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Increase, LPO leads to impaired, Fertility
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Glutathione conjugation leading to reproductive dysfunction via oxidative stress||adjacent||High||High||Leonardo Vieira (send email)||Under Development: Contributions and Comments Welcome|
Life Stage Applicability
Key Event Relationship Description
Evidence Collection Strategy
Evidence Supporting this KER
Biological plausibility of this KER lies in the fact that lipid peroxidation in gonad membranes induces morphological changes in seminiferous tubules, and degeneration of ovarian follicles and Sertoli and Leydig cells in testicles, damage to gametic cells, and, consequently, reduction of their viability. This directly affects animal reproductive capability, for it reduces quality and production of oocytes and spermatocytes, as well as decreases egg and sperm release (spawn), leading to a drop-in fertilization rate (Tillitt et al. 2010; Papoulias et al. 2014; Song et al. 2014; Dasmahapatra et al. 2020; Biswas et al. 2020; Mu et al. 2022).
Just like the other KERs, the adjacent relation here assessed is also observed in different species and models used in toxicological studies. Nevertheless, evidence gathered here shows that occurrence of lipid peroxidation triggered by ATZ, DEM and Hg leading to fertility impairment is limited to fishes and mammals. In this case, mammals have their reproductive capability reduced mainly because of morphological changes and poor quality of gametes.
Sexually mature female Wistar rats treated by a daily gavage of 0, 5, 25 and 125 mg/Kg ATZ for 28 consecutive days exhibited lipid peroxidation and ovarian atresia significantly increased in a dose-dependent manner in ATZ-treated animals (Zhao et al. 2014). In male Sprague-Dawley rats exposed to ATZ by gavage (0, 38.5, 77, and 154 mg/Kg bw/day) for 30 days had significant adverse effects on the reproductive system, with the animals showing a decreased level of total antioxidant capacity (TAC) in a dose-dependent manner, a depletion in GSH and an increased MDA content at the highest dose, followed by not only irregular and disordered arrangement of the seminiferous epithelium, but also a decreased number of spermatozoa and augmented spermatozoa abnormality rate in groups treated with 77, and 154 mg/Kg of ATZ (Song et al. 2014).
Corroborating these data, Farombi et al. (2013) showed that male Wistar rats administered with ATZ at a dose equivalent to 120 mg/Kg body weight each day for 16 days displayed augmented MDA levels in testicles and epididymis, as well an increased number of sperm abnormalities and reduced sperm production, sperm motility and epididymal and testicular sperm numbers. Moreover, degeneration of seminiferous tubules in testicles with the presence of defoliation was noted as well (Farombi et al. 2013). In adult male Albino rats, ATZ (120 mg/Kg bw) causes significantly increased malondialdehyde (MDA) serum level and also diminished total antioxidant capacity (TAC), besides inducing a significant rise in sperm cell abnormalities (Abdel Aziz et al. 2018). In addition, pathological lesions such as disorganized seminiferous tubules with degenerated and irregularly arranged necrotized germinal cells were also reported (Abdel Aziz et al. 2018). This very ATZ dosage orally administered in rats caused an increase in MDA formation in the liver, testis and epididymis, along with an inhibition of GST activities, and decreased epididymal and testicular sperm number, sperm motility, daily sperm production and increased number of dead and abnormal sperm in animals (Adesiyan et al. 2011).
Kalia & Bansal (2008) found in their study that male Balb/c mice treated with DEM (52 μM) underwent a decrease in GSH content, and increased ROS generation and lipid peroxidation in testicles, followed by augmented apoptosis in germ cells, as well as a significant reduction in the number of these cells (Kalia and Bansal 2008). A lower dose of this compound (8.7 μM) daily and intraperitoneally injected, for two weeks, resulted in depleted GSH and increase in testis GSSG levels. As a consequence sperm motility was decreased by 40%, and epididymal sperm count was significantly reduced in DEM-treated animals. Beyond that, fertility status was also affected by DEM exposure, with a 34% diminishment compared to the control group, and there was a reduction in litter size as well (Kaur, Kalia, and Bansal 2006).
