A Review of Organochlorine-induced Male Reproductive Disorders

 

A. Vasanth*, Santhosh Gopi, Sushmitha Akkaiah

Student, 5th Year Pharm. D, Arulmigu Kalasalingam College of Pharmacy, Krishnankoil,

Virudhunagar - 626126, Tamilnadu, India.

*Corresponding Author E-mail: vasantharun203@gmail.com

 

ABSTRACT:

Organochlorines are a group of chlorinated hydrocarbons widely used as pesticides in many countries. Various studies conducted by researchers have revealed that these chemicals can potentially cause male reproductive disorders. In today's world, both humans and wildlife are constantly exposed to numerous chemical residues present in the air, food, and water. Organochlorines, which consist of carbon, hydrogen, and chlorine, are pervasive pollutants encompassing a range of compounds, including chlorinated insecticides, solvents, and fumigants used worldwide. Exposure to organochlorine chemicals has raised concerns due to their association with various detrimental effects on human health. One particular concern is their potential implication in reproductive toxicity and endocrine disruption, as these chemicals persist in the environment. Organochlorines have the ability to interfere with normal hormonal function in both animals and humans. Laboratory animals and wildlife exposed to these endocrine-disrupting chemicals have exhibited reproductive abnormalities such as the feminization of males, abnormal sexual behavior, birth defects, altered sex ratios, decreased sperm production, reduced testicular size, infertility, and thyroid dysfunction. This review focuses on the adverse effects of different organochlorine chemicals on the male reproductive system, emphasizing the need for limited use of organochlorines to enhance the quality of life and promote human welfare.

 

KEYWORDS: Organochlorines, Persistent Organic Pollutants (POP), Male Reproductive System Toxicity, Endocrine-disrupting chemicals, Infertility.

 

 


INTRODUCTION:

Organochlorines (OC) are a group of chlorinated compounds which are mostly used as pesticides. These substances are from the class of persistent organic pollutants (POPs) with high persistence in the environment. OC insecticides were successfully used in the control of malaria and rickettsiosis, but they are banned in most of the advanced countries1. The review on the utilization of different pesticides shows that 40% of all pesticides used are from the organochlorine class of chemicals2. Due to their lesser cost and the need against a wide variety of pests, organochlorine insecticides such as DDT, hexachlorocyclohexane (HCH), aldrin and dieldrin are among the most used pesticides in developing countries of Asia3,4.and organochlorine pesticides can affect various living organisms due to their chemical nature.

 

the various adverse effects on human fertility occur when exposure to compounds with endocrine-disrupting capabilities, which are suspected to interfere with the development and functioning of sex hormone-regulated processes such as sperm production and ovulation5,6. Due to interference with hormone receptors or steroid-producing or degrading enzymes, even low concentrations of these compounds could affect endocrine-regulated processes.7

 

Various environmental pollutants can be measured in human biological samples from almost all people worldwide. And some of the environmental pollutants detected at the highest concentrations in human serum belong to the group of organochlorine pollutants. Among the organochlorine pollutants, the polychlorinated biphenyl (PCB) congener PCB-153 and the dichlorodiphenyltrichloroethane (DDT) degrading product dichlorodiphenyldichloroethylene (DDE) are generally the most commonly detected compounds in human serum samples8. The chemical structures of PCB and DDE resemble steroid hormones and endocrine properties have been demonstrated for these compounds9,10. Studying the effects of selected organochlorine pollutants on human reproductive health may provide a piece of information on whether or not exposure to a low level of environmental chemicals affects human reproductive health7.

 

POPs (Persistent organic pollutants) are organic compounds that are highly resistant to environmental degradation, with half-lives in the environment and in living organisms in the range of several years. Persistent organic pollutants bioaccumulate in fatty tissues in organisms and become biomagnified through the food chain from lower organisms to top predators, including humans. Organochlorines are an important class of POP which includes several synthetic compounds that were manufactured on a large scale since the 1930s. Concentrations of the most common PCB congeners and DDE and several other organochlorines such as aldrin, chlordane, dieldrin, dioxins, hexachlorobenzene, and toxaphene were found to be highly correlated with serum samples from the general human population, and exposure to the most common PCB-congener (CB-153) has therefore been suggested as an indicator of the overall level of exposure to persistent organochlorines11,12. However, the congener profile of PCBs and correlations with other organochlorine compounds can differ noticeably between populations due to differences in the sources of exposure and the time since peak exposure13, and therefore different exposure profiles between countries may induce heterogeneity in exposure-response associations based on single contaminant measurements.

