Development of Reproductive System in the Fetus: Genetic, Endocrine and Environmental Factors - Term Paper Example

Development of Reproductive System in the Fetus: Genetic, Endocrine and Environmental Factors Introduction It has been suggested that genes are important to, but not sufficient for, not only development but also the explanation of development. It is a fact that the key to sex determination of the fetus lies in the male spermatogenesis and the genetic constitution of the sperms. Out of 23 pairs of somatic chromosome in humans, 22 pairs are somatic and 1 pair is sex chromosomes. The gametes or reproductive cells are haploid, with only 22 representing somatic chromosomes and one sex chromosome. In case of males, the sex chromosome may be of X or Y type, whereas in case of the female partner, this is universally only Y type During sexual intercourse, in the process of a male sperm uniting with a female ovum, millions of sperms approach a single ovum ultimately to be united, to create a zygote that has again the diploid chromosome numbers restored. The question of interest is given the sheer overpopulation of the sperms, it appears that the selection of the sperm is a chance phenomenon dictated by randomization. It is also important to note that depending on the type of the sperm and its genotype with respect to the sex chromosome, X or Y, the sex of the developing fetus will be determined. This means either a sperm with X chromosome will unite with the ovum with x chromosome or a sperm with y chromosome will do the same, thereby creating the zygote with either XX or XY sex chromosomal pattern. If it is XX, the fetus will eventually become female and if it is XY, the fetus will become a male (Wilson et al. 2007). To answer the questions, how a sperm is selected, there were many theories, speculations, and observations. Research has explored the nuances of this mechanism quite effectively, but much is still unknown. Therefore, there is a need to update the recent knowledge from recent research, so a consensus can be drawn to determine the role of different other factors in the sex determination of the developing fetus. Background Genes by themselves are not causally efficacious, as genes and environments interact in the generation of any phenotypic trait. While it is development of a male or a female fetus that is inherent in the genetic information, the ultimate phenotypic expression is dependent on appropriate endocrine environment. There are two control mechanisms which are involved in the regulation of spermatogenesis: hormonal and genetic (Tobet, 2002. It has been known that environmental factors may alter the genetic determinants of gonadal sex, the hormonal determinants of phenotypic sex, fetal gametogenesis, reproductive tract differentiation, as well as postnatal integration of endocrine functions. These factors all together may affect the genetic expression leading to processes essential for the propagation of the species. Environmental factors have also been known to affect or modify sexual differentiation and thus development of reproductive capacity, may be through action on the endocrine synthesis and function. Although there are perceptions that these factors all have their secular roles to play in human fetal sexual differentiation, current research indicates that they are very much interrelated (Vidaeff et al. 2005) Literature Review: At this juncture it is important to have a review of scientific research articles including reviews in order to gather the recent evidence of environmental, endocrine, and genetic influences on sexual differentiation of the embryo. Fisher in his review article, "Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome" finds out evidence in favor of link between disruption of hormonal environment by environmental antiandrogens and their effects on development of testes and reproductive tract. The author presents evidence from an exhaustive review that endocrine disrupting chemicals from the environment can act as estrogens, anti-estrogens, antiandrogens, and steriodogenic enzyme inhibitors. These have been shown to act via interaction with thyroid hormones and their receptors, even through actions on the brain and hypothalamo-pituitary axis and via influence on the immune system. Phthalate esters that are used in manufacturing may cause disruption of male organogenesis if exposure during pregnancy occurs. The mechanism by which they act may be through large reduction in fetal testosterone synthesis and then androgen levels that in turn may affect virilization of the male reproductive tract. In this regard, an exposure can comprise of a mixture of environmental substances (Fisher 2004. Investigation to this area suggests environmental hormonal disruptors may have strong influence in sexual differentiation of developing fetus. The review article by McLachlan highlights the roles of xenoestrogens, environmental hormones, hormonally active agents, and environmental cross-talk signals. Although there are debates, inconsistencies, and controversies due to challenges thrown by environmental-endocrine hypothesis to the conventional knowledge in this area, much research has been conducted in this area. The steroid/thyroid/retinoid or nuclear receptor gene family have large areas with no known function or ligand. These are known as orphan receptors. The orphan receptor steroid-xenobiotic receptor has actually