncbi.nlm.nih.gov/books/NBK222332/)
Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K & Skakkebaek NE 1994 Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. Journal of Clinical Endocrinology and Metabolism 78 744–752. (doi:10.1210/jcem.78.38126152)
Keen CL, Ensunsa JL, Watson MH, Baly DL, Donavan SM & Monaco MH 1999 Nutritional aspects of manganese from experimental studies. Neurotoxicology 20 213–224.
Keen KL, Wegner FH, Bloom SR, Ghatei MA & Terasawa E 2008 An increase in kisspeptin-54 release occurs with the pubertal increase in luteinizing hormone-releasing hormone-release in the stalk-median eminence of female rhesus monkeys in vivo. Endocrinology 149 4151–4157. (doi:10.1210/en.2008-0231)
Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P & Sabatini DM 2002 mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110 163–175. (doi:10.1016/50092-8674(02)00808-5)
Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV & Sabatini DM 2003 GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Molecular Cell 11 895–904. (doi:10.1016/s1097-2765(03)00114-x)
Laskey JW, Rehnberg JF, Hein JF & Carter SD 1982 Effects of chronic manganese (Mn3O4) exposure on selected reproductive parameters in rats. Journal of Toxicology and Environmental Health 9 677–687. (doi:10.1080/15287398209530195)
Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE & Welch DR 1996 Kiss-1, a novel human malignant melanoma metastasis-suppressor gene. Journal of National Cancer Institute 88 1731–1737. (doi:10.1093/jnci/88.23.1731)
Lee B, Pine M, Johnson L, Rettori V, Hiney JK & Dees WL 2006 Manganese acts centrally to activate reproductive hormone secretion and pubertal development in male rats. Reproductive Toxicology 22 580–585. (doi:10.1016/j.reprotox.2006.03.011)
Lee B, Hiney JK, Pine MD, Srivastava VK & Dees WL 2007 Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action. Journal of Physiology 578 765–772. (doi:10.1113/jphysiol.2006.123083)
Lehman MN, Merkley CM, Coolen LM & Goodman RL 2010 Anatomy of the kisspeptin neural network in mammals. Brain Research 1364 90–102. (doi:10.1016/j.brainres.2010.09.020)
Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonefant D, Oppliger W, Jenroe P & Hall MN 2002 Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Molecular Cell 10 457–468. (doi:10.1016/s1097-2765(02)00636-6)
Long X, Lin Y, Ortiz-Vega S, Yonezawa K & Avruch J 2005 Rheb binds and regulates the mTOR kinase. Current Biology 15 702–713. (doi:10.1016/j.cub.2005.02.053)
Manning BD 2004 Balancing Akt with S6K: implications for both metabolic disease and tumorigenesis. Journal of Cell Biology 167 399–403. (doi:10.1083/jcb.200408161)
Manning BD, Tee AR, Logsdon MN, Blenis J & Cantley LC 2002 Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinistide 3-kinase/Akt pathway. Molecular Cell 10 151–162. (doi:10.1016/S1097-2765(02)00568-3)
Mena I 1974 The role of manganese in human disease. Annals of Clinical and Laboratory Science 4 487–491.
Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D & Carlton MB et al. 2005 Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. PNAS 102 1761–1776. (doi:10.1073/pnas.0409330102)
Moreno JA, Streifel KM, Sullivan A, Legare ME & Tjalkens RB 2009 Developmental exposure to manganese increases adult susceptibility to inflammatory activation of glia and neuronal protein nitration. Toxicological Sciences 112 405–415. (doi:10.1093/toxsci/kfp221)
Navarro VM, Castellano JM, Fernandez-Fernandez R, Barriero ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L & Tena-Sempere M2004a Developmental and hormonally regulated mRNA expression of Kiss-1 and its putative receptor, GPR54, in rat hypothalamus and potent LH-releasing activity of Kiss-1 peptide. Endocrinology 145 4565–4574. (doi:10.1210/en.2004-0413)
Navarro V, Fernandez-Fernandez R, Castellano JM, Roa J, Mayen A, Barreiro ML, Gaytan F, Aguilar E, Pinilla L & Dieguez C et al. 2004b Advanced vaginal opening and precocious activation of the reproductive axis by Kiss-1 peptide, the endogenous ligand of GRP54. Journal of Physiology 561 379–386. (doi:10.1113/jphysiol.2004.072298)
Newland MC 1999 Animal models of manganese neurotoxicity. Neurotoxicology 20 415–432.
