**3.1 Hormonal system disruption**

Insecticides could be characterized as "endocrine disrupters" due to their adverse effects on reproductive hormone pathway [15]. The half-life of endocrinedisrupting insecticides changes from hours to months in the environment. Insecticides may have toxic effects on synthesis, secretion, transport, binding to target receptors, intracellular transmission and elimination processes of reproductive hormones. In addition, insecticides alter hormone-receptor binding via chancing receptor affinity or agonist/antagonist effects, since, they mimic hormones. Thus, many of insecticides have estrogenic, androgenic or anti-estrogenic and antiandrogenic effects. Furthermore, insecticides could bind several types of receptors such as membrane, nuclear, orphan and neurotransmitter receptors. Endocrinedisrupting insecticides also exert toxic effects via inducing cell death in reproductive system cells playing a role from hormone synthesis to germ cell axis. Different studies confirmed that insecticides irreversibly affect hypothalamic-pituitary axis due to their mimicking properties of hormones or undesired inhibition or activation of metabolic pathways [15–17].

Pyrethroids, synthetic esters of pyrethrins, widely used worldwide are important endocrine-disrupting chemicals. In animal studies, contradictory results were obtained about the effects of pyrethroids on HPG axis. It has been shown that permethrin, fenvalerate and cypermethrin exposure decreased serum testosterone levels and increased follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels. Lower levels of testosterone constitute negative feedback in HPG axis resulting in increased levels of FSH and LH. However, in another study, delthamethrin exposure caused increased levels of testosterone, FSH and LH [18].

Elbetieha et al. [19] demonstrated that cypermethrin exposure decreased the serum testosterone, FSH and LH levels in male rats. On the other hand, different studies reported that pyrethroids have no effects on hypothalamus functions and

#### **Figure 1.**

*Schematic representation of insecticides on male and female reproductive system via HPG axis (32).*

gonadotropin releasing hormone (GnRH) levels. There are few studies demonstrating that gonadotropic cells' function and expression of LH and FSH coding genes have changed with pyrethroids exposure [20]. Dohlman et al. [21] reported that permethrin caused reduction in progesterone levels in beef heifers. Overall, it has been concluded that changes of hormone production due to exposure of pyrethroids depend on dose and duration of the exposure.

Soljjou et al. [22] demonstrated that thiacloprid, a neonicotinoid, and delthamethrin, a pyrethroid, exposure decreased GnRH, LH, FSH and testosterone serum levels in the hypothalamus in a dose-dependent manner; and, interfered with steroidogenesis in testicular tissues. Annabi and Dhouib [23] showed that imidacloprid, a neonicotinoid, affected the biochemical pathways of hypothalamicpituitary-adrenal (HPA) axis via induction of oxidative stress.

Heptachlor, an organochlorine, may induce testosterone synthesis via 16-α and 16-β hydroxylases. Thiram, sodium N-methyldithiocarbamate and other dithiocarbamate insecticides inhibit the dopamine-β-hydroxylase activity and result in higher LH production, which prolonged proestrus stage. It has been reported that chlordimeform and amitraz interfere with the norepinephrine by binding to α2-andrenoreceptors and disrupt the GnRH release. Some other insecticides such as methoxychlor, DDT endosulfan, toxaphene, dieldrin, triadimefon, aldrin, methiocarb, chlordecone, malathion and sumithrin affect the HPA axis via binding receptors, mimicking the hormones and have shown estrogenic effects [24, 25]. In **Table 1** [3], selected insecticides and their endocrine-disrupting effects are listed.

### **3.2 Toxicity on male reproductive system**

Dysfunction of male reproductive system represents a fundamental issue for livestock industry. Impairment of spermatogenesis, anti-androgenic effects, alterations in reproductive enzyme pathways, decreased sperm quality and motility


**241**

*Reproductive Toxicity of Insecticides*

DNA integrity [32].

number decrease [26].

abnormalities in human [33].