 

Table 1: Name and structural formula of endocrine disrupting compounds and most potent natural androgen and estrogen compounds

Name of the compound

Chemical structure

AndrogenicA

EstrogenicA

Reference

PCB-153

 

Figure 1: Chemical structure ofPCB-153

 

 

 

 

0

 

 

 

 

_

 

 

 

 

10

p,p’-DDT

 

Figure 2: Chemical structure of p,p’-DDT

 

 

_

 

 

+

 

 

14,15

p,p’-DDE

 

Figure 3: Chemical structure ofp,p’-DDE

 

 

 

_

 

 

0

 

 

16

Dihydrotestosterone

 

Figure 4: Chemical structure of Dihydrotestosterone

 

 

 

+

 

 

 

+

 

 

 

14

17b- oestradiol

 

Figure 5: Chemical structure of17b-oestradiol

 

 

 

+

 

 

 

+

 

 

 

14

Aindicates whether or not the selected compounds showed endocrine activity when assessed in vitro assays: + = agonistic effect; - = antagonistic effect, 0 = no (anti)oestrogenic or (anti)androgenic effects.

 

Male fertility and organochlorine exposure:

Endocrine-disrupting chemicals during several critical stages of development may affect Spermatogenesis, including testicular development and maturation, specifically in-utero development and puberty. The largest number of studies have been conducted on adult populations based on spermatogenesis and organochlorines. they are classified into two categories: (1) these studies have primarily consisted of presumed fertile population or general population samples17,18. concentrations of p’-DDE in men in Chiapas, Mexico: a cross-sectional study19,20,21,22. p’-DDE and male reproductive function23 and (2) studies conducted in andrology or infertility clinic settings that evaluated associations between spermatogenesis and organochlorines comparing groups of men with male factor infertility with men from couples identified with female factor infertility, which on occasion also include a subgroup of men with idiopathic infertility24,25,26,27,28. many of these existing studies were highly cross-sectional in design with serum or plasma collected at the same. A regional variation of both organochlorine exposure and semen quality was suggested by the summarized literature. A group of studies supports weak associations between decreased sperm motility and exposure to DDT and/or PCB or its metabolites. However, the overall weight of the evidence does not support an association between impaired spermatogenesis and DDT or PCB exposure. It is difficult to disentangle PCB and DDT due to their potentially independent effects on spermatogenesis their exposures are often highly correlated making. Further, there are some studies of other organochlorine exposure such as toxaphene chlordane, and HCB that it is unclear whether a dose-response relationship exists between spermatogenesis and organochlorine exposure.

 

Finally, based on two studies, there is some evidence that exposure to organochlorines may impact sperm motility in early life or in-utero stage. During critical periods of development, the lack of research on endocrine disrupting chemicals was given, puberty, in-utero, and early life, additional studies of organochlorine exposure and spermatogenesis, specifically PCB and DDT, are warranted.29,30

 

LINDANE:

92

Figure 6: Chemical structure of lindane

 

Impairments in biological functions have been reported due to exposure to lindane, consisting of reproduction in animals and humans. It has harmful effects on the male reproductive system through various hormone-dependent reactions. Several studies have shown that lindane disrupts the reproductive function in male and female animals31,32. Chronic lindane exposures markedly reduce sperm counts, and sperm motility and impair spermatogenesis in male rats. In addition, lindane intoxication causes decreased serum concentrations of testosterone33,34,35. In adult rats oxidative stress in the testis as well as in the epididymis and sperm dynamics has been induced by lindane36,37,38. Exogenous treatment with lindane decreases serum testosterone levels had demonstrated by Some studies, and from those studies, it is confirmed that inhibition in testicular steroidogenesis has been caused by lindane exposure39,40. It causes alterations in Sertoli and Leydig cells by impairing their functions41.

 

Disrupted testicular morphology, decreased spermatogenesis, inhibition in testicular steroidogenesis, reduced plasma androgen concentrations, and may adversely affect reproductive performances in males can occur when treated with 1-40mg of lindane/kg body weight42. Due to exposure to lindane consequences such as reduced sperm count and an increased incidence of sperm abnormalities have been evidenced43. Also, as an endocrine-disrupting chemical, it may interfere with fertility and male reproductive performance.

 

A study conducted in animals on intraperitoneal administration of lindane at con. of 9 and 18mg/kg body weight twice a week for 60 days then it is observed that at low doses of lindane, the sperm numbers decreased by 42% at higher doses it extended up to 50%, Sperm motility decreased about 45%-68% and decreased relative masses of testis and epididymis. Irregularly shaped cells with marked intracellular space between spermatogenic cells and cell disorganization had shown by histopathological analysis of testicular tissue44.

 

Lindane exposure during lactation may lead to reproductive disorders in male offspring which can be found in their adulthood. Lactating female rats treated with a single dose of 6mg/kg on day 9 or 14 of lactation showed decreased spermatids and sperm count and decreased testicular weight in all treated groups of adulthood. The testosterone level is reduced to approximately 50% in treated groups45.

