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© 2018 Conscientia Beam. All Rights Reserved. 

THE POTENTIAL EFFECT OF ZINC DEFICIENCY ON REPRODUCTIVE PROFILE OF 
MALE RAT AND ITS POSSIBLE CONSEQUENCES   

 

 

Aamir Nawab1 
Yi Zhao2 
Fahar Ibtisham3 
Guanghui Li4 
Mei Xiao5 
Jiang Wu6 
Wenchao Liu7 
Shuyan Tang8 
Lilong An9+ 

 

1Department of Veterinary Medicine, Agricultural College, Guangdong 
Ocean University, Zhanjiang 524088, Guangdong, China; Faculty of 
Veterinary Medicine, PMAS_Arid Agriculture University Rawalpindi, 
Pakistan 

 
2,3,5,6,7,8,9Department of Veterinary Medicine, Agricultural College, Guangdong 
Ocean University, Zhanjiang 524088, Guangdong, China 

 
4Department of Animal Science, Agricultural College, Guangdong Ocean 
University, Zhanjiang 524088, Guangdong, China 

 
 

 
(+ Corresponding author) 

 ABSTRACT 
 
Article History 
Received: 9 August 2018 
Revised: 13 September 2018 
Accepted: 17 October 2018 
Published: 19 November 2018 
 
 

Keywords 
Zn deficiency  
Testes 
Spermatogenesis 
Luteinizing hormone  
Sperm physiology  
Male rats 

 
Zinc (Zn) has antibacterial and antifungal properties, so, it is being widely used in food 
and pharmaceutical industries. Transition metal especially Zn deficiency has deleterious 
effects all over the world due to wide consumption of Zn deficient food byproduct. 
Several studies have reported that transition elements especially Zinc deficiency affects 
the endocrine and reproductive system. This overview comprises the information about 
negative effects of Zn deficiency on reproductive system of male rat and their possible 
outcomes. Scientific studies indicated that Zn deficiency severely affects the 
reproductive physiology of male rats.  Zn deficiency suppresses the function of male rat 
testes inclosing spermatogenesis and steroidogenesis by reducing the production of 
androgen hormone. In addition, Zn deficient rats also indicated testicular atrophy, 
primary and secondary spermatogonial stem cells disruption, lower number of sperm 
cells count, sperm quality, motility, viability, enhance in oxidative stress, inhibition of 
Testosterone (T) level which, in turn may cause infertility. The different consequences 
in animal models by zinc application are dose and duration dependent. Several studies 
propose that both higher and lower Zn concentration can effects the rat reproductive 
function. Therefore, the available outcomes revealed that Zn deficiency might have 
significant influence on luteinizing hormone and follicle stimulating hormone affecting 
the sperm physiology and histology in certain tissues. 
 

Contribution/Originality: This recent study has contributed significant scientific information on a particular 

subject area ―Zinc deficiency‖. A lot of reports have discussed the Zinc and its effects on human but there is lack of 

sufficient data related to Zn deficiency on reproductive profile of male rats. Therefore, this study is one of very few 

studies which have documented that Zinc is necessary in male reproductive system of human and animals. On the 

other side, it is recommended that optimum amount of Zinc supplementation should be used to avoid the deleterious 

effects on male reproductive physiology. 

 

 

Animal Review 
2018 Vol. 5, No. 2, pp. 12-21 
ISSN(e): 2409-6490 
ISSN(p): 2412-3382 
DOI: 10.18488/journal.ar.2018.52.12.21 
© 2018 Conscientia Beam. All Rights Reserved. 

 
 
 

 
 

 
 
 
 
 

https://www.doi.org/10.18488/journal.ar.2018.52.12.21


Animal Review, 2018, 5(2): 12-21 

 

 
13 

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1. INTRODUCTION 

Human, animal and aquatic lives are exposed to certain metals, through different sources. Some of these metals 

and their oxide are lethal to health inclosing reproductive health and few are important in trace quantity for 

numerous physiological functions of the body. In 1746, Zinc (Zn) was discovered by German chemist and it is 

reported as the second most abundant transition metal in the animal body and it is the only element which seems in 

all enzyme classes [1]. It cannot be synthesis in the body [2] and needs daily dietary intake to meet the 

physiological requirements. Zn importance has been recognized many years ago. In biological system, It plays 

structural, regulatory or catalytic roles in more than 200 enzymes [3]. Zn is an essential element of unique biologic 

and public health significance [4]. Zn as an important mineral is essential for animals [5] plants [6] and 

microorganisms [7]. 