**3.3 Toxicity on female reproductive system**

*DOI: http://dx.doi.org/10.5772/intechopen.92890*

balance in secondary endocrine system [26].

are key elements in insecticide-induced male infertility [5]. Insecticides exert their toxic outcomes on male reproductive system by directly affecting reproductive organs (testes, sertoli cells, leydig cells) and germ cells or impairing hormonal

It has been demonstrated in laboratory animals that carbamates have toxic effects on male reproductive system. Alterations of testicular weight and male accessory gland morphology, degeneration of seminiferous tubules and epididymis, spermatogenesis arrest, abnormalities of sperm motility and number, impairment of serum hormone and total proteins levels and estrogen receptor expressions were observed in several studies. However, detailed underlying molecular mechanisms of

Organophosphates could alter the spermatozoon chromatin structure, DNA, acrosome, motility and, have toxic effects on HPG axis. Reduced levels of testosterone were measured with organophosphate exposure due to inhibition of testosterone synthesis, which possibly occurs via reduction of steroidogenic enzymes' expression levels [5]. Organophosphates have dose-dependent detrimental effects on the morphology of testis and seminiferous tubules by causing atrophy and inducing germ cell death [26]. Additionally, organophosphate exposure is associated with decreased levels of sialic acid, glycogen alkaline phosphatase activity and increased levels of total protein, cholesterol and acid phosphatase. These imbalances could lead to induction of oxidative stress in male reproductive system by triggering inflammation, mitochondrial deficiency, DNA fragmentation and apoptosis [30, 31]. In wild birds such as parakeets and munias, organophosphate administration resulted in testicular dysfunctions [32]. Organophosphate insecticides induce DNA damage in sperm chromatin and that alters spermatogenesis pathway and causes infertility in male animals. Germ cell genetic material is protected by structure of male reproductive organs; however, it has been demonstrated that organophosphate insecticide disrupted the germ cell

DDT, methoxychlor, chlordane, heptachlor, aldrin, dieldrin, endrin, toxaphene, mirex and lindane are commonly used organochlorines. Organochlorines have shown their toxic effects via inducing oxidative stress in the epididymis and decreasing antioxidant defense. It has been demonstrated that endosulfan caused abnormal sperm maturation in the epididymis. In addition, organochlorines disrupt male reproductive maturation in adolescence. TCDD (2,3,7,8-tetrachlorodibenzop-dioxin), the most dangerous compound in world history, causes reduced fertility, delayed puberty and reproductive organ weights alterations, and also induces oxidative stress resulting in abnormal sperm morphology, motility and sperm

Pyrethroids are generally accepted as safe; however, their weak toxic effects on reproductive system were demonstrated in limited studies. Pyrethroids have adverse effects such as reducing sperm count and motility, aneuploidy in germ cells, reducing sex hormone levels and reducing semen quality and sperm morphological

Toxic effects of insecticides on female reproductive system were shown in different studies; and, it is concluded that insecticides disrupt female endocrine system and cause alterations in reproductive organs and germ cells [24]. Insecticides disrupt ovarian physiology. This is a two-way street as altering organ functions causes hormone secretion changes and this endocrine changes mostly affect the female reproductive system and result with dysfunctions via HPG axis.

carbamate toxicity on male reproductive organs are still unclear [26–29].

#### **Table 1.**

*Selected insecticides and their effects on endocrine system.*

### *Reproductive Toxicity of Insecticides DOI: http://dx.doi.org/10.5772/intechopen.92890*

*Animal Reproduction in Veterinary Medicine*

depend on dose and duration of the exposure.

**3.2 Toxicity on male reproductive system**

**Pesticide Hormone disruption effects**

Aldrin Androgen receptor binding

Chlorpyrifos-methyl Androgen activity antagonism Cypermethrin Estrogenic effect increase Deltamethrin Estrogenic activity

Fenoxycarb Testosterone metabolism disruption

binding

Tetramethrin Estrogen antagonism in females

*Selected insecticides and their effects on endocrine system.*

Methoxychlor Estrogenic effect, pregnane X cellular receptor binding

Parathion Gonadotrophic hormone synthesis inhibition

Aldicarb 17 beta-estradiol and progesterone inhibition

Bioallethrin Estrogen-sensitive cells proliferation inhibition

Carbofuran Estradiol and progesterone increase; testosterone decrease Chlordane Androgen receptor binding, estrogenic pathway inhibition

Dieldrin Androgen receptor binding, inducing estrogen receptor production in the cell Endosulfan Androgen receptor binding, inducing estrogen receptor production in the cell

Lindane Luteal progesterone decrease, androgen, estrogen and progesterone receptor

pituitary-adrenal (HPA) axis via induction of oxidative stress.

gonadotropin releasing hormone (GnRH) levels. There are few studies demonstrating that gonadotropic cells' function and expression of LH and FSH coding genes have changed with pyrethroids exposure [20]. Dohlman et al. [21] reported that permethrin caused reduction in progesterone levels in beef heifers. Overall, it has been concluded that changes of hormone production due to exposure of pyrethroids

