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Basic Chemical Hazards to Human Health and Safety — II
Published in Jack Daugherty, Assessment of Chemical Exposures, 2020
For males, the time required to restore the sperm count is a significant reproductive effect. Any toxic substance that interferes with the control mechanism for the male pituitary hormones, Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH), can lead to male infertility. LH and FSH are regulated by hypothalamic releasing factors, which are controlled by the pituitary and hypothalamus. LH stimulates Leydig cells, which synthesize steroid hormones, particularly testosterone, which controls the activity of accessory sex organs and the development of secondary sexual characteristics. FSH stimulates the Sertoli cells to initiate spermatogenesis and maintain optimal testicular function. Male germ cells are susceptible to toxic insult during the stages of spermatogenesis, in particular, by either being killed or undergoing heritable alterations or suffering non-heritable alterations that affect morphology, motility, and viability. Reduction of sperm count leads to male infertility, while mutated sperm may lead to adverse effects in a fertilized egg. Abnormal sperm raises the probability of spontaneous abortion, still birth, or any number of birth defects.
Toxic Responses of the Male Reproductive System
Published in Stephen K. Hall, Joana Chakraborty, Randall J. Ruch, Chemical Exposure and Toxic Responses, 2020
The process of spermatogenesis has been summarized in Figure 13.2. Briefly, spermatogonia Type A produce type B spermatogonia. These cells are particularly vulnerable to extraneous influences, such as antiandrogens and irradiation. Spermatogonia type B divide by mitosis to produce primary spermatocytes. The primary spermatocytes are the ones which will undergo the first meiotic division. The long prophase of the first meiotic division is divided into five stages: leptotene, zygotene, pachytene, diplotene and diakinesis. In the zygotene stage, the appearance of the “synaptonemal complex” is the most significant event. The synaptonemal complexes are associated with the chromosomal pairing before crossing over. Therefore, any external influence that impairs the formation of synaptonemal complexes may interfere with the normal chromosome paring and crossing over. The synaptonemal complexes persist in the pachytene stage. In the diplotene stage the chromosomes begin to move apart from each other, they are connected only at the crossing over sites called chiasmata. In diakinesis, the chromosomes become short and thick. Then at the end of prophase, the chromosomes are arranged at the equator, the characteristic of metaphase. Finally, at the completion of anaphase and telophase each homologous chromosome along with two sister chromatids migrates to one pole. After cytokinesis, two secondary spermatocytes are formed. Within a few hours, the secondary spermatocytes undergo a second meiotic division, resulting in the formation of spermatids. The spermatids are haploid cells. They do not undergo further division. By a series of nuclear and cytoplasmic modifications each spermatid is now transformed to a spermatozoon. This long transformation process is called spermiogenesis. This transformation includes the formation of the acrosome, mitochondrial reorganization, nuclear condensation, tail formation and shedding of the excess cytoplasm with remaining organelles. In humans, the entire process takes about 74 days. However, it has been shown that at least 3 to 4 months are needed for production of spermatozoa in a human testis that has been irradiated, therefore, it can be estimated that the spermatogenesis process takes about 100 days in man. The entire process of spermatogenesis occurs in close association with the Sertoli cells.