It is reported that Zn is necessary for immune function, DNA replication, RNA polymerases and some other 

metabolic processes [4]. Another structural role of Zn is in protein synthesis, cell replication and growth processes.  

Zn is necessary for testicular maturation, wound healing, immunocompetence and neurological function [8]. It is 

also required for reproduction [9] gene expression [10] ossification [10] photochemical procedures of vision [11]  

and antibody production [12].  In addition, Zn is counted in many nutritional supplements [13]. Studies reported 

that Zn is also required for normal condition of epidermis, epithelium, skin and hooves [14]. Another study 

reported that in mammalian genomes about 3 to 10 % of all proteins are considered to bind zinc for holding, activity 

and conformational changes [15].  

 In 1934, first time it was reported that Zn was essential for normal growth in rats [16]. After 25 year, some 

authors reported that Zn deficiency were detected in chicks hatched from hens, fed Zn-deficient (ZD) diets and were 

died 4 days after birth [17]. The chicks were described by various skeletal defects and structural abnormalities of 

brain [18]. Several authors [19] stated that rats fed a Zn-deficient (ZD) feed had a fewer live fetuses/litter, and 

were low body weight, and several skeletal and soft tissues anomalies [19]. There were common abnormalities of 

development, deformities of the brain, lungs, heart, and urogenital system. In addition, it comprised the misshaped 

heads and fused or misplaced digits of the feet.  

Zn deficiency has been recognized in small laboratory animals, domestic animals, minks, and monkeys. Zn 

deficiency in mammals reported reduced food intake, growth retardation, testicular atrophy, swelling of feet, skin 

lesions, hair loss and hindered reproduction [18, 20]. Another study in human reported that chronic Zn deficiency 

is connected with immature testes, delayed sexual maturity, lack of appetite, immunosuppression, dwarfism, night 

blindness, spleen and liver abnormalities, reduced secretion of luteinizing hormone (LH) and folate deficiency [14, 

21, 22].  

On the other hand, Zn is thought to be an important ingredient in male reproductive system of the human and 

animals. Therefore, the aim of this review was to analyze the effect of Zn deficiency on reproductive profile of male 

rat and their promising consequences. 

 

1.1. Zn Deficiency and its Adverse Effects 

The surprising increase in the demand of Zn is mostly ascribed due to its superior antibacterial properties 

[22]. It has been reported that due to antimicrobial properties Zn is being utilized in the food industry as 

packaging and additives agent [23]. On the other hand, Zn deficiency has been documented in humans and a wide 

range of animals (Table 1). It shows severe effects on all phases of growth and male reproductive system in an adult. 

In marine invertebrates, Zn plays a significant role in pH regulation of sperm. A report of semen examination 

described that Zn deficiency less than 6.5 µg/L badly affected sperm motility and pH in horseshoe crab (Limulus 

polyphemus), sea urchins (Strongylocentrotus purpuratus), and starfish [7]. Zn deficiency causes injurious effects 

on esophagus, kidney, bone and testes of rats, and it is reported that in bone and plasma, alkaline phosphatase (ALP) 

activity is reduced in ZD pigs, cows and rats [22, 24]. 



Animal Review, 2018, 5(2): 12-21 

 

 
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© 2018 Conscientia Beam. All Rights Reserved. 

