Manganese (Mn) is a natural element that can be both beneficial and toxic. The long-term goal of this study is to define the effects of Mn exposure on the female pubertal process. Our recent studies are the first to show that Mn can stimulate prepubertal luteinizing hormone (LH) secretion by an action at the hypothalamic level, prompting us to question whether Mn is involved in the pubertal process and whether chronic oral exposure to low but elevated levels of Mn at an early age might advance female puberty. Our preliminary evidence indicates that it can advance puberty an action associated with elevated levels of important puberty related hormones. This is a novel and potentially important observation since precocious puberty is a major child health concern and in young girls the cause is often unknown. We hypothesize that if Mn levels rise too early in life, the seemingly beneficial effect of Mn to facilitate LH release may actually cause or contribute to female precocious puberty. The following specific aims will be used to critically address this important health related concern:
AIM 1) Determine the minimum effective dose and critical time of Mn exposure to elicit precocious development.
AIM 2) Assess effects of Mn on hypothalamic genes associated with control of gonadotropin secretion and correlate changes with specific puberty related hormones and receptors.
AIM 3) Conduct hypothalamic and pituitary response tests to demonstrate the Mn influence on precocious puberty is of central origin.
AIM 4) Assess pharmacologically the specific receptors and post-receptor pathways involved in the hypothalamic LH-releasing hormone (LHRH) pathway of secretion to determine the site(s) of Mn action.
AIM 5) Begin assessing mechanism(s) by which Mn facilitates LHRH release. The proposed studies are needed to define the actions and interactions of Mn on female pubertal development and are clearly relevant to child health and well being.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-NMB (04))
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Heindel, Jerrold
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Texas A&M University
Veterinary Sciences
Schools of Veterinary Medicine
College Station
United States
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Dees, William L; Hiney, Jill K; Srivastava, Vinod K (2017) Influences of manganese on pubertal development. J Endocrinol 235:R33-R42
Hiney, Jill K; Srivastava, Vinod K; Dees, William L (2016) Manganese protects against the effects of alcohol on hypothalamic puberty-related hormones. Life Sci 148:106-11
Srivastava, Vinod K; Hiney, Jill K; Dees, William L (2016) Manganese-Stimulated Kisspeptin Is Mediated by the IGF-1/Akt/Mammalian Target of Rapamycin Pathway in the Prepubertal Female Rat. Endocrinology 157:3233-41
Hiney, Jill K; Srivastava, Vinod K; Volz, Claire E et al. (2014) Alcohol alters insulin-like growth factor-1-induced transforming growth factor ?1 synthesis in the medial basal hypothalamus of the prepubertal female rat. Alcohol Clin Exp Res 38:2572-8
Dearth, Robert K; Hiney, Jill K; Srivastava, Vinod K et al. (2014) Prepubertal exposure to elevated manganese results in estradiol regulated mammary gland ductal differentiation and hyperplasia in female rats. Exp Biol Med (Maywood) 239:871-882
Srivastava, Vinod K; Hiney, Jill K; Dees, William L (2013) Early life manganese exposure upregulates tumor-associated genes in the hypothalamus of female rats: relationship to manganese-induced precocious puberty. Toxicol Sci 136:373-81
Hiney, Jill K; Srivastava, Vinod K; Dees, William Les (2011) Manganese induces IGF-1 and cyclooxygenase-2 gene expressions in the basal hypothalamus during prepubertal female development. Toxicol Sci 121:389-96
Prestifilippo, Juan Pablo; Fernandez-Solari, Javier; De Laurentiis, Andrea et al. (2008) Acute effect of manganese on hypothalamic luteinizing hormone releasing hormone secretion in adult male rats: involvement of specific neurotransmitter systems. Toxicol Sci 105:295-302
Lee, Boyeon; Pine, Michelle; Johnson, Larry et al. (2006) Manganese acts centrally to activate reproductive hormone secretion and pubertal development in male rats. Reprod Toxicol 22:580-5
Pine, Michelle; Lee, Boyeon; Dearth, Robert et al. (2005) Manganese acts centrally to stimulate luteinizing hormone secretion: a potential influence on female pubertal development. Toxicol Sci 85:880-5