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Bibliography Tag: male reproductive impacts

Kubsad et al., 2019

Kubsad, D., Nilsson, E. E., King, S. E., Sadler-Riggleman, I., Beck, D., & Skinner, M. K.; “Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology;” Scientific Reports, 2019, 9(1), 6372; DOI: 10.1038/s41598-019-42860-0.


Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations. FULL TEXT

Yousef et al., 1995

Yousef, M. I., Salem, M. H., Ibrahim, H. Z., Helmi, S., Seehy, M. A., & Bertheussen, K., “Toxic effects of carbofuran and glyphosate on semen characteristics in rabbits,” Journal of Environmental Science and Health, Part B, 1995, 30(4), 513-534. DOI: 10.1080/03601239509372951.


The present study was undertaken to investigate the effect of chronic treatment with two sublethal doses of Carbofuran (carbamate insecticide) and Glyphosate (organophosphorus herbicide) on body weight and semen characteristics in mature male New Zealand white rabbits. Pesticide treatment resulted in a decline in body weight, libido, ejaculate volume, sperm concentration, semen initial fructose and semen osmolality. This was accompanied with increases in the abnormal and dead sperm and semen methylene blue reduction time. The hazardous effect of these pesticides on semen quality continued during the recovery period, and was dose-dependent. These effects on sperm quality may be due to the direct cytotoxic effects of these pesticides on spermatogenesis and/or indirectly via hypothalami-pituitary-testis axis which control the reproductive efficiency.

Tiegs et al., 2018

Tiegs, A. W., Landis, J., Garrido, N., Scott, R., & Hotaling, J., “Total motile sperm count trend over time across two continents: evaluation of semen analyses from 119,972 infertile men,” Fertility and Sterility, 2018, 110(4). DOI: 10.1016/j.fertnstert.2018.07.093.


OBJECTIVE: While previous reports of declining sperm counts in the fertile and unselected population are concerning, the most reliable indicator of male fertility, the total motile sperm count (TMSC), has not been previously evaluated (1,2). Furthermore, the TMSC trend in the subfertile population remains unknown. We sought to characterize the TMSC trend over time in a large sample of men from infertile couples in two large fertility centers on separate continents to determine if TMSC was declining over time.

DESIGN: Retrospective cohort

MATERIALS AND METHODS: The first semen analysis (SA) of male patients from Reproductive Medicine Associates of New Jersey (RMANJ) and Instituto Valenciano de Infertilidad (IVI) were identified; SAs from 2002-2017 and 2011-2017, respectively, were included due to robust sample size (n>2000). SAs were excluded if collected retrograde, post-vasectomy, or if TMSC not available. SAs were categorized into 3 clinically relevant groups based on treatment strategy: TMSC >15 million (M) (Group 1), TMSC 5-15M (Group 2), and TMSC 0-5M (Group 3). Linear and logistic regression were used where appropriate to assess the impact of age and estimate TMSC group as a function of collection year. RESULTS: A total of 41809 SAs from RMANJ and 78163 from IVI (129 countries of origin; 74% Spanish) were included. Analyses were performed on RMANJ and IVI data separately. In the RMANJ cohort, linear regression demonstrated TMSC decreased by 1.8% per year in Group 1 (p¼2.2e-16), and the odds of belonging to Group 1 decreased over time (OR ¼ 0.979; 95% CI ¼ 0.974 – 0.985; p¼2.8e-14). Age was associated with TMSC in Group 1: For every 1 yr increase in age, TMSC decreased by 1.1% (p¼2.2e-16), and the odds of belonging to Group 1 decreased with age (OR ¼ 0.977; 95% CI ¼ 0.973 – 0.981; p¼2.2e-16). Similar trends in groups were found in the IVI cohort.

CONCLUSIONS: Although TMSCwas found to marginally decrease over time, the clinical significance of this finding is unclear. This trend may reflect a selection bias, in that more infertile men are presenting for treatment each year, or adverse effects of environmental factors. Whatever the underlying etiology, the shift in groups over time is clinically relevant, as treatment strategies differ by categorization. Longer follow up is necessary to confirm TMSC trends in the infertile population.

Owagboriaye et al., 2017

Owagboriaye, Folarin O., Dedeke, Gabriel A., Ademolu, Kehinde O., Olujimi, Olarenwaju O., Ashidi, Joseph S., & Adeyinka, Aladesida A., “Reproductive toxicity of Roundup herbicide exposure in male albino rat,” Experimental and Toxicologic Pathology, 2017, 69(7), 461-468. DOI: 10.1016/j.etp.2017.04.007.