Table-1. Effects of Zn deficiency on different species 

Species Organs Dose Toxicity Reference 

Mouse  Reproduction 1.5 and 2.5 g/100 mL 
Zinc sulfate 
(ZnSO4) 

Reduced sperm count and motility, 
spermatic arrest. Affect the seminiferous 
tubules and fibrosis in interstitial tissue  

Nicholas and 
Caldart 
[22]  

Rat  Reproduction 7.50-15 and 30 mg/kg 
BW daily Zinc 
chloride (ZnCl2) 

Decreased sperm count and viability Dissanayake, 
et al. [25] 

Human  Reproduction 0.5 mg/kg BW daily Zn have inverse relationship with 
testosterone (T) production 

Manzoor, et 
al. [26] 

   Source:  Kumari, et al. [27] 

 

Zn deficiency is associated with abnormal testicular function in humans and animals and appears to be 

necessary for spermatogenesis and sperm production [27]. An adult male fed ZD diet, reported testicular lesions 

and decreased weight of male accessory sex gland [18]. Hypogonadism and testicular atrophy is reported in ZD 

rats and it causes the spermatic arrest, atrophy of seminiferous tubules and interstitial cells, decreased testosterone 

(T) levels and serum testicular Zn concentrations [28]. In Leydig cells, Zn is necessary for normal testosterone 

metabolism. Calcitonin hinders flow of Zn in the isolated rat Leydig cell, but these sound effects take more than 2 

days and are reported only in Zn deficiency [6]. During maturity of rats, Zn deficiency reduces the action of 

dipeptidyl carboxypeptidase (Dcp) enzyme in the testes and epididymis; this Dcp is essential for maturation of 

sperm cells and decreased activity of Dcp may cause delay in sexual maturity [29].  

 The literature findings demonstrated that both Zn higher and lower concentration may act as testicular toxicant in 

mice [30]. But, it also has been observed that excess dietary Zn may cause subnormal growth, anemia and 

reproductive failure in rats.  

 

1.2. Effect on Male Reproductive System 

Nutritional status plays an energetic role in human and animal reproduction (Table 2). There are some trace 

elements especially Zn is considered an essential ingredients for the optimal performance and normal productivity 

in male reproductive system. Hypogonadism is noticeable characteristic of severe Zn deficiency detected in the 

young and growing male rats [5]. In 1961 and 1963, Prasad reported the first case of Zn deficiency in humans [22, 

31]. Hypogonadic dwarfism was recorded in Iranian and Egyptian children. Prasad proved that this was due to Zn 

deficiency. Another study reported that mild Zn deficiency causes the oligospermic sterility and inability in rats and 

men. These effects have been observed in subjects with drepanocytosis [32] and dialyzed uremia [5]. Several 

authors examined that oligospermia was observed in 4/5 men on a limited 30-week diet containing only 4 mg of Zn 

[24]. In all these anomalies, it is detected that ZD diet below the average supplementation has deleterious effects 

on reproductive profile of human and male rats. 

 
Table-2. Role of Zn in Spermatogenesis 

Phase of Spermatogenesis Role of Zn Reference 

Initial phase of spermatogenesis   Role in ribonuclease (RNase) reaction Cuevas and 
Koyanagi 
[5] 

Medium phase of spermatogenesis    Spermatozoa development and role in preservation 
of germinal epithelium and seminiferous tubule 

Cuevas and 
Koyanagi 
[5] 

Final phase of spermatogenesis   Increase sperm motility Cuevas and 
Koyanagi 
[5] 

        Source: Cuevas and Koyanagi [5] 

 

 

 



Animal Review, 2018, 5(2): 12-21 

 

 
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1.3. Effect on Testicular Growth 

The testicles have main role in sperm production (Table 3). The seminiferous tubules are considered as the 

structural and functional unit of testicles and weight of testes depends on the number of seminiferous tubules. 

Fertility is highly associated with testicles size and poor fertility often being linked with small testicles, because the 

process of spermatogenesis take place in the seminiferous tubules and less testicles weight is considered due to 

lower number or length of seminiferous tubules [33]. 

 
Table-3. Function of male reproductive system 

Male reproductive organs Function Reference 

Testes Testosterone (T) production Ibtisham, et al. [21]  

Epididymis (caput, corpus and cauda) Sperm development, storage and 
motility  

Ibtisham, et al. [21] 

Vas deferens, accessory sex glands and penis Sperm ejaculation into vagina (female 
reproductive tract) 

Ibtisham, et al. [21] 

    Source:  Ibtisham, et al. [21] 
 

 

