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Despite the strong heritability of pubertal timing, our understanding of the underlying genetics is limited. 2021 Jun;9(12):962. doi: 10.21037/atm-21-1632. As described earlier in this article, several international societies have put forth position statements on the importance of future research into the effect of environmental exposures on pubertal timing. Wolff MS, Teitelbaum SL, Pinney SM, Windham G, Liao L, Biro F, et al. These variants have been associated with later age at testicular growth in boys and thelarche in girls [43, 44*, 45**]. 2021 Jul;14(4):1316-1330. doi: 10.1111/1751-7915.13695. Quality of early family relationships and the timing and tempo of puberty: effects depend on biological sensitivity to context. Vasiliu O, Muttineni J, Karmaus W. In utero exposure to organochlorines and age at menarche. Neocleous V, Shammas C, Phelan MM, et al. Urinary oxidative metabolites of di(2-ethylhexyl) phthalate in humans. MKRN3 encodes a protein that resembles E3 ubiquitin ligases, which facilitate ubiquitination of target proteins, leading to degradation by the proteasome or, in some cases, modification of protein function [63*]. Interestingly, genome wide methylation studies have suggested that epigenetic mechanisms are intrinsically involved in the neuroendocrine control of female puberty [26]. They also affect gene expression, which means that they affect a gene's instructions for creating proteins . in 1969 have not changed, the timing of puberty has become dramatically altered over the last several hundred years. Many other studies have examined the relationship between chemical EDCs and the timing of puberty, and several extensive reviews have now been published [1517,64]. Ojeda, S. R., Dubay, C., Lomniczi, A., Kaidar, G., Matagne, V., Sandau, U. S., & Dissen, G. A. Riestra, P., Garcia-Anguita, A., Torres-Cantero, A., Bayonas, M. J., De Oya, M., & Garces, C. (2011). A striking and frequent cause of premature thelarche in children: Blanck HM, Marcus M, Tolbert PE, Rubin C, Henderson AK, Hertzberg VS, et al. Topaloglu, A. K., Reimann, F., Guclu, M., Yalin, A. S., Kotan, L. D., Porter, K. M., Imamoglu, S. (2009). 2009. Environmental influences on the pace of brain development Multiple studies and cross-sectional reviews have identified environmental exposures and endocrine disruptors as likely contributors to the international secular trend in earlier pubertal development. Christoforidis A, Skordis N, Fanis P, et al. 2010). He C, Kraft P, Chasman DI, et al. Merritt RJ, Jenks BH. While numerous studies have examined associations between candidate genes and pubertal timing in small to moderate-sized cohorts [722], this section will focus on large-scale genome-wide association studies (GWAS), which provide the most definitive results to date, and on a series of studies on variants in FSHR, the gene encoding the FSH receptor. Genetic and environmental influences on pubertal timing - PubMed Harris MA, Prior JC, Koehoorn M. Age at menarche in the Canadian population: secular trends and relationship to adulthood BMI. Phthalate exposure and precocious puberty in females. Carty CL, Spencer KL, Setiawan VW, et al. Pediatrics. In summary, multiple lines of evidence exist to suggest a central role of environmental exposures in the modulation of human pubertal timing. How could these genes affect pubertal timing? Given these inconsistent results, more human studies are needed to definitively implicate BPA in the alteration of pubertal timing. MKRN3 mutations in familial central precocious puberty. Over 100 pesticide compounds have been identified as endocrine disruptors and human consumption of them has nearly quadrupled in the last 40 years [81]. Busch AS, Hagen CP, Main KM, et al. That's because brain areas that "run" on dopamine may become overactive. The solid black curve in panel A represents typical hormone production over time, with a period of robust activity in infancy (minipuberty), a relative quiescence in childhood, and reemergence of activity at puberty. These various mechanisms, which are not mutually exclusive, emphasize that puberty is not a single event but rather a process that unfolds over time, and that there has already been significant reproductive endocrine activity by the time physical hallmarks of puberty become apparent. Gajdos, Z. K., Henderson, K. D., Hirschhorn, J. N., & Palmert, M. R. (2010). The consideration of the impact of environmental risk factors in etiopathogenic studies has put the environment in the forefront of research regarding psychotic illnesses. Marshall WA, Tanner JM. Of note, some genes implicated in precocious puberty (DLK1, MKRN3, and KISS1) and in delayed puberty (TACR3) are also associated with variation in normal pubertal timing, indicated by underlining. ; Environmental factors such as diet, temperature, oxygen levels, humidity, light cycles, and the presence of . Phthalate exposure in girls during early puberty. Higher urine and serum phthalate levels in girls have been linked to both isolated early breast development [73] as well as CPP in a study in Puerto Rico where the incidence of premature thelarche is the highest in the world [74]. Environmental factors and puberty timing: expert panel research needs. delivered a presentation on the genetics of pubertal timing at an unrestricted educational symposium sponsored by Endo Pharmaceuticals held at the International Meeting of Pediatric Endocrinology in September 2017. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. Gain-of-function mutations in the genes encoding kisspeptin and its receptor, KISS1 and KISS1R, respectively, have also been suggested to be causes of CPP [70*]. GWAS in men have largely revealed significant overlap between the sexes in the genetic factors that influence pubertal timing. Studies have also investigated the role of common variants in KISS1 and KISS1R in individuals with CPP; these studies have suggested potential associations, but because of the small size of these studies, further replication studies are needed to confirm these findings [70*, 73]. Strom BL, Schinnar R, Ziegler EE, Barnhart KT, Sammel MD, Macones GA, et al. Association of aromatase (TTTA)n repeat polymorphisms with central precocious puberty in girls. Are CYP1A1, CYP17 and CYP1B1 mutation genes involved on girls with precocious puberty? Xita N, Chatzikyriakidou A, Stavrou I, et al. Additionally, it can still be found in humans across the world as it is stored in adipose tissue with an average half life of 10 years [82,83]. The (TTTA)n polymorphism of aromatase (CYP19) gene is associated with age at menarche. Krstevska-Konstantinova M, Tasic VB, Montenegro LR, et al. Central precocious puberty is the most common form of precocious puberty and affects many more girls than boys. However, these findings have not been substantiated in boys [3033]. Matsuzaki CN, Junior JM, Damiani D, et al. Although existing data were felt to be highly suggestive of a link between endocrine disruptors and pubertal timing, it has also been readily acknowledged that association does not prove causality [18]. In most instances a susceptibility gene strongly influences the risk of developing a disease only in response to a specific environmental exposure. Relationship of lead, mercury, mirex, dichlorodiphenyldichloroethylene, hexachlorobenzene, and polychlorinated biphenyls to timing of menarche among Akwesasne Mohawk girls. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. We have organized these as intrinsic factors unique to each individual, naturally occurring endocrine disruptors and chemical endocrine disruptors. Molecular and Cellular Endocrinology, 324(1), 3944. Ultimately, other than anecdotal case reports, the relationship between natural endocrine disruptors and pubertal timing remains inconclusive and in need of further study. Curr Opin Endocrinol Diabetes Obes. Turusov V, Rakitsky V, Tomatis L. Dichlorodiphenyltrichloroethane (DDT): ubiquity, persistence, and risks. Genome-wide association studies have identified hundreds of common genetic loci that affect normal pubertal timing in both sexes and across ethnic groups. He C, Kraft P, Chen C, et al. Lomniczi A, Ojeda SR. The https:// ensures that you are connecting to the Ojeda SR, Lomniczi A, Sandau U, Matagne V. New concepts on the control of the onset of puberty. Frontiers | Genetic, epigenetic and enviromental influencing factors on Careers, Unable to load your collection due to an error. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society Pediatrics. The site is secure. However, another study in Finnish individuals with delayed puberty did not identify an enrichment of mutations in a panel of 24 IHH genes in individuals with delayed puberty compared to controls [89*]. Association studies of common variants in 10 hypogonadotropic hypogonadism genes with age at menarche. Skakkebaek NE, Toppari J, Soder O, Gordon CM, Divall S, Draznin M. The exposure of fetuses and children to endocrine disrupting chemicals: a European Society for Paediatric Endocrinology (ESPE) and Pediatric Endocrine Society (PES) call to action statement. As discussed below, these have reported earlier puberty, later puberty or no effect. Studies investigating the role of common variants in LEP, LEPR, and IGALS have not demonstrated an association with delayed puberty [94, 97]. . Howdeshell KL, Hotchkiss AK, Thayer KA, Vandenbergh JG, vom Saal FS. 8600 Rockville Pike Four heterozygous, potentially pathogenic missense variants in IGSF10 were identified in 28 individuals with delayed puberty from 10 families, and in 7 of these families these variants segregated fully with delayed puberty. Studies in mice show that Dlk1 is expressed in the hypothalamus, and in vitro studies demonstrate that DLK1 may be a regulator of Notch signaling, which appears to be an important component of kisspeptin neuronal development in mice [66**, 68, 69]. Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system. Denham M, Schell LM, Deane G, Gallo MV, Ravenscroft J, DeCaprio AP. This can cause boys, usually between ages 1 and 4, to make testosterone too early. The short answer to this question is that about 60 to 80 percent of the difference in height between individuals is determined by genetic factors, whereas 20 to 40 percent can be attributed to. The Endocrine Society published a scientific statement in 2009 regarding EDCs and the evidence that they potentially impact many aspects of endocrinology including male and female reproductive organ formation and the HPG axis [20]. Corresponding author and person to whom reprint requests should be addressed: Yee-Ming Chan, MD, PhD, Boston Childrens Hospital, 333 Longwood Ave, 6th Floor, Boston, MA 02115, Phone: (617) 355-2156, The publisher's final edited version of this article is available at. The Emerging Role of Epigenetics in the Regulation of Female Puberty. What is an Environmental Factor? The EPA defined an endocrine disrupting chemical (EDC) as an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental processes [20]. The dashed line represents the threshold concentration of gonadotropins and/or sex-steroids needed for the appearance of physical signs of puberty, such as testicular growth in males and thelarche in females. Relation of isoflavones and fiber intake in childhood to the timing of puberty. In 2013, mutations in MKRN3 emerged as an important genetic cause of central precocious puberty (CPP) in both boys and girls from whole-exome sequencing in multiple unrelated families. Qiao L, Zheng L, Cai D. Study on the di-n-butyl phthalate and di-2-ethylhexyl phthalate level of girl serum related with precocious puberty in Shanghai. Gene networks and the neuroendocrine regulation of puberty. Figure 1. The FDA and EPA are in charge of controlling the risk of environmental substances, which is a significantly daunting task in light of how little is known regarding the effects of the numerous chemicals we are exposed to every day [21]. Latronico AC, Brito VN, Carel JC. Ultimately, an individuals environment is likely comprised of many aspects that collectively contribute to the timing of puberty. Liu H, Kong X, Chen F. Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation. 2020 May 4;21(9):3245. doi: 10.3390/ijms21093245. The observation that a lower birth weight alone does not increase a childs chance for earlier puberty but that being longer and lighter at birth does, suggests that under nutrition and possible rapid postnatal weight gain may establish metabolic dysregulation. A Danish study found urine samples from 129 healthy children to be nearly universally contaminated by 11 different phthalate metabolites [67]. The 19992004 NHANES data found a slight statistically significant negative association between cows milk intake during childhood and menarchal age [43]. What causes normal puberty, precocious puberty, & delayed - NICHD Recent studies indicate that the onset of puberty is occurring at increasingly younger ages. Molecular and Cellular Endocrinology, 324(1), 311. Abreu AP, Dauber A, Macedo DB, et al. Silveira LG, Noel SD, Silveira-Neto AP, et al. Evaluation of anti-androgenic activity of di-(2-ethylhexyl)phthalate. Salman Kirmani . Hormone Research in Pdiatrics, 80(4), 257266. The graph schematizes the hormonal and physical events that mark pubertal onset and shows potential mechanisms for variation in pubertal timing. Accessibility Jirtle RL, Skinner MK. One study showed a 1020 times higher risk of CPP in adopted children with decreased risk if the child immigrated with their family and increased risk if adoption occurred after age two [51]. Studies evaluating in utero exposures are unquestionably important in evaluating future health concerns. Crinnion WJ. Ozen S, Darcan S, Bayindir P, Karasulu E, Simsek DG, Gurler T. Effects of pesticides used in agriculture on the development of precocious puberty. Identification of the gut microbiota biomarkers associated with heat cycle and failure to enter oestrus in gilts. Clipboard, Search