Reproductive toxicology

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1. Presented by NATRAJ PREMKUMAR AD20188502 Graduate Researcher (Ph.D.) Dept. of Biochemistry College of Veterinary Medicine. Reproductive Toxicology

2. Contents INTRODUCTION GENERAL PRINCIPLES OF REPRODUCTIVE TOXICOLOGY NEUROENDOCRINE REGULATION OF REPRODUCTION MALE REPRODUCTIVE SYSTEM FEMALE REPRODUCTIVE SYSTEM GENERAL CATEGORIES OF REPRODUCTIVE TOXICANTS

3. WHAT IS REPRODUCTION? Reproduction (or procreation or breeding) is the biological process by which new individual organisms – "offspring" – are produced from their "parents".

4. Reproductive toxicology? ‘‘ Reproductive toxicity is a hazard associated with some chemical substances , that they will interfere in some way with normal reproduction ; such substances are called reprotoxic. It includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring’’

5. GENERAL PRINCIPLES OF REPRODUCTIVE TOXICOLOGY The study of reproductive toxicants because fertility depends on the integrated functions of three heterogeneous organ systems : the central nervous system (e.g., hypothalamus) the endocrine system (e.g., pituitary, gonads) the specialized organs of the male and female reproductive tracts . Among these tissues is a remarkable breadth of specialized cell types that must provide for the generation and delivery of haploid germ cells, provide for the homeostasis and function of the internal and external genitalia , induce and mediate the sexual behaviors necessary for mating, allow for fertilization and implantation of the embryo in the womb , maintain pregnancy and induce parturition, and provide nourishment to offspring.

6. General Mechanisms of Reproductive Toxicants The general principles of pharmacology that concern routes of exposure, metabolic activation , and distribution of toxicants to target tissues are all applicable in reproductive toxicology . The general principles of pharmacokinetics that dictate how toxicants may cause cellular dysfunction and/or death also apply in the case of reproductive toxicants. The relatively high rate of mitotic and meiotic activity in germ cells, continuous proliferation and differentiation of certain somatic cell types in the gonads. The dependency of reproductive functions on the central nervous and endocrine systems also make it especially vulnerable to agents that inhibit the synthesis or action of neurotransmitters and hormones .

7. Cell Signaling and Endocrine Disruption The mechanisms of intercellular signaling are generally described as endocrine , paracrine , or autocrine. The gonadal - derived steroid hormones (or sex steroid hormones) are critical signaling molecules within the gonads ( i.e., auto - and paracrine signaling ) as well as modulate the functions of neuroendocrine and peripheral reproductive tissues via endocrine signaling pathways . In autocrine signaling , a cell signals to itself, releasing a ligand that binds to receptors on its own surface (or, depending on the type of signal, to receptors inside of the cell). This type of signaling, in which cells communicate over relatively short distances, is known as paracrine signaling .

8. SEXUAL DIFFERENTIATION As development proceeds, one of the pairs of ducts develops while the other regresses. This depends on the presence or absence of the sex determining region of the Y chromosome, also known as the SRY gene . In the presence of a functional SRY gene, the bipotential gonads develop into testes. Subsequent development of one set and degeneration of the other depends on the presence or absence of two testicular hormones: testosterone and anti- müllerian hormone (AMH). Disruption of typical development may result in the development of both, or neither, duct system, which may produce morphologically intersex individuals.

9. NEUROENDOCRINE REGULATION OF REPRODUCTION The gonadotrope cells of the anterior pituitary respond to GnRH via the G - protein - coupled GnRH receptor and are stimulated to synthesize and secrete the gonadotropins follicle - stimulating hormone (FSH ) and luteinizing hormone (LH ). FSH and LH enter the circulation and stimulate the gonads to perform two principal functions, gametogenesis and hormone synthesis After reaching a threshold level in the circulation, the gonadal hormones then feedback upon the hypothalamus and pituitary to decrease further GnRH and gonadotropin secretion. These classic negative - feedback loops are obligatory to maintaining the appropriate levels of FSH and LH in the circulation The gonadal peptides known as INHIBINS specifically regulate FSH secretion, whereas gonadal - derived steroid hormones, primarily androgens (i.e ., testosterone ) in males and estrogens (i.e., estradiol ) in females, regulate LH secretion. In some species, however, estrogens and androgens are equally effective in controlling LH secretion in males.