It is reported that in rats Zn deficiency decreases the diameter of seminiferous tubules and also both the basal 

and luminal areas. Severe atrophic variations in spermatogenic cells has been described in ZD animal and 

deterioration of the cellular layer of the seminiferous tubules [13]. According to previous literature, ZD rats may 

cause the decrease in tubular diameter and decrease in the number of germinal cells and Sertoli cells. In rats [26] 

and men [5] Zn deficiency has been found to be associated with low testosterone (T) levels. In rats, testicular 

atrophy was recorded due to Zn deficiency [5]. In rats and boars, Zn deficiency may involve in decreasing the 

growth and development of accessory sex glands. Scrotal size has been shown to be correlated to testicular weight 

and testicular weight has also been associated to sperm production [23]. Taken together, In ZD rats, it has been 

found that there is an obvious decrease in testosterone (T) levels, seminiferous tubular diameter and in the weight 

of male sex organs. 

 

1.4. Effect on Spermatogenesis 

Previous studies in hypophysectomized rats clearly explained that follicle stimulating hormone (FSH) and T 

are main factors for the regulation of spermatogenesis [34]. FSH requires for the development of the undeveloped 

testes by proliferation of Sertoli cells and later development of A and B spermatogonial stem cells [6]. T alone can 

play an important role in spermatogenesis, but the synergistic role of FSH is essential to stabilize the characteristics 

of spermatogenesis [34].  

Zn deficiency impairs the process of spermatogenesis by different pathways. It has been reported that in testes 

of rats, Zn deficiency has been linked with testicular atrophy, destruction of testicular cells and testicular function of 

steroidogenesis [4].  Zn deficiency also has been associated with low T level, which provides a strong proof that Zn 

plays a key role in the production of T, because T is produced and secreted from leydig cells, so Zn deficiency may 

be involve in apoptosis of the Leydig cells. T is considered an important hormone for spermatogenesis. As a result, 

in primary stages of spermatogenesis, Zn deficiency may be linked with apoptosis of testicular cells, as well as 

spermotocyte maturation phase, causing impairment in the late phase of spermatogenesis [33].  

Another study reported that increased oxidative stress, high serum malondialdehyde (MDA) and high tumor 

necrosis factor-alpha (TNF-α) and low levels of total antioxidant activity, serum superoxide dismutase (SOD) and 

alpha-tocopherol was associated in ZD animals. Some factors that incidentally increase the oxidative stress by 

reducing the capacity of cells to resist oxidation will also causes the apoptosis [35]. In light microscopy, Zn 

deficiency has described the spermatogenic arrest at the phase of round and elongated spermatids. This displays 

that high lipid peroxidation hinder the consequence of spermatogenesis, as confirmed by microscopic examination of 

apoptosis in the Sertoli cell linked with oxidative stress and Zn deficiency.  



Animal Review, 2018, 5(2): 12-21 

 

 
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It has been reported in rat study, that Zn deficiency is associated with stress and elevated cortisol levels. Stress 

can affect the spermatogenesis due to variable T secretion. A new invented gonadotropin-inhibitory hormone has an 

inhibitory effect on the hypothalamic–pituitary gonadal axis (Fig. 1). Decrease in T levels has been reported due to 

inhibition of the hypothalamic–pituitary gonadal axis, which may causes the variations in Sertoli cells and tightest 

barrier (blood-testis barrier), as a result which may affects the spermatogenesis. 

Therefore, due to Zn deficiency, oxidative stress, apoptosis and reduced T production is connected with 

impaired process of spermatogenesis. These outcomes propose that Zn deficiency influence the reproductive system 

of male rats. 

 

1.5. Effect on Sperm Morphology 

The main factor in the semen examination is the sperm morphology. Sperm motility plays a fundamental role 

in the fertilization, because abnormal sperm impaired the fertility and leading conception more difficult. Zn is 

considered an important ingredient in the quality; quantity and growth of sperm, but their deficiency produce 

several sperm morphological abnormalities. 

Zn deficiency causes the reduction of T [5] and may also involve in the degenerative variations. A recent study 

reported that abnormal morphology is due to proliferation of the axonemedense fibre-mitochondria complexes. In 

rats, the same variation was found after Fe treatment [13]. In rats testes, high Fe content and lipid peroxidation 

was recorded due to Zn deficiency [36]. Hence, this structural variation can be described by high oxygen free 

radicals formation, which is induced by Fe [7]. 

