CHAPTER ONE

1.0 INTRODUCTION

Reproductive toxicity is linked to the occurrence of adverse effects expressed as alterations to

the males or female reproductive organs, the related endocrine and nervous systems, or

pregnancy outcomes (Kimmel et al., 1995). Male reproductive toxicity may result from

adverse effects on sexual maturation, gamete production and transport, sexual behavior and

fertility (Kimmel et al., 1995). A variety of chemical and physical agents have been

associated with male reproductive toxicity (He et al., 2010, Wang et al., 2010), some of these

agents have been known to target one or several organ-systems notably (but not limited to) the

reproductive system that ensures the existence of humans causing negative effects under

certain conditions (Bonde, 1996). These chemical and physical agents also known as toxicants

may interfere with reproductive ability of exposed individuals from puberty throughout

adulthood. They can target the reproductive system and affect sperm count or shape, alter

sexual behavior, and increase infertility.

The male reproductive system has been an organ of concern as a result of its highly sensitive

nature especially in respect to a number of toxicants and their deleterious effects. It is made up of

the testes, a series of ducts and accessory sex glands (Stuart, 2011). The testes are responsible for

sperm production which is transported through the epididymis, ductus deferens, ejaculatory duct

and urethra (Davis, 2007; Stuart, 2011). The accessory glands produce secretions that become

part of semen, the fluid that is ejaculated from the penile urethra. These glands include the

seminal vesicles, prostate gland, and bulbourethral glands (Davis, 2007). A number of

determining factors have been discovered to interfere with the steroidogenic and spermatogenic
pathways which results in deraignment in the quantity and quality of sperm cells produced by the

testes which may invariably lead to infertility among males. Exposure to toxins during

spermatogenesis may target germ cells and consequently result in abnormal functioning of the

reproductive system and incase of the occurrence of pregnancy, it may lead to adverse pregnancy

outcomes (Robaire and Hales, 1993).

Infertility whether temporary or permanent, resulting from toxicants is increasingly becoming a

public health concern. Certain xenobiotics (for example: drugs, solvents, herbal formulations,

ethanol among others) have been known to adversely affect the reproductive system (Fody and

Walker, 1989). A myriad of drugs (prescription or ‘over-the-counter’) have been implicated for

their toxicity potential to the gonads namely protein and steroid hormones, analgesics, histamine

antagonists, anesthetics, cardioactive drugs, antimicrobials among others (Fody and Walker,

1989; Olayemi, 2010). Fortunately, some of these drug-induced toxicities have also been

observed to be reversible following cessation of the pharmacotherapy.

Histamine (H2) - receptor antagonists are widely used in the treatment of dyspepsia, peptic ulcers

and gastroesophageal reflux disease. They are a class of medications that block the action of

histamine H2 receptors of the parietal cells in the stomach thus decreasing the production of

stomach acid (Eriksson et al., 1995).

Cimetidine is a potent histamine H 2-receptor antagonist (Hamid et al., 2010) that is widely

prescribed worldwide (Al-Nailey, 2010), and is also available without prescription (Luangpirom

and Komnont, 2011; Aprioku et al., 2014). Cimetidine is an important drug commonly used in

the treatment of gastric and duodenal ulcers (Aprioku et al., 2014). Because it is a H2-receptor

antagonist it has the ability to block the actions of histamine on H 2-receptors (Winters et al.,

1979; Katzung, 1989; Ronald and Ashley, 2003) in the parietal cells of the stomach, thereby
preventing the production of acid (Rang et al., 2012; Altman, 1998). Thus, it promotes the

healing of these ulcers and can also be used for prophylaxis of stress ulcers (Schupp et al., 2003).

However in spite of its therapeutic importance, a wide range of adverse effects including

reproductive toxicity has been reported following cimetidine treatment in humans as well as

experimental animals. Cimetidine has been reported to be a reproductive toxicant causing

alterations in the histology of the testis with marked degeneration of seminiferous epithelium,

vacuolization and maturation arrest of spermatogenic cells (Franca et al., 2000; Sasso-Cerri et

al., 2001; Sasso-Cerri and Cerri, 2008; Aprioku et al., 2014). The drug has been shown to cause

modest decrease in sperm count and motility (Wang et al 1982; Kazerouni and Nayeri, 2000) and

impotence (Sawyer et al., 1981) resulting in decrease in sexual desire and drive.

Traditionally medicine has been the mainstay of primary health care in developing countries.

Humans have used various forms of traditional medicine in the management of ailments. The use

of plant-based therapy is as old as mankind and comparable to synthetic medications. Plants

provide a vibrant source for drug discovery and serve as potential leads for development of novel

therapeutic compounds (Newmann and Cragg, 2007; Geleldenhuys et al., 2012; Nahida et al.,

2012).

Curcuma Longa (Linn.), commonly called turmeric, is a perennial plant cultivated extensively

throughout the tropical parts of the world including India, Pakistan, China, Kenya, Ghana

Nigeria (Usman et al., 2009). It is propagated asexually through rhizome cuttings of which at

least one bud or protruding shoot is present (Samy, 2005). It belongs to the botanical family

Zingiberaceae. Curcumin is an important constituent of rhizomes of the plant Curcuma Longa

(Osawa et al., 1995). It is used as a spice to give a specific flavor and yellow colour to curry

(Pari et al., 2008). Curcumin has been found to contain a variety of biological and
pharmacological properties such as anti-tumor (Strofer et al., 2012), antioxidant (Venkatesan and

Chandrakasan 1995), anti-inflammatory properties and antiviral activities (Mazumder et al.,

1995). It has also shown to be a powerful antioxidant through inhibiting generation of reactive

oxygen species (ROS) both in vitro and in vivo with no side effect (Joe and LoKesh, 1994;

Osawa et al., 1995; Khanna 1999).

Nevertheless, there is dearth of literature on the effect Curcuma Longa (Linn.) on cimetidine-

induced reproductive toxicity hence, this study.

1.1 SPECIFIC OBJECTIVES OF THE RESEARCH

The specific objectives of this research are to;

(a) determine the plasma level of reproductive hormones such as testosterone, follicle

stimulating hormone (FSH) and luteinizing hormone following treatment with

acetone extract of Curcuma longa (AECUL) in Wistar rats with cimetidine-induced

reproductive toxicity;

(b) assess sperm characteristics such as sperm count, motility and viability using

spermatozoa obtained from the caudal epididymis of the AECUL treated rats;

(c) determine the level of reduced glutathione (GSH)as an index of oxidative stress in the

brain and testicular homogenates of the AECUL treated rats; and

(d) evaluate the effect of AECUL treatment on the histology of the pituitary gland and

testis of Wistar rats with Cimetidine-induced reproductive toxicity.

1.2 STATEMENT OF RESEARCH PROBLEM

The high cost of management of fertility-related disorders and its social stigmatization remains

the leading causes of public health concerns globally. Available pharmacotherapies have been

marred by their rising cases of severe adverse effects. Curcuma longa (Linn) is a locally

affordable herb that is reputed for its many medicinal properties. However, there exists a paucity

of literature on its neuro-endocrine effects in conditions of cimetidine-induced reproductive

toxicity, hence this study.

1.3 EXPECTED CONTRIBUTION TO KNOWLEDGE

This study will provide information on the neuro-endocrine effects of AECUL in Wistar rats

with Cimetidine-induced reproductive toxicity.