Abstract
Menarche is the first occurrence of menstrual bleeding and one of the most important events of female puberty. Alarmingly, over the last several decades, the mean age at menarche (AAM) has decreased. Environmental endocrine disruptors (EEDs) are chemicals that may interfere with the endocrine system, resulting in adverse developmental, immunological, neurological, and reproductive effects in humans. Thus, the effects of EEDs on fertility and reproduction are growing concerns in modern societies. In this study, we aimed to determine the influence of genetic and environmental factors on AAM. We used data from an AAM genome-wide association study of 329,345 women to conduct a transcriptome-wide association study (TWAS) with FUSION software. As references, we determined the gene-expression levels in the hypothalamus, pituitary gland, ovaries, uterus, and whole blood. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses using the significantly dysregulated genes identified by the TWAS. Using the STRING database, we also generated a protein–protein-interaction network to analyze common AAM-specific genes identified by the TWAS with different tissues. We performed chemical-related gene set enrichment analysis (CGSEA) and identified significant TWAS genes to uncover relationships between different chemicals and AAM. The TWAS identified 9,848 genes; among these, 1580 genes were significant (P < 0.05), and 11 genes were significant among the hypothalamus, pituitary, ovary, uterus, and whole blood. CGSEA identified 1,634 chemicals, including 120 chemicals significantly correlated with AAM. In summary, we performed a TWAS (for genetic factors) and CGSEA (for environmental factors) focusing on AAM and identified several AAM-associated genes and EEDs. The results of this study expand our understanding of genetic and environmental factors related to the onset of female puberty.
Highlights
Puberty is a complex process occurring between childhood and adulthood, producing internal and external physical changes that promote the development of primary and secondary sexual characteristics important for sexual reproduction [1]
Functional Exploration of TWAS-Identified Genes Associated With age at menarche (AAM)
163 TWAS-identified significant AAM-specific genes were associated with the hypothalamus: 38 significant genes were associated with the hypothalamus and pituitary gland; 7 significant genes were associated with the hypothalamus, pituitary, and ovary; and 11 significant genes were associated with the hypothalamus, pituitary, ovary, uterus, and whole blood
Summary
Puberty is a complex process occurring between childhood and adulthood, producing internal and external physical changes that promote the development of primary and secondary sexual characteristics important for sexual reproduction [1]. Sex hormones are responsible for the physical manifestations of female puberty, including thelarche, pubarche, and menarche [2]. EEDs are common in human living environments and include pesticides, plasticizers, industrial byproducts, drugs, and some naturally occurring phytochemicals [6]. These exogenous chemicals can interfere with the complex endocrine system, causing adverse health effects, such as reproductive disorders, metabolic diseases, and various cancers [7]. Chronic exposure to EEDs may play a role in accelerating or delaying the onset of menarche, and extensive research has shown that pesticides, phenols, polycyclic aromatic hydrocarbons, phthalates, and some heavy metals are responsible for hormone metabolism disorders occurring during puberty [8]. The effects of EEDs on fertility and reproduction are a growing concern in modern societies [9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