Soljjou et al. [22] demonstrated that thiacloprid, a neonicotinoid, and delthamethrin, a pyrethroid, exposure decreased GnRH, LH, FSH and testosterone serum levels in the hypothalamus in a dose-dependent manner; and, interfered with steroidogenesis in testicular tissues. Annabi and Dhouib [23] showed that imidacloprid, a neonicotinoid, affected the biochemical pathways of hypothalamic-

Heptachlor, an organochlorine, may induce testosterone synthesis via 16-α and 16-β hydroxylases. Thiram, sodium N-methyldithiocarbamate and other dithiocarbamate insecticides inhibit the dopamine-β-hydroxylase activity and result in higher LH production, which prolonged proestrus stage. It has been reported that chlordimeform and amitraz interfere with the norepinephrine by binding to α2-andrenoreceptors and disrupt the GnRH release. Some other insecticides such as methoxychlor, DDT endosulfan, toxaphene, dieldrin, triadimefon, aldrin, methiocarb, chlordecone, malathion and sumithrin affect the HPA axis via binding receptors, mimicking the hormones and have shown estrogenic effects [24, 25]. In **Table 1** [3], selected insecticides and their endocrine-disrupting effects are listed.

Dysfunction of male reproductive system represents a fundamental issue for livestock industry. Impairment of spermatogenesis, anti-androgenic effects, alterations in reproductive enzyme pathways, decreased sperm quality and motility

**240**

**Table 1.**

are key elements in insecticide-induced male infertility [5]. Insecticides exert their toxic outcomes on male reproductive system by directly affecting reproductive organs (testes, sertoli cells, leydig cells) and germ cells or impairing hormonal balance in secondary endocrine system [26].

It has been demonstrated in laboratory animals that carbamates have toxic effects on male reproductive system. Alterations of testicular weight and male accessory gland morphology, degeneration of seminiferous tubules and epididymis, spermatogenesis arrest, abnormalities of sperm motility and number, impairment of serum hormone and total proteins levels and estrogen receptor expressions were observed in several studies. However, detailed underlying molecular mechanisms of carbamate toxicity on male reproductive organs are still unclear [26–29].

Organophosphates could alter the spermatozoon chromatin structure, DNA, acrosome, motility and, have toxic effects on HPG axis. Reduced levels of testosterone were measured with organophosphate exposure due to inhibition of testosterone synthesis, which possibly occurs via reduction of steroidogenic enzymes' expression levels [5]. Organophosphates have dose-dependent detrimental effects on the morphology of testis and seminiferous tubules by causing atrophy and inducing germ cell death [26]. Additionally, organophosphate exposure is associated with decreased levels of sialic acid, glycogen alkaline phosphatase activity and increased levels of total protein, cholesterol and acid phosphatase. These imbalances could lead to induction of oxidative stress in male reproductive system by triggering inflammation, mitochondrial deficiency, DNA fragmentation and apoptosis [30, 31]. In wild birds such as parakeets and munias, organophosphate administration resulted in testicular dysfunctions [32]. Organophosphate insecticides induce DNA damage in sperm chromatin and that alters spermatogenesis pathway and causes infertility in male animals. Germ cell genetic material is protected by structure of male reproductive organs; however, it has been demonstrated that organophosphate insecticide disrupted the germ cell DNA integrity [32].

DDT, methoxychlor, chlordane, heptachlor, aldrin, dieldrin, endrin, toxaphene, mirex and lindane are commonly used organochlorines. Organochlorines have shown their toxic effects via inducing oxidative stress in the epididymis and decreasing antioxidant defense. It has been demonstrated that endosulfan caused abnormal sperm maturation in the epididymis. In addition, organochlorines disrupt male reproductive maturation in adolescence. TCDD (2,3,7,8-tetrachlorodibenzop-dioxin), the most dangerous compound in world history, causes reduced fertility, delayed puberty and reproductive organ weights alterations, and also induces oxidative stress resulting in abnormal sperm morphology, motility and sperm number decrease [26].

Pyrethroids are generally accepted as safe; however, their weak toxic effects on reproductive system were demonstrated in limited studies. Pyrethroids have adverse effects such as reducing sperm count and motility, aneuploidy in germ cells, reducing sex hormone levels and reducing semen quality and sperm morphological abnormalities in human [33].