Using Hg in order to induce oxidative stress, these kinds of results also occur in different taxa. Male Wistar rats continuously exposed to 0, 50 and 100 ppm Hg for 90 days through oral administration in the drinking water displayed a significant increase in testicular MDA, along with specific alterations in the histoarchitecture of testis, including disintegration of germinal epithelium of seminiferous tubules, detachment and degenerative changes of lining cells, increased space between the seminiferous tubules and their lumen enlarged in a dose-dependent manner (Boujbiha et al. 2009). Interestingly, Hg-treated males were mated with normal cyclic females and they showed a decline in reproductive performance. In another study, the heavy metal led to an increase in ROS and MDA levels in testes and epididymis 60 days post-exposure in Wistar rats submitted to a first dose of 4.6 μg/Kg and subsequent doses of 0.07 μg/Kg/day, as well as decreased sperm number, increased sperm transit time in epididymis and impaired sperm morphology (Rizzetti et al. 2017). In fishes, sublethal doses of mercury (II) chloride (0.04 and 0.12 ppm) for 30 days caused a significant increase in testicle lipid peroxidation, DNA fragmentation, and a decrease in sperm count, activity and motility in relation to the control group in African sharptooth catfish (Clarias gariepinus) (Ibrahim, Banaee, and Sureda 2019). In addition to that, histopathological alterations in testis sections including rupture of interlobular connective tissue, lessening of spermatogonia, derangement of spermatogenesis and low spermatozoa counting were also observed (Ibrahim, Banaee, and Sureda 2019).
Uncertainties and Inconsistencies
Known modulating factors
Quantitative Understanding of the Linkage
With regard to KER4, several studies have brought quantitative data concerning the negative correlation between lipid peroxidation and fertility disorders of vertebrate organisms (Gomez, Irvine, and Aitken 1998; Hsieh, Chang, and Lin 2006; Aitken et al. 2007; Abarikwu et al. 2010; Mihalas et al. 2017).
According to (Gomez, Irvine, and Aitken 1998), there is a negative relationship between malondialdehyde and 4-hydroxyalkenal production (MDA + 4-HA) and loss of motility in human spermatozoa. The higher the amount of these peroxidation products, the lower the cell motility. A negative correlation between sperm numbers and testicular and epididymal MDA levels (-0.85 and -0.68 correlation coefficient r, respectively) was also found by (Abarikwu et al. 2010) in rats exposed to ATZ for 7 and 16 days. Conversely, the authors observed a positive correlation between abnormal sperm rate and testicular and epididymal MDA levels (+0.78 and +0.89). Hsieh et al. (2006), assessing MDA levels and sperm quality of 51 subfertile men, were able to establish two formulas to associate lipid peroxidation with sperm concentration and motility, which are represented, respectively, by:
MDA = - 0.0045 x sperm cell concentration + 2.23;
MDA = - 0.014 x sperm motility + 2.62.
On the other hand, (Mihalas et al. 2017) brought important quantitative data about the direct relation between lipid peroxidation and reduction of quality in oocytes. Experimental evidences showed that the lipid peroxidation product 4-HNE, at 0, 5, 10, 20, 30 and 50 µM, induces a dose-dependent decrease in meiotic competence during in vitro oocyte maturation, as well as aneuploidies in germinal vesicle (GV) oocytes from 20 µM of 4-HNE. They still reported this happens because tubulins, component proteins of microtubules of the mitotic spindle, generate adducts with 4-HNE.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Tillitt, Donald E., Diana M. Papoulias, Jeffrey J. Whyte, and Catherine A. Richter. 2010. “Atrazine Reduces Reproduction in Fathead Minnow (Pimephales Promelas).” Aquatic Toxicology 99 (2): 149–59.
Papoulias, Diana M., Donald E. Tillitt, Melaniya G. Talykina, Jeffrey J. Whyte, and Catherine A. Richter. 2014. “Atrazine Reduces Reproduction in Japanese Medaka (Oryzias Latipes).” Aquatic Toxicology 154 (September): 230–39.
Song, Yang, Zhen Chao Jia, Jin Yao Chen, Jun Xiang Hu, and Li Shi Zhang. 2014. “Toxic Effects of Atrazine on Reproductive System of Male Rats.” Biomedical and Environmental Sciences: BES 27 (4): 281–88.
Dasmahapatra, Asok K., Doris K. Powe, Thabitha P. S. Dasari, and Paul B. Tchounwou. 2020. “Assessment of Reproductive and Developmental Effects of Graphene Oxide on Japanese Medaka (Oryzias Latipes).” Chemosphere 259 (November): 127221.
Biswas, Subhasri, Soumyajyoti Ghosh, Anwesha Samanta, Sriparna Das, Urmi Mukherjee, and Sudipta Maitra. 2020. “Bisphenol A Impairs Reproductive Fitness in Zebrafish Ovary: Potential Involvement of Oxidative/nitrosative Stress, Inflammatory and Apoptotic Mediators.” Environmental Pollution 267 (December): 115692.
Mu, Xiyan, Suzhen Qi, Jia Liu, Hui Wang, Lilai Yuan, Le Qian, Tiejun Li, et al. 2022. “Environmental Level of Bisphenol F Induced Reproductive Toxicity toward Zebrafish.” The Science of the Total Environment 806 (Pt 1): 149992.