Another study detected that structural abnormalities are due to irregular arrangement of outer dense fibres 

(ODF) like uncoiling and flattening shape (fig 2). These abnormalities were not present in Fe-treated rats testes. 

90% of the sperm Zn is attach to SH-groups of ODF [37]. Thus, due to Zn deficiency, Zn may be detached from 

SH-groups of ODF followed by their structural alteration leading to uncoiling and flattening. In addition, ODF 

consist of two [37] or more than two proteins [36] with diverse molecular mass and amino acid composition. The 

proteins are connected by SS-bond and display a keratin-like structure [37]. ODF may provide elasticity in sperm 

circulation [37] and may provide safety in mammalian sperm against impairment [38]. The uncoiled and flattened 

dense fibres in Zn deficiency may also considered as functionally damaged.  

From clinical point of view, these results have more importance. Infertile men show a high quantity of sperm 

with abnormally developed ODF [36] and orally Zn intake has enhanced sperm motility in infertile men with 

astenospermia and oligospermia [39]. But, in another research this outcome of Zn treatment was not observed 

[20]. In male, sperm morphology exhibited a minor increase in round sperm head due to Zn deficiency [23]. Sperm 

with increased axonemedense fibre-mitochondria complexes were not explained. But, it is detected that it may be 

due to mild Zn deficiency [23] or abnormal sperm which were reduced during maturation and so could not be seen.  

A similar study showed that essential fatty acid composition is influenced by Zn deficiency in rats testes. This 

altered fatty acid may involve in reduction of testicular function, spermatogenesis and androgenesis. These results 

suggest that Zn deficiency linked with abnormal testicular function is followed by alterations in membrane fatty 

acid composition, and thus affects the sperm integrity. However, the specific function of this process is remained 

unclear. It is thought that it can be due to arrested spermatogenesis or testicular necrosis. Additionally, abnormal 

sperm motility was found  in the Japanese eel and goat due to decreased Zn concentration in feed [11, 40]. Sertoli 

and Leydig cells showed insignificant morphological changes. In control study, rats testes did not show any 

morphological changes. 

 

1.6. Effect on Histopathology 

The testes are the main organs of the male reproductive system. They consist of seminiferous tubules, Sertoli 

cells and Leydig cells [41]. In the presence of luteinizing hormone (LH), Leydig cells are responsible for production 

Figure.1; near here 

https://en.wikipedia.org/wiki/Luteinizing_hormone


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© 2018 Conscientia Beam. All Rights Reserved. 

of androgen, like testosterone (T). FSH involves in the development of the immature testis by proliferation of 

Sertoli cell and later spermatogonial stem cells [7]. T alone can play an important role in spermatogenesis, but the 

synergistic role of FSH is essential to normalize the process of spermatogenesis [35, 42]. 

Deficiency of Zn has negative effect on the reproductive profile of humans and animals and it is an enormous 

problem to nutritionist. Normal histology of testes depends on normal testicular functions (spermatogenesis and 

steroidogenesis). In histopathological examination, it has been reported that ZD rat presented a number of 

abnormalities, compared to control group [41] which may affect sperm physiology. 

A study on ZD rat showed cytological degenerative changes in germ cells of seminiferous tubules, leading to 

less number of germ cell, sertoli cells, interstitial cells, primary and secondary spermatogonia, and spermatocytes 

(sperm cells). Histological study carried by Ashrafi, et al. [3] reported that Zn deficiency in rats, explained the 

atrophy of seminiferous tubules in some ZD rats. An 8-week feeding trials have been conducted, containing a total 

of 22 ZD (Zn-deficient) and 19 ZC (Zn-control) male rats.  