10. Reproductive Toxins: Drugs, Environnemental Chemicals male female Bisulfan Bisulfan Chlorambucil Chlorambucil Cyclophosphamide Cyclophosphamide Nitrogen mustard Nitrogen mustard Adriamycin Corticosteriods Cystosine arabinoside Methotrexate Procarbazine Vincristine

11. HPG Axis as a Target for Toxicants The complex nature of the HPG axis and its dependence on a variety of hormones and endocrine pathways makes it especially susceptible to toxicants. Physical agents or xenobiotic that alter the synthesis or action of a particular hormone are likely to have profound downstream effects that may ultimately compromise fertility . GnRH Analogs - This physiological phenomenon is oft en exploited for the clinical treatment of women exhibiting irregular menstrual cycles or ovarian dysfunction , for which treatments with a GnRH agonist (e.g., leuprolide acetate ) are prescribed to transiently shut down the HPG axis . More recently, GnRH analogs that act as antagonists ( e.g., Antagon ) have been developed and are advantageous over the earlier agonists because they do not elicit a transient period of heightened gonadotropin secretion and hypergonadism. These compounds are also employed in the treatment of certain steroid - dependent breast and prostate cancers . Disruption of Neurotransmitters - Several different types of neurotransmitters influence the GnRH - secreting neurons in the hypothalamus . Catecholamine neurotransmitters such as epinephrine and norepinephrine primarily exert a direct stimulatory action on GnRH secretion.

12. Contd… Consequently, toxicants that disrupt ( i) norepinephrine synthesis, such as dopamine β- hydroxylase inhibitors (e.g., the pesticide Thiram ), ( ii) norepinephrine postsynaptic action, such as α- adrenergic antagonists (e.g., the pesticide chlordimeform ), ( iii) or presynaptic storage, such as certain alkaloids (e.g., Reserpine), can potentially inhibit GnRH secretion and ovulation . Steroids and Endocrine-Disrupting Chemicals - Given the significant role of steroid hormones in modulating hypothalamic and pituitary function xenobiotics that possess progestin, androgenic, or estrogenic activities, whether agonistic or antagonistic , or affect the synthesis of sex steroids could be expected to have profound effects on the HPG axis. In contrast, xenobiotics that act as antagonists for endogenous estradiol (e.g., clomiphene citrate ) or testosterone (e.g., the pesticide vinclozolin ) can inhibit negative feedback in the hypothalamus of females and males , respectively, leading to increased gonadotropin secretion and hyper stimulation of the gonads (i.e ., hyper gonadotropic hypergonadism ).

13. MALE REPRODUCTIVE SYSTEM The male reproductive tract consists of the ( i) testes, which serve as the site of gamete and steroid hormone production, (ii) excurrant ducts and epididymes for the transport, maturation, and storage of sperm, (iii) accessory sex glands for the production of seminal fluid, and ( iv) penis, for copulation and delivery of mature sperm to the female reproductive tract Spermatogenesis is the process of germ cell division and differentiation to produce spermatozoa, the mature male germ cell. All spermatogenesis occurs within the seminiferous tubules of the testes, where germ cells compose almost 90% of the seminiferous epithelium . Sertoli Cells are the somatic cellular component of the seminiferous epithelium. These are highly specialized cells that employ tight intercellular cytoskeletal adhesions, known as ectoplasmic specializations, to form a syncytium around the lumen of the tubule. Leydig Cells and Steroidogenesis: Leydig cells are the primary steroidogenic cell type in the testis and are located in the vascularized interstitial compartments. Leydig cells constitutively express the LH receptor and require LH to induce expression of the enzymes necessary for steroid biosynthesis.

14. Efferent Ducts and Epididymis as Targets for Toxicants The efferent ducts primarily serve to transport spermatozoa from the testis to the epididymis , as well as reabsorb luminal fluids and in effect concentrate the ejaculate. The epididymes also function as transport to the final storage location in the distal regions as well as serve as a site for final maturation. Any agent that accelerates this transit time is likely to cause reduced sperm numbers and compromised maturation. Androgens, most especially DHT, are essential to ensuring the optimal rate of sperm transport. Therefore , androgen receptor antagonists ( e.g., cyproterone acetate, flutamide ) or 5α- reductase inhibitors ( e.g., finasteride ) can disrupt the time of epididymal sperm transport and thereby their maturation . Estrogens , too, can accelerate the rate of epididymal sperm transport in mice. Several xenobiotics are also known to alter epididymal function, including certain fungicides (e.g., benzimidazole and ornidazole ).