Zhao, Fan, Kun Li, Lijing Zhao, Jian Liu, Qi Suo, Jing Zhao, Hebin Wang, and Shuhua Zhao. 2014. “Effect of Nrf2 on Rat Ovarian Tissues against Atrazine-Induced Anti-Oxidative Response.” International Journal of Clinical and Experimental Pathology 7 (6): 2780–89.
Farombi, E. O., S. O. Abarikwu, A. C. Adesiyan, and T. O. Oyejola. 2013. “Quercetin Exacerbates the Effects of Subacute Treatment of Atrazine on Reproductive Tissue Antioxidant Defence System, Lipid Peroxidation and Sperm Quality in Rats.” Andrologia 45 (4): 256–65.
Abdel Aziz, Rabie L., Ahmed Abdel-Wahab, Fatma I. Abo El-Ela, Nour El-Houda Y. Hassan, El-Shaymaa El-Nahass, Marwa A. Ibrahim, and Abdel-Tawab A. Y. Khalil. 2018. “Dose- Dependent Ameliorative Effects of Quercetin and L-Carnitine against Atrazine- Induced Reproductive Toxicity in Adult Male Albino Rats.” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 102 (June): 855–64.
Adesiyan, Adebukola C., Titilola O. Oyejola, Sunny O. Abarikwu, Matthew O. Oyeyemi, and Ebenezer O. Farombi. 2011. “Selenium Provides Protection to the Liver but Not the Reproductive Organs in an Atrazine-Model of Experimental Toxicity.” Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Fur Toxikologische Pathologie 63 (3): 201–7.
Kalia, Sumiti, and M. P. Bansal. 2008. “Diethyl Maleate-Induced Oxidative Stress Leads to Testicular Germ Cell Apoptosis Involving Bax and Bcl-2.” Journal of Biochemical and Molecular Toxicology 22 (6): 371–81.
Kaur, Parminder, Sumiti Kalia, and Mohinder P. Bansal. 2006. “Effect of Diethyl Maleate Induced Oxidative Stress on Male Reproductive Activity in Mice: Redox Active Enzymes and Transcription Factors Expression.” Molecular and Cellular Biochemistry 291 (1-2): 55–61.
Boujbiha, Mohamed Ali, Khaled Hamden, Fadhel Guermazi, Ali Bouslama, Asma Omezzine, Abdelaziz Kammoun, and Abdelfattah El Feki. 2009. “Testicular Toxicity in Mercuric Chloride Treated Rats: Association with Oxidative Stress.” Reproductive Toxicology 28 (1): 81–89.
Rizzetti, Danize Aparecida, Caroline Silveira Martinez, Alyne Goulart Escobar, Taiz Martins da Silva, José Antonio Uranga-Ocio, Franck Maciel Peçanha, Dalton Valentim Vassallo, Marta Miguel Castro, and Giulia Alessandra Wiggers. 2017. “Egg White-Derived Peptides Prevent Male Reproductive Dysfunction Induced by Mercury in Rats.” Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 100 (February): 253–64.
Ibrahim, Ahmed Th A., Mahdi Banaee, and Antoni Sureda. 2019. “Selenium Protection against Mercury Toxicity on the Male Reproductive System of Clarias Gariepinus.” Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP 225 (November): 108583.
Gomez, E., D. S. Irvine, and R. J. Aitken. 1998. “Evaluation of a Spectrophotometric Assay for the Measurement of Malondialdehyde and 4-Hydroxyalkenals in Human Spermatozoa: Relationships with Semen Quality and Sperm Function.” International Journal of Andrology 21 (2): 81–94.
Hsieh, Yao-Yuan, Chi-Chen Chang, and Chich-Sheng Lin. 2006. “Seminal Malondialdehyde Concentration but Not Glutathione Peroxidase Activity Is Negatively Correlated with Seminal Concentration and Motility.” International Journal of Biological Sciences 2 (1): 23–29.
Aitken, R. John, Jordana K. Wingate, Geoffry N. De Iuliis, and Eileen A. McLaughlin. 2007. “Analysis of Lipid Peroxidation in Human Spermatozoa Using BODIPY C11.” Molecular Human Reproduction 13 (4): 203–11.
Mihalas, Bettina P., Geoffry N. De Iuliis, Kate A. Redgrove, Eileen A. McLaughlin, and Brett Nixon. 2017. “The Lipid Peroxidation Product 4-Hydroxynonenal Contributes to Oxidative Stress-Mediated Deterioration of the Ageing Oocyte.” Scientific Reports 7 (1): 6247.
Abarikwu, S. O., E. O. Farombi, and A. B. Pant. 2011. “Biflavanone-Kolaviron Protects Human Dopaminergic SH-SY5Y Cells against Atrazine Induced Toxic Insult.” Toxicology in Vitro: An International Journal Published in Association with BIBRA 25 (4): 848–58.