 

Decreased sperm count in the testes has been caused by a lindane oral dose of 6mg/kg for 5 days or a single dose of 6mg/kg. Fragmentation or complete loss of organelles with ballooning of Sertoli has been revealed by a histological investigation by electron microscopy46.

 

ENDOSULFAN

92

Figure 7: Chemical structure of Endosulfan

 

It is an organochlorine compound used as a pesticide. It consists of alpha-: 64–67%; beta-: 29–32% isomers compared to beta-isomer alpha-isomer is more toxic47. Interference in hormone synthesis and delayed sexual maturity may occur in children due to endosulfan exposure48. It may cause an increase in testicular and prostate cancer, defects in male sex organs, and a decrease in semen quality49. Endosulfan exposure in animals at a dose of 3mg/kg body weight for 35 days caused loss of sperm tail, decreased testosterone, increased LH, coiled tail, and degenerated across some were observed this confirms infertility and testicular dysfunctions50. Exposure of endosulfan to pregnant rats at a dose of 1mg/kg/day from day 12 onwards through parturition causes decreased spermatogenesis in offspring51,52. In younger animals, endosulfan at 2.5mg/kg/day revealed decreased daily sperm  production 53. In the testes of male rabbits, subacute poisoning of endosulfan causes degenerative areas in the testes and decreased number of spermatozoon54.

 

 

 

HEXACHLOROCYCLOHEXANE

[92]

Figure 8: chemical structure of Hexachlorocyclohexane

 

Exposure of 50mg or 100mg/kg/day of hexachlorocyclohexane for 120 days results in decreased sperm motility, sperm count, and an increased percentage of abnormal sperm. In the testes of treated rats there is an accumulation of hexachlorocyclohexane and its isomers in their testes also its exposure leads to declined testosterone levels55. The HCH testicular toxicity in rats may be due to the induction of oxidative stress in the testis during the treatment of the pesticide56,57. Testicular functions in mice and rats are known to affect by HCH exposure 58,59.

 

METHOXYCHLOR

92

Figure 9: Chemical structure of Methoxychlor

 

1, 1, 1-Trichloro-2,2-bis(4-methoxyphenyl) ethane (methoxychlor) is an organochlorine pesticide that is estrogenic and causes adverse reproductive outcomes in male and female mammals60,61. It is used as an insecticide. It is now considered a major endocrine disruptor. It is weakly estrogenic62. But the metabolite of methoxychlor HPTE (2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane) exerts more potent ant-androgenic, estrogenic, and anti-estrogenic activities than its parent compound63.

 

In methoxychlor-treated rats decreased weights of testis; seminal vesicles, ventral prostrate, and epididymis were reported64. The increased levels of lipid peroxidation and hydrogen peroxide generation and decreased antioxidant enzyme activities such as glutathione reductase, glutathione peroxidase, superoxide dismutase, and catalase in testes65. Reduced serum testosterone, dehydroepiandrosterone, and decreased seminal vesicle weight in rats have been shown when administration methoxychlor at a dose of 200mg/kg body weight66. Impairment in the reproductive system was observed in rats when it is exposed to methoxychlor67. In prepubertal rats, it suggests a direct effect on Leydig cells, administration of methoxychlor reduces intestinal fluid testosterone content, testicular steroidogenesis, and spermatogenesis68. Inhibition of side-chain cleavage enzyme (P450scc) and decreased utilization of cholesterol in Leydig cells has been reported in rats when they are exposed to HPTE69. Oxidative stress in the epididymal sperm of goats has been induced by methoxychlor. Peroxidative damage to the plasma membrane caused due to excessive generation of reactive oxygen species may cause impaired sperm function70. 3β-HSD and 17β-HSD3 enzyme activity has been directly inhibited by HPTE. Suppression of steroidogenesis in gonadal tissues and implications for testis functions has been associated with the inhibition of enzymatic activity71.

 

ATRAZINE

92

Figure 10: Chemical structure ofAtrazine

 

