Identification of Environmental Compounds That May Trigger Early Female Puberty by Activating Human GnRHR and KISS1R

Author:

Yang Shu1,Zhang Li1,Khan Kamal2,Travers Jameson1ORCID,Huang Ruili1,Jovanovic Vukasin M1ORCID,Veeramachaneni Rithvik1,Sakamuru Srilatha1,Tristan Carlos A1,Davis Erica E23,Klumpp-Thomas Carleen1,Witt Kristine L4,Simeonov Anton1,Shaw Natalie D5ORCID,Xia Menghang1ORCID

Affiliation:

1. Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , Bethesda, MD 20892 , USA

2. Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University , Chicago, IL 60611 , USA

3. Department of Pediatrics, Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611 , USA

4. Division of Translational Toxicology, National Institute of Environmental Health Sciences , Research Triangle Park, NC 27709 , USA

5. Pediatric Neuroendocrinology Group, Clinical Research Branch, National Institute of Environmental Health Sciences , Research Triangle Park, NC 27709   USA

Abstract

Abstract There has been an alarming trend toward earlier puberty in girls, suggesting the influence of an environmental factor(s). As the reactivation of the reproductive axis during puberty is thought to be mediated by the hypothalamic neuropeptides kisspeptin and gonadotropin-releasing hormone (GnRH), we asked whether an environmental compound might activate the kisspeptin (KISS1R) or GnRH receptor (GnRHR). We used GnRHR or KISS1R-expressing HEK293 cells to screen the Tox21 10K compound library, a compendium of pharmaceuticals and environmental compounds, for GnRHR and KISS1R activation. Agonists were identified using Ca2+ flux and phosphorylated extracellularly regulated kinase (p-ERK) detection assays. Follow-up studies included measurement of genes known to be upregulated upon receptor activation using relevant murine or human cell lines and molecular docking simulation. Musk ambrette was identified as a KISS1R agonist, and treatment with musk ambrette led to increased expression of Gnrh1 in murine and human hypothalamic cells and expansion of GnRH neuronal area in developing zebrafish larvae. Molecular docking demonstrated that musk ambrette interacts with the His309, Gln122, and Gln123 residues of the KISS1R. A group of cholinergic agonists with structures similar to methacholine was identified as GnRHR agonists. When applied to murine gonadotrope cells, these agonists upregulated Fos, Jun, and/or Egr1. Molecular docking revealed a potential interaction between GnRHR and 5 agonists, with Asn305 constituting the most conservative GnRHR binding site. In summary, using a Tox21 10K compound library screen combined with cellular, molecular, and structural biology techniques, we have identified novel environmental agents that may activate the human KISS1R or GnRHR.

Funder

National Institute of Environmental Health Sciences

NCATS

NIH

Publisher

The Endocrine Society

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