Ohtaki T, Shintani Y, Honda S, Matsumoto A, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y & Mosuda Y et al. 2001 Metastasis suppressor gene Kiss-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 411 613–617. (doi:10.1038/35079135)
Oulhote Y, Mergler D & Bouchard MF 2014 Sex- and age-differences in blood manganese levels in the U.S. general population: national health and nutrition examination survey 2011–2012. Environmental Health 13 87. (doi:10.1186/1476-069X-13-87)
Parent AS, Teilmann G, Fuul A, Skakkebaek NE, Toppaari J & Bourguignon JP 2003 The timing of normal puberty and the age limits sexual precocity: variations around the world, secular trends and changes after migration. Endocrine Reviews 24 668–693. (doi:10.1210/er.2002-0019)
Pine MD, Lee B, Dearth RK, Hiney JK & Dees WL 2005 Manganese acts centrally to stimulate luteinizing hormone secretion: a potential influence on female pubertal development. Toxicological Sciences 85 880–885. (doi:10.1093/toxsci/kfi134)
Roa J, Garcia-Giliano D, Varela L, Sanchez-Garrido MA, Pineda R & Tena-Sempere M 2009 The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic KiSS1 system. Endocrinology 150 5016–5026. (doi:10.1210/en.2009-0096)
Rosenfield RL 2002 Puberty in the female and its disorders. In Pediatric Endocrinology, 2nd edn, ch 16, pp 455–518. Ed Sperling MA. Philadelphia, PA, USA: Saunders. (doi:10.1016/8978-1-4557-4858-7.00024-x)
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM & Hendrick AG et al. 2003 The GPR54 gene as a regulator of puberty. New England Journal of Medicine 349 1614–1627. (doi:10.1056/NEJMoa035322)
Shahab M, Mastronardi C, Seminara S, Crowley WF, Ojeda SR & Plant TM 2005 Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. PNAS 102 2129–2134. (doi:10.1073/pnas.0409822102)
Simoni M, Weinbauer GF, Gromoll J & Niesclag E 1999 Role of FSH in male gonadal function Annales d'Endocrinologie 60 102–106.
Smith SE, Medlicott M & Ellis GH 1944 Manganese deficiency in the rabbit. Archives of Biochemistry and Biophysics 4 281–289.
Smith JT, Clay CM, Caraty A & Clark IJ 2007 Kiss-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season. Endocrinology 148 1150–1157. (doi:10.1210/en.2006-1435)
Srivastava VK, Hiney JK & Dees WL 2013 Early life manganese exposure upregulates tumor-associated genes in the hypothalamus of female rats: relationship to manganese-induced precocious puberty. Toxicological Sciences 136 373–381. (doi:10.1093/toxsci/kft195)
Srivastava VK, Hiney JK & Dees WL 2016 Manganese-stimulated kisspeptin is mediated by the IGF-1/Akt/mammalian target of rapamycin pathway in the prepubertal female rat. Endocrinology 157 3233–3241. (doi:10.1210/en.2016-1090)
Takeda A, Ishiwatari S & Okada S 1999 Manganese uptake into rat brain during development and aging. Journal of Neuroscience Research 56 93–98. (doi:10.1002/(SICI)1097-4547(19990401)56:1<93::AID-JNR12>3.0.CO;2-P)
Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA & Bloom SR 2004 Central and peripheral administration f kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. Journal of Neuroendocrinology 16 850–858. (doi:10.1111/j.1365-2826.2004.01240.x)
Terasawa E & Fernandez DL 2001 Neurobiological mechanisms of the onset of puberty in primates. Endocrine Reviews 22 111–151.
Wilson ME 1998 Premature elevation of serum insulin-like growth factor-1 advances first ovulation in monkeys. Journal of Endocrinology 158 247–257. (doi:10.1677/joe.0.1580247)
Urbanski HF & Ojeda SR 1987 Activation of lutenizing hormone releasing hormone release advances the onset of female puberty. Neuroendocrinology 46 273–276. (doi:10.1159/000124831)
Wullschleger S, Loewith R & Hall MN 2004 TOR signaling in growth and metabolism. Cell 124 471–484. (doi:10.1016/j.cell.2006.01.016)
Xie J, Tian C, Zhu Y, Zhang L, Lu L & Luo X 2014 Effects of inorganic and organic manganese supplement on gonadotropin-releasing hormone-I and follicle-stimulating hormone expression and reproductive performance of broiler breeder hens. Poultry Science 93 959–969. (doi:10.3382/ps.2013-03598)
Zheng W, Kim H & Zhao Q 2000 Comparative toxicokinetics of manganese chloride and methylcyclopentadienyl manganese tricarbonyl (MMT) in Sprague-Dawley rats. Toxicological Sciences 54 295–301. (doi:10.1093/toxsci/54.2.295)