The incidence of infertility in human is on the increase and the use of Roundup herbicide and presence of its residues in foodstuff is a major concern. This study therefore aim to assess the effect of Roundup on the reproductive capacity of 32 adult male albino rats randomized into 4 groups of 8 rats per group orally exposed to Roundup at 3.6mg/kg body weight(bw), 50.4mg/kgbw and 248.4mg/kgbw of glyphosate concentrations for 12 weeks while the control group was given distilled water. Serum level of reproductive hormone (testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin), oxidative stress indices in the testicular tissue, epididymal sperm morphology assessment and testicular histopathology of the rats were used as a diagnostic marker of reproductive dysfunction. Significant (p<0.05) alterations in the level of all the reproductive hormones and oxidative stress markers assayed were observed in rats exposed to Roundup. Significant reductions (p<0.05) in sperm count, percentage motility and significant (p<0.05) increased in abnormal sperm cells were observed in the exposed rats. Histopathologically, severe degenerative testicular architectural lesions were seen in the Roundup exposed rats. Roundup may interfere with spermatogenesis and impair fertility in male gonad.

Chang et al., 2018

Chang, S., Nazem, T. G., Gounko, D., Lee, J., Bar-Chama, N., Shamonki, J. M., Antonelli, C., & Copperman, A. B., “Eleven year longitudinal study of U.S. sperm donors demonstrates declining sperm count and motility,” Fertility and Sterility, 2018, 110(4), e54-e55. DOI: 10.1016/j.fertnstert.2018.07.170.


OBJECTIVE: Physicians and public health experts have been investigating whether there is evidence of deterioration in semen quality.1-3 Investigators who believe in a decline point to the concomitant increase in the incidence of genitourinary abnormalities.3-5 Others have focused on increased exposure to environmental endocrine disruptors and changes in diet and BMI. One obstacle to understanding male fertility is possible geographic variations in semen quality, which may be due to differences in climate, pollution, occupational exposure, lifestyle, and social habits. This study sought to evaluate semen quality in geographically diverse US sperm donors.

DESIGN: Retrospective.

MATERIALS AND METHODS: Semen analyses (SA) from 2007-2017 were examined. The sperm donors (ages 19-38) originated from Los Angeles, Palo Alto, Houston, Boston, Indianapolis and New York City. Total sperm count, average concentration and total motile count were analyzed as a whole and by region. Data was analyzed using a general estimate equation model with an exchangeable working correlation structure.

RESULTS: A total of 124,107 SA specimens were analyzed. Controlling for BMI, there was a decline in total sperm count (b¼-2.9, p<0.01), concentration (b¼-1.76, p<0.01) and total motile sperm count (b¼-2.45, p<0.01) over the 11-year study. There were decreases in SA parameters in all regions except New York City, which showed no change in total sperm count, concentration or total motile sperm count. Boston showed a decline in concentration and total motile sperm count but no difference in total sperm count.

CONCLUSIONS: Changes in our modern environment—chemical exposures or increasingly sedentary lifestyles—may negatively affect spermatogenesis. We demonstrated a time-related decline in semen quality. Given that donors have higher than average sperm counts, these trends would likely be magnified in the general population. If confirmed, these findings would serve as a public health warning, particularly with the simultaneous increase in other male disorders, including testicular cancer.5 The magnitude of semen quality decline varied by region, with only samples from New York City consistent throughout the study. To further investigate geographical differences, future prospective studies should investigate potential causes for this decline. Identifying modifiable risk factors is the first step in determining how to reverse these trend.

Cai et al., 2017

Cai, Wenyan, Ji, Ying, Song, Xianping, Guo, Haoran, Han, Lei, Zhang, Feng, Liu, Xin, Zhang, Hengdong, Zhu, Baoli, & Xu, Ming, “Effects of glyphosate exposure on sperm concentration in rodents: A systematic review and meta-analysis,” Environmental Toxicology and Pharmacology, 2017, 55, 148-155. DOI: 10.1016/j.etap.2017.07.015.


BACKGROUND: Correlation between exposure to glyphosate and sperm concentrations is important in reproductive toxicity risk assessment for male reproductive functions. Many studies have focused on reproductive toxicity on glyphosate, however, results are still controversial. We conducted a systematic review of epidemiological studies on the association between glyphosate exposure and sperm concentrations of rodents. The aim of this study is to explore the potential adverse effects of glyphosate on reproductive function of male rodents.

