Effects of Manganese on the Hypothalamic Regulation of Reproduction

Martina Azzopardi, Ashli Welcome, Clare Wilson

Introduction

The hypothalamus is a portion of the brain consisting of a number of small nuclei with a variety of functions; most importantly, it provides a link between the nervous system and endocrine system via the hypophysis. Manganese is a naturally-occurring metal required for normal mammalian reproductive function. It is able to cross the blood-brain barrier and accumulate in the hypothalamus, where it exerts its effect. It does so through several carriers in different oxidation states, specifically via:

* Divalent metal transporter 1 (DMT1)

* Transferrin receptors (TfR)

* Divalent metal/bicarbonate ion symporters ZIP8 and ZIP14

* Various calcium channels

* Solute carrier-39 (SLC39) family of zinc transporters

* Park9/ATP13A2 * Magnesium transporter hip14

* Transient receptor potential melastatin 7 (TRPM7) channels/transporters

* Homomeric purine receptors (P2X and P2Y)

* Citrate transporter.

Manganese is able to directly influence neuroendocrine effect related to reproduction. Manganese crosses the blood-brain barrier more effectively, and is eliminated with greater difficulty, in younger animals; subsequently, it can exert its effect in the developing reproductive system readily. Hormones released by the hypothalamus are directly affected: namely, direct stimulation of the secretion of gonadotropin releasing hormone (GnRH). GnRH is a neuropeptide molecule (comprised of 10 amino acids) which is produced by the parvocellular cells of the hypothalamus. GnRH is an integral component of reproductive development through its direct stimulation of the production and secretion of gonadotropin hormones by hypophyseal cells: specifically, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both FSH and LH are essential for sexual maturation and typical reproductive processes.

Typical manganese levels in different species

Pathogenicity: a summary of the effects of manganese in reproduction

Manganese is responsible for reproductive development, and so high levels trigger the early onset of puberty by increasing the expression of GnRH genes. Manganese is present in the plasma of mothers & the umbilical cord blood of premature and full-term babies. Limited information suggests that higher-than-usual amounts of Mn can cause birth defects.

Insufficient levels of manganese in young animals leads to abnormal skeletal development (bone stiffness, reduced bone strength, etc), retarded growth, and delayed development. In adult animals this deficiency leads to decreased reproductive performance: conception is difficult, perinatal death is common, abortion may occur, and oestrous cycles are irregular or absent http://www.nap.edu/read/9791/chapter/7#66. The lack, or irregularity of oestrous cycles occurs in cases of manganese deficiency as without manganese sGC is not activated, so the cGMP-PKG pathway is not stimulated, and ultimately GnRH is not produced. A lack of GnRH means that little/no FSH and LH are produced. As FSH and LH are responsible for the production of the key reproductive hormones, oestrogen and progesterone respectively. Furthermore, ovulation is triggered by the LH surge, so it stands to reason that if without LH there can be no ovulation, and no oestrous. In males suffering from a deficiency of manganese, symptoms include decreased sperm production, testicular degeneration, and a lack of libido. http://www.odon.uba.ar/uacad/fisiologia/docs/nuevos/acute.pdf

Pathogenic effects as a result of deficiency or surplus of Mn are discussed in further detail according to which species is affected in the following paragraphs below.

== Species-specific effects of manganese ==

Rodents - Rattus norvegicus

Due to manganese’s role as a cofactor to many enzymes it is fundamental to many biological reactions. Despite being a necessary trace element, elevated levels of manganese can negatively affect reproductive function, and deficiency can cause impairment of reproductive development. Exposure of prepubertal female rats (Rattus norvegicus) to elevated levels of manganese results in premature puberty. This is because manganese triggers the release of puberty related hormones, specifically GnRH. An experiment found that female rat pups exposed postnatally to elevated levels of manganese had a precocious increase in GnRH gene expression in the hypothalamus http://www.ncbi.nlm.nih.gov/pubmed/23997110. Increased levels of manganese in prepubertal rats therefore provoke the secretion of GnRH from the medial basal hypothalamus. GnRH causes the release of LH and FSH, which in turn trigger ovulation and follicle release respectively. Manganese restriction in pregnant mice has been found to cause delay in achievement of developmental milestones (e.g. opening of the eyes, descent of the testicles). Additionally, maternal manganese deficiency has been linked to a significant increase in pup death in the weeks preceding and following birth. http://www.ncbi.nlm.nih.gov/pubmed/11943509