2 – Chloro – 4 ethylamino -6- isopropylamino-S-trazine (ATRAZINE) is an organochlorine compound. It is a pre and post-emergence herbicide used on a variety of crops, forests, residual turf, and recreational areas72. i.p administration of atrazine in adult rats at doses of 60mg and 120mg/kg body weight twice a week. After 60 days it showed increased testicular sperm number due to reduced sperm motility73. Cell disorganization and cell clusters in spermatocytes had shown by histological analysis of atrazine-treated rats. Workers exposed to atrazine had reduced semen quality74. Leydig cell steroidogenesis gets affected by atrazine exposure due to inhibition of steroidogenesis along with decreased androgenesis, it may have the ability to interfere with testicular spermatogenesis75. Studies conducted on treated groups exposed to doses of 200 and 300mg/kg BW for 1, 14, and 28 days have shown that atrazine can disrupt the endocrine function of male reproduction. Specifically, these groups exhibited a significant decrease in sperm count, viable sperm count, and the number of normally moving sperm, while the number of abnormal sperm was higher. Histological examination also revealed a reduced number of spermatid and spermatocyte layers76. Furthermore, chronic exposure to atrazine can lead to histological damage in testicular tissue due to the induction of inflammation and severe oxidative stress. Considering these findings, atrazine can be regarded as a potentially toxic compound that negatively affects sperm quality77. Exposure to atrazine at nanomolar concentrations has been found to have harmful effects on the structure and fine morphology of the testes, leading to severe impairment in spermatozoa formation and ultimately affecting reproductive potential78. Atrazine likely reduces the secretion of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone by decreasing the weight of the pituitary gland and the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This, in turn, decreases the activities of the pituitary-testis axis and disrupts spermatogenesis processes.79,80

 

DICOFOL:

92

Figure 11: Chemical structure of Dicofol

 

Dicofol, which is an organochlorine acaricide, is extensively utilized in the control of mites on crops, ornamentals, and in and around agricultural and domestic structures.81 It tends to accumulate in steroid-producing organs such as the adrenal gland, testes, and ovaries.82 Additionally, dicofol exhibits antispermatogenic and antiandrogenic properties.83

 

The administration of dicofol, an organochlorine pesticide, to male albino rats through oral intake in varying doses resulted in impaired testicular functions.84 Rats treated with dicofol at doses of 4.19 and 16.75 mg/kg body weight/day, administered via drinking water (at concentrations of 30 and 120 parts per million, respectively) for a consecutive period of 90 weeks, exhibited decreased sperm count, sperm motility, viability, and maturity, along with increased abnormal sperm morphology. Furthermore, there was a decline in serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels. The rats also showed elevated lipid peroxidation (LPO) index and decreased glutathione levels. Additionally, dicofol led to an increase in total protein levels in the testes while reducing the activities of enzymes involved in spermatogenesis, such as lactate dehydrogenase, acid phosphatase, and alkaline phosphatase.85

 

DIOXIN:

Dioxin, specifically polychlorinated dibenzo-p-dioxins (PCDDs) or dibenzofurans (PCDFs), is a type of organochlorine compound. It falls under the category of persistent polychlorinated aromatic hydrocarbons and is recognized as one of the most potent environmental contaminants. Dioxins have been found to elicit various toxic effects in experimental animals, including reproductive, developmental, and immunological toxicity, as well as carcinogenic properties.86

 

92

Figure 12: chemical structure of Dioxin

 

Dioxins, such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), have the potential to impact libido and fertility in various species, including fish, birds, mammals, and reptiles. The reproductive system is particularly sensitive to the effects of dioxins,87 making it a significant target for their toxic actions. TCDD, a well-known dioxin, is produced unintentionally during the manufacturing of chlorinated hydrocarbons. It has been found to interfere with libido and has been extensively studied for its impact on development and reproductive sites.

 

High exposure to TCDD and similar compounds, as evaluated by Eskenazi and Kimmel,88 can lead to decreased antioxidant enzyme activity, triggering oxidative stress in the epididymis and epididymal sperm. In male rats exposed to TCDD, there were reductions in sperm count and an increase in abnormal sperm in the epididymis.89 These rats also exhibited reduced fertility, delayed puberty, and altered weights of reproductive organs. TCDD is known to have anti-androgenic and anti-estrogenic effects,90 leading to a decrease in the testicular response to luteinizing hormone (LH).91

 

CONCLUSION:

In conclusion, the observed abnormalities in the reproductive system induced by organochlorine pesticides can be attributed to disruptions in the balance between androgen and estrogen hormones, as well as oxidative stress and impairment of testicular functions. Although the exact interplay between these events is not fully understood, it is hypothesized that their combined impact results in noticeable changes in sex hormone balance and inhibition of spermatogenesis. To mitigate the potential risks associated with organochlorine pesticides, it is essential to limit their application to well-designed programs and exercise caution in their handling to minimize hazards to both wildlife and humans. Furthermore, public education is crucial to promote vigilant and responsible use of these pesticides. Conducting risk assessments for pesticides that have already been shown to be toxic to the reproductive system in animal studies is of utmost importance to ensure the safety of human exposure.

 

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Received on 26.05.2023                    Modified on 11.09.2023

Accepted on 15.11.2023                   ©AJRC All right reserved

Asian J. Research Chem. 2024; 17(1):59-66.

DOI: 10.52711/0974-4150.2024.00012