METHODS: Systematic and comprehensive literature search was performed in MEDLINE, TOXLINE, Embase, WANFANG and CNKI databases with different combinations of glyphosate exposure and sperm concentration. 8 studies were eventually identified and random-effect model was conducted. Heterogeneity among study results was calculated via chi-square tests. Ten independent experimental datasets from these eight studies were acquired to synthesize the random-effect model.

RESULTS: A decrease in sperm concentrations was found with mean difference of sperm concentrations (MDsperm)=−2.774×106/sperm/g/testis(95%CI=−0.969 to −4.579) in random-effect model after glyphosate exposure. There was also a significant decrease after fitting the random-effect model: MDsperm=−1.632×106/sperm/g/testis (95%CI=−0.662 to −2.601).

CONCLUSIONS: The results of meta-analysis support the hypothesis that glyphosate exposure decreased sperm concentration in rodents. Therefore, we conclude that glyphosate is toxic to male rodent’s reproductive system. FULL TEXT

Nardi et al., 2017

Nardi, Jessica, Moras, Patricia Bonamigo, Koeppe, Carina, Dallegrave, Eliane, Leal, Mirna Bainy, & Rossato-Grando, Luciana Grazziotin, “Prepubertal subchronic exposure to soy milk and glyphosate leads to endocrine disruption,” Food and Chemical Toxicology, 2017, 100, 247-252. DOI: 10.1016/j.fct.2016.12.030.


Lactose intolerance is characterized by low or inexistent levels of lactase, and the main treatment consists of dietary changes, especially replacing dairy milk by soy milk. Soy contains phytoestrogens, substances with known estrogenic activity, besides, glyphosate-based herbicides are extensively used in soy crops, being frequently a residue in soy beans, bringing to a concern regarding the consumption of soy-based products, especially for children in breastfeeding period with lactose intolerance. This study evaluated the pubertal toxicity of a soy milk rich feeding (supplemented or not with glyphosate, doses of 50 and 100 mg/kg) during prepubertal period in male rats. Endocrine disruption was observed through decrease in testosterone levels, decrease in Sertoli cell number and increase in the percentage of degenerated Sertoli and Leydig cells in animals receiving soy milk supplemented with glyphosate (both doses) and in animals treated only with soy milk. Animals treated with soy milk with glyphosate (both doses) showed decrease spermatids number and increase of epididymal tail mass compared to control, and decrease in the diameter of seminiferous tubules compared to soy milk control group. Animals receiving soy milk supplemented with 100 mg/kg glyphosate showed decrease in round spermatids and increase in abnormal sperm morphology, compared to control. FULL TEXT

Jiang et al., 2018

Jiang, X., Zhang, N., Yin, L., Zhang, W. L., Han, F., Liu, W. B., Chen, H. Q., Cao, J., & Liu, J. Y., “A commercial Roundup(R) formulation induced male germ cell apoptosis by promoting the expression of XAF1 in adult mice.,” Toxicology Letters, 2018, 296, 163-172, DOI: 10.1016/j.toxlet.2018.06.1067.


Roundup(R) is extensively used for weed control worldwide. Residues of this compound may lead to side effects of the male reproductive system. However, the toxic effects and mechanisms of Roundup(R) of male germ cells remain unclear. We aimed to investigate the apoptosis-inducing effects of Roundup(R) on mouse male germ cells and explore the role of a novel tumor suppressor XAF1 (X-linked inhibitor of apoptosis-associated factor 1) involved in this process. We demonstrated that Roundup(R) can impair spermatogenesis, decrease sperm motility and concentration, and increase the sperm deformity rate in mice. In addition, excessive apoptosis of germ cells accompanied by the overexpression of XAF1 occurred after Roundup(R) exposure both in vitro and in vivo. Furthermore, the low expression of XIAP (X-linked inhibitor of apoptosis) induced by Roundup(R) was inversely correlated with XAF1. Moreover, the knockdown of XAF1 attenuated germ cell apoptosis, improved XIAP expression and inhibited the activation of its downstream target proteins, caspase-3 and PARP, after Roundup(R) exposure. Taken together, our data indicated that XAF1 plays an important role in Roundup(R)-induced male germ cell apoptosis. The present study suggested that Roundup(R) exposure has potential negative implications on male reproductive health in mammals.

de Souza et al., 2017

de Souza, Janaina Sena, Kizys, Marina Malta Letro, da Conceicao, Rodrigo Rodrigues, Glebocki, Gabriel, Romano, Renata Marino, Ortiga-Carvalho, Tania Maria, Giannocco, Gisele, da Silva, Ismael Dale Cotrim Guerreiro, Dias da Silva, Magnus Regios, Romano, Marco Aurelio, & Chiamolera, Maria Izabel, “Perinatal exposure to glyphosate-based herbicide alters the thyrotrophic axis and causes thyroid hormone homeostasis imbalance in male rats,” Toxicology, 2017, 377, 25-37. DOI: 10.1016/j.tox.2016.11.005.


