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Differences in reproductive toxicity of TBBPA and TCBPA exposure in male Rana nigromaculata
2018
Zhang, Hangjun | Liu, Wenli | Chen, Bin | He, Jianbo | Chen, Feifei | Shan, Xiaodong | Du, Qiongxia | Li, Ning | Jia, Xiuying | Tang, Juan
Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) are persistent toxic environmental pollutants that cause severe reproductive toxicity in animals. The goal of this study was to compare the reproductive toxic effects of TBBPA and TCBPA on male Rana nigromaculata and to expound on the mechanisms leading to these effects. Healthy adult frogs were exposed to 0, 0.001, 0.01, 0.1, and 1 mg/L of TBBPA and TCBPA for 14 days. Sperm numbers were counted by erythrometry. Sperm mobility and deformities were observed under a light microscope (400 ×). We used commercial ELISA kits to determine the serum content of testosterone (T), estradiol (E2), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Expression of androgen receptor (AR) mRNA was detected using real-time qPCR. Sperm numbers and sperm mobility were significantly decreased and sperm deformity was significantly increased in a concentration dependent manner following exposure to TBBPA and TCBPA. Sperm deformity was significantly greater in the 1 mg/L TCBPA (0.549) treatment group than in the 1 mg/L TBBPA (0.397) treatment group. Serum T content was significantly greater in the 0.01, 0.1 and 1 mg/L TBBPA and TCBPA experimental groups compared with controls, while E2 content was significantly greater in only the 1 mg/L TBBPA and TCBPA experimental groups. Expression levels of LH and FSH significantly decreased in the 1 mg/L TBBPA and TCBPA treatment groups. AR mRNA expression decreased markedly in all the treated groups. Our results indicated that TBBPA and TCBPA induced reproductive toxicity in a dose-dependent manner, with TCBPA having greater toxicity than TBBPA. Furthermore, changes in T, E2, LH, and FSH levels induced by TBBPA and TCBPA exposure, which led to endocrine disorders, also caused disturbance of spermatogenesis through abnormal gene expressions of AR in the testes.
Show more [+] Less [-]Estrogenic potency of MC-LR is induced via stimulating steroidogenesis: In vitro and in vivo evidence
2018
Hou, Jie | Su, Yujing | Lin, Wang | Guo, Honghui | Li, Li | Anderson, Donald M. | Li, Dapeng | Tang, Rong | Chi, Wei | Zhang, Xi
Waterborne microcystin-LR (MC-LR) has been reported to disrupt sex hormones, while its estrogenic potency remains controversial. We hypothesized that MC-LR could induce estrogenic effects via disrupting sex hormone synthesis, and verified this hypothesis by in vitro and in vivo assays. Effects of MC-LR (1, 10, 100, 500, 1000 and 5000 μg/L) on steroidogenesis were assessed in the H295R cells after 48 h. The contents of 17β-estradiol (E2) and testosterone (T) increased in a non-dose-dependent manner, which showed positive correlations with the expression of steroidogenic genes. In the in vivo assay, adult male zebrafish were exposed to 0.3, 1, 3, 10 and 30 μg/L MC-LR for 30 d. Similarly, E2 and T contents in the testis were increased, accompanied by extensive up-regulation of steroidogenic genes, especially cyp19a. Meanwhile, the percentage of spermatid in the testis declined. In the liver, the vtg1 gene was significantly up-regulated while both the transcriptional and protein levels of the estrogenic receptor (ER) declined. These results indicate that MC-LR induced non-dose-dependent estrogenic effects at environmental concentrations, which may result from steroidogenesis stimulation via a non-ER-mediated pathway. Our findings support a paradigm shift in the risk assessment of MC-LR from traditional toxicity to estrogenic risk, particularly at low concentrations, and emphasize the potential threat to the male reproductive capacity of wildlife in bloom areas.
Show more [+] Less [-]Alterations of cytochrome P450 and the occurrence of persistent organic pollutants in tilapia caged in the reservoirs of the Iguaçu River
2018
Yamamoto, F.Y. | Diamante, G.D. | Santana, M.S. | Santos, D.R. | Bombardeli, R. | Martins, C.C. | Oliveira Ribeiro, C.A. | Schlenk, D.
Environmental chemicals originating from human activities, such as persistent organic pollutants (POPs), may interfere with the endocrine system of aquatic organisms. The effect of these chemicals on biota and human populations is of high public concern but remains poorly understood, especially in aquatic environments of South America. The aim of this study was to investigate the bioavailability of POPs and the related effects in caged male tilapia (Oreochromis niloticus) in four cascading reservoirs of the Iguaçu River, Southern Brazil. POPs including organochlorine pesticides (OCPs), polychlorinated biphenyl (PCBs), and polybrominated diphenyl ethers (PBDEs) were determined in the reservoir water and tissue samples of tilapia after two months of exposure. The PCB levels in water (14.7 ng L−1) were 14 times higher than the limits permitted by the Brazilian legislation in the Salto Santiago (SS) reservoir. Similarly, concentrations of aldrin and its metabolites (6.05 ng L−1) detected in the water sample of the Salto Osório (SO) reservoir were also above the permitted limits. RT-qPCR analysis revealed different transcript levels of cytochrome P450 enzymes (CYP1A and CYP3A) in the liver among the four groups, with induced activity in tilapia from the SS reservoir. Quantification of the CYP3A mRNA expression and catalytic activity showed higher values for fish caged at the SS reservoir. The fish from this site also had a higher number of eosinophils observed in the testes. Although overt measurements of endocrine disruption were not observed in caged fish, alteration of CYP enzymes with co-occurrence of organochlorine contaminants in water may suggest bioavailability of contaminants from agricultural sources to biota. Additional studies with feral or caged animals for a longer duration may be necessary to evaluate the risks of the waterways to humans and wildlife.