ability to recognize many classes of xenobiotic chemicals and with appropriate exposure activates a response that culminates into xenobiotic metabolizing enzymes providing a link between internal and external environments. The author provides evidence from literature that environmental agents may influence the endocrine axis, and environment may contain estrogenic contaminations from several sources. There is considerable evidence that environmental estrogens may come from many sources to interact with the developmental phenotype of the developing fetus since they are considered reversible cellular signals that result in organ growth, cell proliferation, and target gene expression. The actual mechanism underlying the molecular feminization of genes by extraneous estrogens has still not been elucidated. The most likely process could be activation of secondary hormonal cues through estrogenic imprints or genetic DNA methylation that can lead to alterations of signaling pathways at key points in cell differentiation (McLachlan 2001). What exactly is the mechanism still remains to be known, and what is known for sure is that environment also influences determination of sex of a developing fetus. It has also been suggested that the development of hypothalamic-pituitary axis and the associated synthesis of gonadotrophins is potentially sensitive to nutritional, high temperature stress, and other environmental influences which are mediated through endogenous endocrine influences (Rhind et al. 2001). Fleming et al. has dealt with the activity of germ cells which are remarkably different from somatic cells to elucidate the effects of genetic makeup in fetal sexual differentiation. They undergo meiosis, represent a haploid genome and give rise to totipotent diploid zygotes. Within the promoter region of protamine-1 and protamine-2, a sequence of 113 nucleotides and 859 nucleotides respectively, have been demonstrated to be sufficient for specific gene expression in haploid spermatids. Before sexual differentiation, both male and female embryos have bipotential gonads, as they possess both Wolffian and Mullerian ducts. These ducts can differentiate into male or female reproductive organs according to the hormonal status of the fetus. Owing to the expression of Sry, the bipotential gonad of males becomes the testis, which secretes several hormones including testosterone, MIS, or AMH and Insl3. Testosterone promotes Wolffian duct differentiation into the male reproductive tract, and MIS eliminates the Mullerian ducts. In females, the bipotential gonad becomes the ovary. In the absence of male hormones, the Wolffian ducts regenerate, whereas the Mullerian ducts persist and differentiate into the female reproductive tract. Thus far is known about the genetic and endocrine influences on sexual differentiation of the reproductive system in a developing fetus. Testosterone is secreted by the Leydig cells of the testes. During fetal life, testosterone promotes virilization of the urogenital tract in two ways. First, it stimulates the mesonephric or Wolffian ducts to develop and differentiate into the epididymides, the seminal vesicles, and the vasa deferentia. Second, in the early urogenital sinus and external genitalia, testosterone is rapidly transformed into dihydrotestosterone by the enzyme steroid 5a-reductase to induce the development of the male urethra, the prostate, the penis, and the scrotum (Fleming et al. 2004). Wilson and Davies in their review titled, "The control of sexual differentiation of the reproductive system and brain" discusses the genetic factors that determine the human sexual differentiation in the developmental phases. The genetic influence of sexual differentiation is indicated by the fact that the sexual differentiation begins almost as early as day-2 post fertilization. At this early stage, only genetic factors and endocrine factors, altered or unaltered can influence the determined phenotypic expression. Very early male embryos show more cells and higher metabolic activity, and a working model of the mediation of this function may be accelerating effects of the Y chromosome and retarding effect of the X chromosome, although endocrine factors continue to work until the differentiation of the genital ridge to develop into ovary or testes. Thus genetically directed and determined, the phenotype of the fetus still remains bipotent reproductively making it vulnerable to changes with the changes in the internal endocrine milieu. In this relation, as highlighted earlier, the male differentiation is important since the key remains in the genotype of the sperm, X or Y. The defining sex determining events of differentiation of genital ridge into testis leading to formation of Sertoli cells are mediated by candidate genes SRY and ZFY, with the SRY being ascertained to be the testis determining factor. The SRY gene has also been expressed in the brain of the developing fetus, from where the main endocrine stimuli at this stage of development generate. This shows the genetic influence on fetal sexual differentiation that may act through influence on the endocrine axis (Wilson et al. 2007). Viger and colleagues further probe into the area through their review. Hormonal regulation of spermatogenesis is organized as a control circuit with a negative feed-back mechanism involving the hypothalamus, pituitary gland, and testis. Specific neurons of the hypothalamus