Glyphosate-based herbicides (GBHs) are widely used in agriculture. Recently, several animal and epidemiological studies have been conducted to understand the effects of these chemicals as an endocrine disruptor for the gonadal system. The aim of the present study was to determine whether GBHs could also disrupt the hypothalamic-pituitary-thyroid (HPT) axis. Female pregnant Wistar rats were exposed to a solution containing GBH Roundup((R))Transorb (Monsanto). The animals were divided into three groups (control, 5mg/kg/day or 50mg/kg/day) and exposed from gestation day 18 (GD18) to post-natal day 5 (PND5). Male offspring were euthanized at PND 90, and blood and tissues samples from the hypothalamus, pituitary, liver and heart were collected for hormonal evaluation (TSH-Thyroid stimulating hormone, T3-triiodothyronine and T4-thyroxine), metabolomic and mRNA analyses of genes related to thyroid hormone metabolism and function. The hormonal profiles showed decreased concentrations of TSH in the exposed groups, with no variation in the levels of the thyroid hormones (THs) T3 and T4 between the groups. Hypothalamus gene expression analysis of the exposed groups revealed a reduction in the expression of genes encoding deiodinases 2 (Dio2) and 3 (Dio3) and TH transporters Slco1c1 (former Oatp1c1) and Slc16a2 (former Mct8). In the pituitary, Dio2, thyroid hormone receptor genes (Thra1 and Thrb1), and Slc16a2 showed higher expression levels in the exposed groups than in the control group. Interestingly, Tshb gene expression did not show any difference in expression profile between the control and exposed groups. Liver Thra1 and Thrb1 showed increased mRNA expression in both GBH-exposed groups, and in the heart, Dio2, Mb, Myh6 (former Mhca) and Slc2a4 (former Glut4) showed higher mRNA expression in the exposed groups. Additionally, correlation analysis between gene expression and metabolomic data showed similar alterations as detected in hypothyroid rats. Perinatal exposure to GBH in male rats modified the HPT set point, with lower levels of TSH likely reflecting post-translational events. Several genes regulated by TH or involved in TH metabolism and transport presented varying degrees of gene expression alteration that were probably programmed during intrauterine exposure to GBHs and reflects in peripheral metabolism. In conclusion, the role of GBH exposure in HPT axis disruption should be considered in populations exposed to this herbicide. FULL TEXT

Anifandis et al., 2017

Anifandis, G., Amiridis, G., Dafopoulos, K., Daponte, A., Dovolou, E., Gavriil, E., Gorgogietas, V., Kachpani, E., Mamuris, Z., Messini, C. I., Vassiou, K., & Psarra, A. G., “The In Vitro Impact of the Herbicide Roundup on Human Sperm Motility and Sperm Mitochondria,” Toxics, 2017, 6:1, DOI:10.3390/toxics6010002.


Toxicants, such as herbicides, have been hypothesized to affect sperm parameters. The most common method of exposure to herbicides is through spraying or diet. The aim of the present study was to investigate the effect of direct exposure of sperm to 1 mg/L of the herbicide Roundup on sperm motility and mitochondrial integrity. Sperm samples from 66 healthy men who were seeking semen analysis were investigated after written informed consent was taken. Semen analysis was performed according to the World Health Organization guidelines (WHO, 2010). Mitochondrial integrity was assessed through mitochondrial staining using a mitochondria-specific dye, which is exclusively incorporated into functionally active mitochondria. A quantity of 1 mg/L of Roundup was found to exert a deleterious effect on sperm’s progressive motility, after 1 h of incubation (mean difference between treated and control samples = 11.2%) in comparison with the effect after three hours of incubation (mean difference = 6.33%, p < 0.05), while the relative incorporation of the mitochondrial dye in mitochondria of the mid-piece region of Roundup-treated spermatozoa was significantly reduced compared to relative controls at the first hour of incubation, indicating mitochondrial dysfunction by Roundup. Our results indicate that the direct exposure of semen samples to the active constituent of the herbicide Roundup at the relatively low concentration of 1 mg/L has adverse effects on sperm motility, and this may be related to the observed reduction in mitochondrial staining. FULL TEXT

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