15. According to the theory, increased exposure of the fetus to the oestrogens at a very early stage of gonadal development, that is about 8th to 10th week, may lead to a variety of defects of male reproductive organs. FSH production down division of Sertoli cells down MIS no longer can ensure a normal descent of male gonads, and the normal replication of germ cells some pesticides, phenols, detergents, metals, organic solvents have been shown to possess an oestrogenic-like bioactivity

16. XENOBIOTIC A xenobiotic is a chemical substance found within an organism that is not naturally produced by or expected to be present within.

17. Xenobiotics Affect Spermatogenesis Toxicants selective for sperm dev’t stage(s) DNA repair mech’s stage-specific Sperm metabolism alteration may affect fertilizing capacity Testosterone Spermatogenesis progression, maturation, maintenance Accessory sex glands Negative feedback to anterior pituitary Alterations Anesthetics, stimulants, drugs of abuse Alter hypothal -pit-gonadal axis (so GnRH, FSH, LH) Exogenous steroids, alcohol Interfere w/ steroid metabolism May affect hormonal balance

18. FEMALE REPRODUCTIVE SYSTEM The female reproductive system consists of a pair of gonads (ovaries), each attached to the abdominal wall via a specialized ligament ( mesovarium ) and joined to the reproductive ducts via an oviduct or a fallopian tube, depending on the species . The oviducts serve as the site of fertilization and transport for the developing embryo to the uterus. The uterus is a hollow, muscular organ in the female pelvic region that functions as the site of embryo implantation and pregnancy . Whereas the male reproductive system is responsible for providing and delivering a haploid germ cell, the female reproductive system is responsible for these functions as well as providing the site of fertilization and pregnancy, delivery of offspring, and nourishment during neonatal development. Therefore , a toxic insult to fecund females will likely have drastic consequences on the reproductive capabilities of a population or species.

19. Toxicants that block the synthesis or actions of estradiol or progesterone are likely to compromise the development and differentiation of the mammary glands during puberty or pregnancy. In addition, continued exposure to exogenous estrogens or estrogenic xenobiotics during the postnatal period may inhibit lactation. This approach is often used clinically in women that opt not to breastfeed. Because prolactin secretion from the pituitary is under the negative control of dopamine, toxicants that increase dopamine secretion or action (e.g., bromocriptine ) may inhibit lactation, while toxicants that block dopamine synthesis or action ( e.g .,certain neuroleptics) can cause hyperprolactinemia, leading to gynecomastia and galactorrhoea .

20. GENERAL CATEGORIES OF REPRODUCTIVE TOXICANTS Type I reproductive toxicants are those that cause inactivity or quiescence in both the gonads and reproductive organs. The primary effect of a Type I toxicant is likely to involve inhibition of gonadotropin secretion via actions on the hypothalamus or pituitary , or impairment of gonadal steroidogenesis . Because steroidogenesis and folliculogenesis are concomitant processes in the ovary, a Type I toxicant may also prevent steroid production in the ovary by inhibiting follicle growth as well versus direct inhibitory actions on the steroidogenic pathway. Type II reproductive toxicants are described as those causing inactivity in the gonads but preserved health and perhaps even hyperactivity in the genitalia. These are most often endocrine disrupting chemicals that act as agonists in the sex steroid signaling pathways. For example , an estrogenic toxicant will activate estrogen - mediated negative feedback in the hypothalamic – pituitary axis, thereby leading to reduced gonadotropin secretion. Hence reduce ovarian function, but will directly stimulate the estrogen sensitive organs of the reproductive tract (i.e., uterus, vagina) and cause these tissues to appear relatively normal or even have enhanced functions .

21. Type III reproductive toxicant causes hyperactivity among both the gonads and reproductive tract tissues. These are usually peptide compounds able to stimulate excess secretion of GnRH from the hypothalamus (i.e., GnRH agonists ) or preparations of exogenous gonadotropins or gonadotropin – like peptides and are often used in the clinical treatment of infertility