Abstract:
Certain synthetic chemicals found in cosmetics, hygiene, and cleaning products are known to be endocrine disruptors (EDs). New research reveals that girls exposed to these disruptors may experience early puberty, which is linked to several health risks. These chemicals, including musk ambrette, can stimulate key receptors in the brain that control puberty. This suggests that exposure to these substances may prematurely activate the reproductive system in children.
In recent years, a global trend towards early breast development (called thelarche) in girls has been observed. This phenomenon has important health implications, as early puberty is associated with a range of health problems, including psychosocial difficulties, obesity, diabetes, cardiovascular disease and even an increased risk of developing breast cancer in the future.
Typically, the onset of puberty is influenced by both genetics and environment. However, the rapid pace of change in recent decades suggests that environmental factors may be playing a larger role than genetics, since genetic evolution occurs much more slowly. Several studies have been conducted to better understand this relationship, including a recent study published in the journal Endocrinology.
In this study, conducted by scientists at the National Institutes of Health and Northwestern University, the researchers investigated the influence of environmental factors on the early onset of puberty. Specifically, they looked at the presence of chemicals that can interfere with the endocrine system – known as endocrine disruptors.
These chemicals are present in many everyday products, such as plastics, cosmetics, and processed foods, and can alter the body’s hormonal balance, contributing to the early development of sexual characteristics, such as breast development.
Puberty is controlled by a network of neurons that release a hormone called GnRH (gonadotropin-releasing hormone). These neurons are located in a specific area of the brain called the arcuate nucleus (ARC), which is part of the hypothalamus, a region that regulates several important functions in the body.
When GnRH is released rhythmically, it stimulates a gland called the pituitary gland, located at the base of the brain, to release two hormones: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones, in turn, signal the ovaries (in girls) and testes (in boys) to start producing the sex hormones estrogen and testosterone. These hormones are responsible for the physical changes of puberty, such as breast growth, menstruation, or body hair growth.
However, the exact details of how the brain “decides” to start puberty are still a mystery. A substance called kisspeptin, which is also produced in the brain, is known to be an important activator of GnRH.
Interestingly, the neurons that produce kisspeptin have receptors for hormones such as glucocorticoids (related to stress), leptin (which is linked to body fat levels), and insulin (which controls blood sugar). This suggests that emotional state and nutritional status may influence when puberty begins.
It has therefore been hypothesized that these neurons may be influenced by external factors such as stress or exposure to chemicals in the environment, which may explain why some girls are starting puberty earlier than normal.
To overcome the limitations of traditional studies in children, the researchers used a technique called quantitative high-throughput screening (qHTS) to identify environmental substances that may activate the brain’s reproductive system. They used human embryonic kidney cells (HEK293) genetically modified to include receptors for kisspeptin (KISS1R) and the hormone GnRH (GnRHR), both fluorescently labeled for easy visualization.
In addition, adult rat hypothalamic cells and human neuron-derived cells created from stem cells were used in the study, as well as a line of rat pituitary tumor cells. For experiments with living organisms, zebrafish larvae were used.
The study tested chemicals from the Tox21 library, which contains about 10,000 compounds, including drugs and environmental substances, 8,312 of which are unique.
The tests used a technique that measures the release of calcium (Ca2+) in cells, generating light emission or fluorescence, to determine whether these substances could activate the KISS1R and GnRHR receptors or both, functioning as potential activators of the reproductive system.
After the initial screening, 45 compounds were identified as potential activators of the GnRHR and KISS1R receptors. Some of them bound only to GnRHR (like methacholine), others only to KISS1R (like musk ambrette), and others acted on both receptors (like mefloquine).
The next step was to verify whether these compounds, in addition to binding to the receptors, were capable of activating the cells and causing them to perform their functions.
To do this, the researchers tested whether the compounds stimulated the phosphorylation of a protein kinase ERK (p-ERK), a sign that the cell is activating its internal functions.
Of the compounds tested, only musk ambrette was able to both bind to the receptors and stimulate the cells to release kisspeptin, in addition to activating the expression of the Gnrh1 gene in rat hypothalamic cells (and GNRH1 in human cells) and the Gnrh3 gene in zebrafish larvae.
The figure shows that musk ambrette treatment induces dose-dependent effects on GnRH3 neurons in developing zebrafish. https://doi.org/10.1210/endocr/bqae103
These results indicate that musk ambrette can rapidly stimulate GnRH production, similar to how intravenous kisspeptin causes a rapid increase in luteinizing hormone levels in humans. This suggests that musk has the potential to significantly influence the reproductive system.
Musk ambrette is a type of synthetic fragrance that is used in products such as soap, detergent, creams, lotions, perfumes, and even some foods and beverages. However, studies on rats, it has been linked to neurological problems, which led the European Union to ban its use in cosmetics and personal care products in the 1990s.
Even so, it is still produced in countries such as China and India and can be found in other products in the United States.
This chemical has also been detected in aquatic environments, such as rivers and freshwater fish, raising concerns that children may be exposed to it through their diet or water. Because musk remains in the environment for a long time, there are concerns about the risks of prolonged exposure.
"Thus, it is conceivable that ambrette musk and/or related synthetic nitro-musks in the environment may be contributing to the trend toward earlier puberty in girls through activation of KISS1R. Although our in vitro and in vivo data do not provide direct evidence supporting an effect on puberty, they represent a first step toward linking ambrette musk to neuroreproductive axis activity during development. This possibility warrants further study," says Natalie Shaw, one of the study's authors.
READ MORE:
Identification of Environmental Compounds That May Trigger Early Female Puberty by Activating Human GnRHR and KISS1R
Shu Yang, Li Zhang, Kamal Khan, Jameson Travers, Ruili Huang, Vukasin M Jovanovic, Rithvik Veeramachaneni, Srilatha Sakamuru, Carlos A Tristan, Erica E Davis
Endocrinology. doi.org/10.1210/endocr/bqae103
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.
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