Maternal bisphenol A exposure disrupts spermatogenesis in adult rat offspring
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Patricia De Campos, Isabela M. Oliveira, Janaina Sena de Souza, Rodrigo Rodrigues Da Conceição, Gisele Giannocco, Maria I Chiamolera, Magnus R.Dias-Da Silva, Marco A. Romano, Renata Marino Romano
The expression of genes is an important step to cellular function. All types of information are necessary in order for each cell type to develop its function which is stored in DNA in the form of genes. To be functional, DNA is converted into RNA during transcription, which is regulated by stimulation and repression factors, according to cellular function status. In the cytoplasm, the mRNA is recruited by polysomes to be translated into proteins. The proteins develop their functions including binding receptors, acting as enzymes, or constituents of the cell structure. In this manner, the cell regulates its biological function stimulating or repressing genes through transcription and translation processes (Alberts et al. 2002). As mRNA is critical for protein production, the up- or down-regulation of genes by chemicals may markedly affect cellular function. The results of the present study also demonstrated that perinatal exposure to BPA led to a significant reduction in Ar mRNA expression. Androgen receptor is highly expressed in the testes, especially in Sertoli cells; and plays a key role in the maintenance of spermatogenesis, as evidenced by diminished spermatogenesis and lowered response of Leydig cells to testosterone that occurs as a result of a reduction in expression of Ar (Qiu et al. 2013). The action of androgens in spermatogenesis occurs via Sertoli cells, as germinative cells do not possess receptors for androgens and are required for maintenance of blood-testis barrier, adhesion, and release of sperm from Sertoli cells (Smith and Walker 2014). In ArKO mice, a reduction in the number of spermatids was observed, possibly due to a severe disruption of germ cell development and decreased adhesion of spermatids by Sertoli cells (De Gendt et al. 2004; Wang et al. 2006). Interestingly, it is well-established that testosterone stimulates synthesis of AR and stabilizes mRNA (Mora, Prins, and Mahesh 1996), which accumulates in the polysomes (Mora and Mahesh 1999). However, in the present study, the elevation in testosterone levels was accompanied by inhibition in Ar expression, indicating possible multiple effects of BPA on endocrine regulation. The reduction in Ar expression might also be involved in the decreased caput and corpus epididymis weight. In contrast, the seminal vesicle fluid was increased in the higher BPA-treated group, indicating that androgen-sensitivity of this tissue is maintained.
A male germ cell assay and supporting somatic cells: its application for the detection of phase specificity of genotoxins in vitro
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Khaled Habas, Martin H. Brinkworth, Diana Anderson
Sertoli cells (SC) play an important role in activating and regulating spermatogenesis because their actin cytoskeleton maintains vesicle transport, cell junctions, protein anchoring, and spermiation (Liu et al. 2018). Several investigators reported that the Sertoli cell is vital for differentiation, development, and adult function in the testis (Palmer and Burgoyne 1991; Rebourcet et al. 2014). Further, these cells regulate creation of the seminiferous tubules, Leydig cell progress, peritubular myoid cell function, blood-testis barrier (BTB), and germ cell development (Rebourcet et al. 2017). D’Aurora et al. (2015) noted that a vast number of deregulated transcripts were expressed by Sertoli cells. Biological and functional testing of the deregulated transcripts showed that alterations of genes involved steroidogenesis, cell death, response, lipid metabolism, BTB formation and maintenance, and spermatogenesis failure. Chemotherapeutic drugs were found to induce the Sertoli cell population as determined by the presence of undifferentiated Sertoli cells in regions of damaged spermatogenesis in adult testis, following drug therapy through childhood (Maymon et al. 2002). The Sertoli cell cytoskeleton was reported to be one of the main targets of environmental toxicants (Cheng 2014; Johnson 2014). Phthalates, such as di-(2-ethylhexyl) phthalate (DEHP), are universal environmental toxicants able to induce testicular atrophy (Boekelheide 2005). The active metabolite of DEHP was found to specifically target and inhibits Sertoli cell function resulting in a rapid generation of male germ cell apoptosis (Lee et al. 1997; Richburg et al. 2000). Choi et al. (2018) demonstrated that DEHP exerted testicular damage in rats in the mechanism of action associated with oxidative stress. Johnson (2014) in a rodent study noted that the MT-based cytoskeleton, specifically in the Sertoli cell, was related to disruption during toxicant-induced testis damage following treatment with phthalates Disruption of the MT-based cytoskeleton induced by toxicants, leads to failure and defects in spermatid transport and spermiation as well as failure in fluid secretion by Sertoli cells and germ cell apoptosis (Johnson 2014). Another study reported that Sertoli cells were the main target of phthalate toxicity, resulting in a significant histological abnormality, tubular vacuolation indicative of a breakdown in the junctions between Sertoli and germ cells (Xie, Li, and Zhu 2014). Further Zhang et al. (2017) found that phthalates such as mono-(2-ethylhexyl) phthalate (MEHP) induce prepubertal Sertoli cell damage through oxidative stress similar to actions attributed to DEHP (Choi et al. 2018).