In histological examination, the testes of rats after 8-weeks on ZD diet again verified the previous results of 

several authors [3]. Complete or Partial degeneration of the germ cells epithelium had examined in 17/22 rats. It 

was clear that the matured testes composed of healthy tubule and consists of a less number of sperms in the 

epididymis. Apparently healthy but immature testicular tissue was present in 3 ZD rats and the remaining 2 

exposed all degenerative phases of spermatogenesis. However, one of these, which was recently matured were 

examined no sperms in the epididymis. The other numerous sperms were present in the epididymis were less than 

the controls group. Normal mature testes including the large numbers of sperms in the epididymis was recorded in 

control rats. In all ZD rats, the interstitial cells were detected in the testes, except for reduced size, but looked 

normal. In ZD rats, decreased size of epithelial layer, small acini, less secretion were observed in all accessory sex 

organs but no additional pathological variations were detected in these tissues. In ZD rats, the dorsolateral prostate 

glands associated to Zn- specific stain were negative or slightly positive. 

In the control groups, the lateral edges of the glands revealed a clear positive reaction. In ZD rats, 

gonadotrophs and thyrotrophs were characterized in pituitary glands stained with a glycoprotein stain compared 

with the control groups. In ZD rats, testes demonstrated atrophy of the tubular epithelium. Taken together, ZD 

group influence the male reproductive system of the rats and cause the reduction in all sex organs, testicular 

atrophy, clear atrophy of the tubular epithelium, and reduced Zn concentrations in testes, epididymis, and 

dorsolateral prostate glands. 

 

2. CONCLUSION 

The overall consequences of this overview provide a confirmation that certain essential elements especially Zn 

deficiency may affect the male rat reproductive system inclosing the function of spermatogenesis, sperm motility, 

secretion of accessory glands, fertility, T-level and antioxidant defense system. Experimental studies on rats 

explained that Zn deficiency depends on dose and time duration and their effects are also variable. The available 

data reported that 5 mg/day per rat Zn supplementation is considered as optimum level without causing any 

harmful effects on libido and sexual ability of male rats. Therefore, it is recommended that optimum amount of Zinc 

supplementation should be used to avoid the deleterious effects on male reproductive physiology. 

 

Abbreviation 

Zn; Zinc, T; Testosterone, FSH; Follicle stimulating hormone, LH; Luteinizing hormone, ZD; Zinc deficient, 

ZC; Zinc control , ALT; Alanine aminotransferase, ALP; Alkaline phosphatase , LDH; Lactate dehydrogenase, ZnO 

nP; Zinc oxide nanoparticle, ZnO mP; Zinc oxide microparticle, MDA; Malondialdehyde , TNF-α; Tumor necrosis 

factor-alpha,  SOD; Serum superoxide dismutase , GnIH; Gonadotropin-inhibitory hormone , HPG; hypothalamic–



Animal Review, 2018, 5(2): 12-21 

 

 
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© 2018 Conscientia Beam. All Rights Reserved. 

pituitary gonadal, ODF; Outer dense fibres, ZnCl2; Zinc chloride, ZnSO4; Zinc sulfate, Fe; Iron, SH; Sulfhydral, S-S 

bond; Disulfide bond, DCP; Dipeptidyl carboxypeptidase  

 

Funding: This study received no specific financial support.    
Competing Interests: The authors declare that they have no competing interests.  
Contributors/Acknowledgement: Special thanks to Animal Review Journal for giving an opportunity to 
share knowledge on Zinc deficiency and its possible consequences on male rats reproductive system and 
strategies to overcome this problem. The author wish to thank beloved parents (Rana Nawab Ahmad and 
Mrs. Sultana), grandparents (Saith Bachal Din), uncle (Rana Maqbool Ahmad) and brother (Rana Kashif 
Nawab) for continued support and excellent mentorship. 

 

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Fig-1. FSH and LH plays a key role in sperm production and in the process of spermatogenesis. But, various studies reported that gonadotropin-
inhibitory hormone (GnIH) negatively affects the hypothalamic–pituitary gonadal axis (HPG axis) and disturb the testosterone level and 
ultimately hinder the spermatogenesis. 
Source: Shahraki, et al. [1]  

 



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Fig-2. Sperm morphology plays an important role in ova fertilization. Healthy sperm consists of normal head, middle and tail piece. By electron 
microscopic examination of rat sperm, it is reported that Zn deficiency affects the middle piece (ODF) of sperm and produce the sperm structural 
abnormalities. As consequences it may lead to infertility.  

Source: Yatoo, et al. [2] 

 

 

 

 

 

 

 

 

 

 

 

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