synthesize gonadotropin-releasing hormone (GnRH), which induces the production of two hormones within the pituitary, luteinizing hormone (LH) and follicle stimulating hormone (FSH).While a high pulse rate of GnRH release in the form of 1 impulse per 1 h results in the production of LH, a low pulse rate of GnRH release in the form of 1 impulse per 2 h results in the production of FSH. Within the testis, LH causes synthesis of testosterone by intertubular Leydig cells, which negatively influences hormone release in the hypothalamus and pituitary. By contrast, FSH acts on intratubular Sertoli cells. It induces the production of androgen-binding protein (ABP) by means of which testosterone can pass the Sertoli-Sertoli junctional complexes, and also induces the production of activin and inhibin by Sertoli cells which both influence hormone release in the hypothalamus and pituitary. The early embryo contains an indifferent gonad exhibiting no histological signs of sex differentiation in either female or male direction. However, the final sex determination is already established within the zygote lacking or containing a Y chromosome. The first histological sign of male sex differentiation within the indifferent gonad is the appearance of pre-Sertoli cells forming primitive testicular cords. Pre-Sertoli cells play a crucial role for correct testicular development, as these cells accept the primordial germ cells migrating from the yolk sac to the primitive seminiferous cords and prevent these cells from entering meiosis and express the gene for the sex-determining region of the Y chromosome (SRY) initiating the genetic sex determination of the embryo. Moreover they secrete the anti-Mllerian hormone (AMH) causing regression of the Mllerian ducts initiating the hormonal sex determination of the embryo. Simultaneously, secretion of testosterone by interstitial Leydig cells plays a vital role for downstream masculinization events inducing the differentiation of the Wolffian ducts into the male efferent seminal ducts and the descent of the testes into the scrotum, being a prerequisite for the production of fertile sperm in adulthood (Viger et al. 2005). Discussion: Sexual differentiation begins almost as early as day-2 post fertilization. At this early stage, only genetic factors and endocrine factors, altered or unaltered can influence the determined phenotypic expression. This is mediated through expression of SRY genetic regions. Considerable evidence suggests that specific fetal neurons the developing hypothalamus synthesize gonadotropin-releasing hormone (GnRH), which induces the production of two hormones within the pituitary, luteinizing hormone (LH) and follicle stimulating hormone (FSH). These hormones play to provide the internal endocrine environment for fetal differentiation. Although most authors agree on this, there is considerable difference of opinion as to how external environment can initiate a cross-talk with the genetic pattern or influence endocrine systems to influence fetal sexual differentiations. Many agents have been suggested, few agreed upon, few disagreed, the mechanism is mostly unknown, but all agree that external environment may act through modification of endocrine system to affect sexual differentiation in a developing fetus Conclusion: There exists an enormous volume of research literature in this area of human embryology with very little consensus in the narrowed area covering details. In the span of this assignment, it is difficult to include all. From the studies reviewed here it is very clear that all authors agree to the fact that the strongest influence is genetic inherent in the genotype of the sperm that unites with the ovum, for the fullest expression of which a suitable endocrine environment is necessary. Apart from the maternal endocrine milieu, a considerable part of the endocrine stimulus for fetal sexual differentiation comes from the fetal brain and fetal testosterones. These express genetic regions in the chromosomes that ultimately drive the process of differentiation. Environment plays a role through intercepting the normal hormonal axis operative in this process, but despite suggestions, the exact mechanism remains to be elucidated. Most likely the model would be a genetic-endocrine-environmental influence on fetal sexual differentiation. References Fisher JS. 2004. Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction. 127: 305 - 315. Fleming A & Vilain E. 2004. The endless quest for sex determination genes. Clinical Genetics. 67: 15-25. McLachlan JA. 2001. Environmental Signaling: What Embryos and Evolution Teach Us About Endocrine Disrupting Chemicals Endocr. Rev. 22: 319 - 341. Rhind SM, Rae MT and Brooks AN. 2001. Effects of nutrition and environmental factors on the fetal programming of the reproductive axis. Reproduction. 122: 205 - 214. Tobet SA. 2002. Genes controlling hypothalamic development and sexual differentiation. European Journal of Neuroscience. 16: 373-362. Vidaeff AC. & Sever LE. 2005. In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence. Reproductive Toxicology. 20: 5-20. Viger RS, Silversides DW & Tremblay JJ. 2005. New insights into the regulation of mammalian sex determination and male sex differentiation. Vitamins and Hormones. 70: 387-413. Wilson CA and Davies DC. 2007. The control of sexual differentiation of the reproductive system and brain. Reproduction. 133: 331 - 359. Read More