History, and several other advanced features are temporarily unavailable. Frederiksen H, Sorensen K, Mouritsen A, Aksglaede L, Hagen CP, Petersen JH, et al. (2010). Would you like email updates of new search results? Parent AS, Teilmann G, Juul A, et al. More recent studies show a questionable continual decrease in the age at the start of puberty. Kang JH, Kondo F, Katayama Y. The most notorious of these are plant derived phytoestrogens such as those found in soy. Curr Opin Endocrinol Diabetes Obes. Notably, dieting behavior is quite common in industrialized countries throughout the world, yet AN and BN affect only an estimated 0.3 to 0.7 percent, and 1.7 to 2.5 percent, respectively, of females in the general population. The Interaction of Biology and Environment - New America A ~14 kb deletion in DLK1was found to segregate with all four affected female members from a Brazilian family of African descent. Nonetheless, these data are intriguing and require further investigation prior to declaring a younger puberty trend in boys. One such study evaluated children diagnosed with CPP and found higher plasma levels of DDE in those who were adopted or immigrated from foreign countries compared with ones native to the country [84]. Genome-wide association studies of age at menarche and age at natural menopause. Genetic determinants of pubertal timing in the general population. This paper describes in more detail the different hereditary and environmental factors that act during the fetal period and postnatally, and which play a role in human growth and pubertal development. Girls exposed to high PBB levels in utero reached menarche at 11.6 years compared to 12.212.6 years in girls with low exposure [63]. Association of the Q223R polymorphism with age at menarche in the leptin receptor gene in humans. Investigation of relationships between urinary biomarkers of phytoestrogens, phthalates, and phenols and pubertal stages in girls. However, two recent case reports suggested that both male and females with paternally inherited MKRN3 defects can sometimes be asymptomatic carriers [54*, 62]. Phytoestrogens share a chemical structure with estrogen and have the ability to be both stimulatory and inhibitory at the level of the estrogen receptor [55]. Children and infants are especially vulnerable to pollution and other environmental factors that may cause serious health problems. Central Precocious Puberty This type of early puberty, also known as gonadotropin-dependent precocious puberty, occurs when the abnormality is located in the brain. Consistent with this imprinting pattern, only individuals who inherit an MKRN3 mutation from their father develop CPP [51]. official website and that any information you provide is encrypted Stroheker T, Cabaton N, Nourdin G, Regnier JF, Lhuguenot JC, Chagnon MC. Macedo DB, Silveira LF, Bessa DS, et al. Environmental factors and puberty timing: expert panel research needs. Safety of soy-based infant formulas containing isoflavones: the clinical evidence. Soto N, Bazaes RA, Pena V, Salazar T, Avila A, Iniguez G, et al. Gladen BC, Klebanoff MA, Hediger ML, Katz SH, Barr DB, Davis MD, et al. Journal of Biological Chemistry, 278(30), 2765227657. HHS Vulnerability Disclosure, Help There has been increasing interest in the effects of intrauterine growth, birth weight and the pace of early weight gain on fetal programming and subsequent pubertal development. Encyclopedia of Evolutionary Psychological Science pp 17Cite as. The most important conclusion is that further study is needed to address the question of what environmental factors affect puberty and how we can best eliminate relevant exposures with the goal of maximizing the health and well-being of todays children and future generations to come. Predict the risks to prenatal development posed by exposure to teratogens. Trends in puberty timing in humans and environmental modifiers. Frontiers | Genetic, epigenetic and enviromental influencing factors on the regulation of precocious and delayed puberty This study demonstrated premature first estrus in mice that were born to mothers fed BPA. https://doi.org/10.1007/978-3-319-16999-6_2463-1, DOI: https://doi.org/10.1007/978-3-319-16999-6_2463-1, eBook Packages: Springer Reference Behavioral Science and PsychologyReference Module Humanities and Social Sciences, Encyclopedia of Evolutionary Psychological Science, https://doi.org/10.1007/978-3-319-16999-6_2463-1, Springer Reference Behavioral Science and Psychology, Reference Module Humanities and Social Sciences. Demerath EW, Liu CT, Franceschini N, et al. Environmental and Genetic Influences on Pubertal Development - Springer MKRN3 has therefore been postulated to have an inhibitory influence on reproductive endocrine activity in the hypothalamus in prepubertal children [64, 65]. NCI CPTC Antibody Characterization Program. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. A GPR54-activating mutation in a patient with central precocious puberty. This article will summarize the current understanding of the major environmental influences on pubertal timing with a focus on physiologic HPG axis activation rather than variants such as premature adrenarche. Day FR, Perry JR, Ong KK. Historical data have demonstrated a definite decrease in the age at puberty initiation from the 1800s to the mid 1900s [6]. Ann Transl Med. (2010). Genetic Influences of Puberty. An official website of the United States government. This section reviews current knowledge regarding the effects of natural endocrine disruptors on pubertal timing. Summary: Puberty is initiated by gonadotropin-releasing hormone from the hypothalamus followed by a complex sequence of endocrine changes and is regulated by both genetic and environmental factors. Regulation of Notch1 signaling by Delta-like ligand 1 intracellular domain through physical interaction. In psychology and other sciences, this was known as the . Effects of natural exposures on puberty timing. Li Y, Tollefsbol TO. High urinary phthalate concentration associated with delayed pubarche in girls. In one study of 1151 girls, the effects of 5 different phenol environmental toxins were examined [79]. Adgent MA, Daniels JL, Rogan WJ, Adair L, Edwards LJ, Westreich D, et al. Particular areas targeted for future investigation include etiologies of earlier puberty, critical exposure times and mechanisms of disrupting agents [19]. The Cannabinoid Receptor 2 Q63R Variant Modulates the Relationship between Childhood Obesity and Age at Menarche. Age at menarche and age at natural menopause in East Asian women: a genome-wide association study. Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls. Luo Y, Liu Q, Lei X, et al. Unauthorized use of these marks is strictly prohibited. Current age of onset of puberty. In large familial cases, there is complete penetrance of MKRN3 mutations. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. What is Epigenetics? | CDC Simon D, Ba I, Mekhail N, et al. Lomenick JP, Calafat AM, Melguizo Castro MS, Mier R, Stenger P, Foster MB, et al. Ioannides Y, Lokulo-Sodipe K, Mackay DJ, et al. Ultimately, an individual's environment is likely comprised of many aspects that collectively contribute to the timing of puberty. Dimitrova-Mladenova MS, Stefanova EM, Glushkova M, et al. However, most of boys and girls follow a predictable course through pubertal maturation. The exposed women and their offspring have been extensively studied. pubertal timing, central precocious puberty, delayed puberty, genetics, genome-wide association. Qiao L, Zheng L, Cai D. Study on the levels of the bisphenol A, octylphenol, 4-nonylphenol in serum of precocious girls. These statements highlight the need to examine the consequences of EDCs and other types of environmental exposures during critical periods of development including the prenatal period, infancy and throughout childhood. Purpose of review: Biehl MJ, Raetzman LT. Rbpj-kappa mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons. Moreover, both human and animal studies have implicated epigenetic changes resulting from exposures to different types of EDCs in the genesis of altered pubertal timing, as will be discussed in a later section of this review [27,28]. Lima CJ, Cardoso SC, Lemos EF, et al. Xiao W, Ke Y, He J, et al. Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy in patients with congenital hypogonadotropic hypogonadism: a multicentre clinical study. This section will specifically focus on three of the most widely studied chemical EDCs which are phthalates, bisphenol-A (BPA) and pesticides. Candidate genes from disorders that include delayed puberty or IHH as a feature have been proposed, including LEP and LEPR [94, 95], IGSF1 [96], IGFALS [97], and GHSR [98]. The Environmental Effect on Puberty - Scientific American Early-life soy exposure and age at menarche. In contrast, in idiopathic hypogonadotropic hypogonadism (IHH), another condition that presents with delayed puberty, puberty does not start or is incomplete by adulthood [86]. It is hypothesized that a stressful environment interrupts neuroendocrine control and that this may alter the start of puberty. Of note, a recent study did not identify significantly enrichment of IGSF10 mutations in individuals with delayed puberty compared to controls, but the high rate of variation in IGSF10 (a large gene) in control populations makes such enrichment difficult to demonstrate [89*]. Yuan Y, Hu J, Sun L, Zhang Y, Wang B, Yao R, Han H, Fu L. Sci Rep. 2021 Mar 4;11(1):5217. doi: 10.1038/s41598-021-84711-x. Investigations of both common and rare variants in genes identified in GWAS (LIN28B, TACR3, LEPR, and ESR1 [2**, 33]) have not revealed any definitive associations with precocious puberty [70*, 7479]. Cukier, P., Wright, H., Rulfs, T., Silveira, L. F. G., Teles, M. G., Mendonca, B. Age at menarche and menopause is not associated with two common genetic variants in the methylenetetrahydrofolate reductase (MTHFR) gene. Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Pril (Makedon Akad Nauk Umet Odd Med Nauki). Euling SY, Herman-Giddens ME, Lee PA, Selevan SG, Juul A, Sorensen TI, et al. The .gov means its official. Accessibility Frederiksen H, Aksglaede L, Sorensen K, Skakkebaek NE, Juul A, Andersson AM. Evolutionary psychology focuses on how universal patterns of behavior and cognitive processes have evolved over time. Correspondence to sharing sensitive information, make sure youre on a federal Variations resulting in differences in pubertal timing are depicted in gray; these include variation in the timing of activation of the GnRH neuronal network (B), in the rate of rise of gonadotropins/sex-steroids (C), and in end organ responsiveness to gonadotropins and/or sex steroids (D). Adair LS. Age at Menarche, Depression, and Antisocial Behavior in Adulthood. The brain signals the pituitary gland to begin puberty at an early age. It will be imperative to investigate which specific exposures and at what points in an individuals development the effects are the most harmful. Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitarygonadal hormones, and pubertal stage. Cukier P, Wright H, Rulfs T, et al. government site. Such outcomes are affected by molecular, often epigenetic, processes involving gene-environment (G-E) interplay that can influence gene expression. Please enable it to take advantage of the complete set of features! The association of sexual abuse and earlier menarche was explored using data from the Black Womens Health Study [54]. Styne DM, Grumbach MM. What is in our environment that effects puberty? - PubMed official website and that any information you provide is encrypted Besides the ingestion of known endocrine disruptors such as phytoestrogens, which are reviewed in the next section, the impact of specific dietary exposures on the timing of puberty has also been examined. In each category, evidence was found for and against the involvement of specific environmental factors on pubertal timing. Evolutionary psychology examines the connection between biological adaptation and preferences in mate selection. There was also a slight association of menarche prior to age 12 with physical abuse. Henley DV, Lipson N, Korach KS, Bloch CA. 13 Moreover, numerous descriptions of AN date from the middle of the 19th century suggesting that factors other than . Joustra SD, Wehkalampi K, Oostdijk W, et al. Dauber A, Cunha-Silva M, Macedo DB, et al. Chou IC, Wang CH, Lin WD, et al. Curr Opin Pediatr. Bookshelf Ravnborg TL, Jensen TK, Andersson AM, Toppari J, Skakkebaek NE, Jorgensen N. Prenatal and adult exposures to smoking are associated with adverse effects on reproductive hormones, semen quality, final height and body mass index. Exposure to hazardous substances and male reproductive health: a research framework. Martos-Moreno, G. A., Chowen, J. However, recent GWAS have not associated these FSHR variants with age of menarche in girls or age at voice breaking in boys [2**]. In males, age at voice breaking has been used as a similar marker. Tither JM, Ellis BJ. Potential mechanisms for how these genetic loci influence pubertal timing may include effects on the development and function of the GnRH neuronal network and the responsiveness of end-organs. Opposing influences of prenatal and postnatal growth on the timing of menarche. Mendoza N, Moron FJ, Quereda F, et al. Two independent studies have found maternal smoking to be associated with earlier puberty [46,47]. This mechanism could explain how genes involved in the development and migration of GnRH neurons, such as the ANOS1 gene (also known as KAL1) affect pubertal timing [2**, 86]. Effects of Environmental Endocrine Disruptors on Pubertal Development A novel MKRN3 nonsense mutation causing familial central precocious puberty. These mechanisms are not mutually exclusive. Genetic variation and reproductive timing: African American women from the Population Architecture using Genomics and Epidemiology (PAGE) Study. Thus, the true impact of soy ingestion on pubertal timing is far from clear.