Influences of manganese on pubertal development

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.

Keywords: hypothalamus; manganese; puberty.

Figure 1

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 which 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 which 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 ±SEM. The number of samples is depicted within each panel. *p<0.05;**p<0.01 vs. basal (Adapted from Pine et al., 2005)

Figure 2

The effect of MnCl₂ on LHRH release from the medial basal hypothalamus in vitro. Each concentration point indicates basal LHRH levels versus 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 ±SEM. The number of samples is depicted within each panel. *p<0.05;**p<0.02. (Adapted from Pine et al., 2005)

Figure 3

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 ±SEM. N= 4 for saline-treated; N-6 for acyline-treated. (Adapted from Pine et al., 2005)

Figure 4

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 versus basal levels. Each bar resents the mean (±SEM). N=8 for both A and B. (Adapted from Lee et al., 2007)

Figure 5

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 represent tissues exposed to the different concentrations of MnCl₂. Note that the 1mM dose did not stimulate IGF1 over medium only controls, but that the 10mM and the 20mM doses of MnCl₂ stimulated increases in IGF1 release over the controls and those exposed to 1mM. The respective bars illustrate the mean (± SEM) of an N of 8–10 nimals/group. *p<0.05; **p<0.01 versus medium only. (Adapted from Srivastava et al., 2016)

Figure 6

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 (10µg/3µl) or saline and IGF1R and Akt proteins were assessed in the POA/RHA tissue fragment 4 hours 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 (± SEM) of an N of 8 per group. *p<0.05; **p<0.01 versus saline-treated animals. (Adapted from Srivastava et al., 2016)

Figure 7

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 figure 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 β-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 (± SEM) of an N of 8 per group. *p<0.05; **p<0.01 versus saline treated animals. (Adapted from Srivastava et al., 2016)

Figure 8

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 figure 6. (A) Densitometric quantitation of all bands from two immune blots 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 β-actin protein. Central Mn administration also increased KP protein expression when compared to saline-treated animals. The respective bars illustrate the mean (± SEM) of an N of 8 per group. *p<0.05 versus saline controls. (Adapted from Srivastava et al., 2016)

Figure 9

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. Mn, manganese; POA/RHA, preoptic area/rostral hypothalamic area; IGF1, insulin like growth factor 1; IGF1R, IGF1 receptor; TSC2, tuberous sclerosis complex 2; Rheb, ras homologue enriched in brain; mTOR, mammalian target of rapamycin, KP, kisspeptin

Figure 10

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 sGC/cGMP/PKG pathway. POA/RHA, preoptic area/rostral hypothalamic area; IGF1, insulin like growth factor 1; GPR54, G protein receptor 54; KP, kisspeptin; MBH, medial basal hypothalamus, sGC, soluble guanosine cyclase; cGMP, cyclic guanosine monophosphate; PKG, protein kinase G.