Show more [+] Less [-]Reproductive effects linked to DNA methylation in male zebrafish chronically exposed to environmentally relevant concentrations of di-(2-ethylhexyl) phthalate
2018
Ma, Yan-Bo | Jia, Pan-Pan | Junaid, Muhammad | Yang, Li | Lu, Chun-Jiao | Pei, De-Sheng
Di-(2-ethylhexyl) phthalate (DEHP) possesses the potential to interfere with the male reproductive endocrine system in mammals; however, its reproductive toxicity in male zebrafish and associated epigenetic studies have not been explored. In this study, three-month-old male zebrafish were exposed to environmentally relevant concentrations of DEHP (0, 10, 33 and 100 μg/L) for 3 months, and then the impact on the reproduction of males and the underlying mechanism were investigated. Histological testing showed that an exposure concentration of 100 μg/L DEHP significantly inhibited spermatogenesis, with an associated decline in capability to fertilize untreated oocytes. Electron microscopic examinations also revealed noticeable damage to the testicular ultrastructure at the 100 μg/L DEHP exposure level. In addition, exposure to 33 and 100 μg/L of DEHP resulted in a decline of circulating testosterone (T) and an increase in the level of 17β-estradiol (E2), both of which were possibly derived from the downregulation of cyp17a1 and hsd17b3 genes and the upregulation of the cyp19a1a gene in the gonads. The DNA methylation statuses of these genes were altered within their promoter regions. A significant increase in global DNA methylation in both the male testes and their offspring larvae was observed at higher exposure concentration of DEHP. Our findings demonstrate that exposure to environmentally relevant concentrations of DEHP can damage the testes, disturbe the sex hormones production, and inhibite spermatogenesis, which ultimately impairs the reproduction of male zebrafish.
Show more [+] Less [-]Manganese accumulates in the brain of northern quolls (Dasyurus hallucatus) living near an active mine
2018
Amir Abdul Nasir, Ami Fadhillah | Cameron, Skye F. | von Hippel, Frank A. | Postlethwait, John | Niehaus, Amanda C. | Blomberg, Simon | Wilson, Robbie S.
Mining is fundamental to the Australian economy, yet little is known about how potential contaminants bioaccumulate and affect wildlife living near active mining sites. Here, we show using air sampling that fine manganese dust within the respirable size range is found at levels exceeding international recommendations even 20 km from manganese extraction, processing, and storage facilities on Groote Eylandt, Northern Territory. Endangered northern quolls (Dasyurus hallucatus) living near mining sites were found to have elevated manganese concentrations within their hair, testes, and in two brain regions—the neocortex and cerebellum, which are responsible for sensory perception and motor function, respectively. Accumulation in these organs has been associated with adverse reproductive and neurological effects in other species and could affect the long-term population viability of northern quolls.
Show more [+] Less [-]Effects of the bioconcentration and parental transfer of environmentally relevant concentrations of difenoconazole on endocrine disruption in zebrafish (Danio rerio)
2018
Teng, Miaomiao | Qi, Suzhen | Zhu, Wentao | Wang, Yao | Wang, Dezhen | Dong, Kai | Wang, Chengju
Difenoconazole, a typical triazole fungicide, inhibits lanosterol-14R-demethylase (CYP51) to prevent fungal sterol synthesis and its residues are frequently detected in the environment due to its wide application. Previous studies have demonstrated that difenoconazole altered the triglyceride levels, and gene expression relevant to cholesterol biosynthesis in zebrafish. However, endocrine-disruption in the hypothalamus-pituitary-gonadal-liver (HPGL) axis, the effects of transferring to offspring, and the underlying mechanisms of difenoconazole in aquatic organisms are still unknown. In this study, we defined the effects of difenoconazole at environmental concentrations on endocrine disturbance using zebrafish as an experimental model. The results indicated that difenoconazole induced a significant change in the somatic index, and pathological variations in tissues, and steroid hormone levels. RT-PCR experiments further confirmed that difenoconazole significantly induced expression alteration of lhr, hsd3β, hsd11β, cyp19a in the ovary and star, cyp19a, cyp3c1 in the testis, and erα genes in livers. In addition, difenoconazole exposure in parental zebrafish affected the hatchability and length of its offspring. Moreover, the burdens of difenoconazole and difenoconazole alcohol in females were higher than in males. These findings highlighted that difenoconazole exposure at environmentally relevant concentrations elicited estrogenic endocrine-disruption effects via altering homeostasis of sex steroid hormones in the HPGL axis and the adverse effects can be transferred to the offspring.
Show more [+] Less [-]TERT regulates telomere-related senescence and apoptosis through DNA damage response in male germ cells exposed to BPDE in vitro and to B[a]P in vivo
2018
Ling, Xi | Yang, Wang | Zou, Peng | Zhang, Guowei | Wang, Zhi | Zhang, Xi | Chen, Hongqiang | Peng, Kaige | Han, Fei | Liu, Jinyi | Cao, Jia | Ao, Lin
Increasing evidence shows that impaired telomere function is associated with male infertility, and various environmental factors are believed to play a pivotal role in telomerase deficiency and telomere shortening. Benzo[a]pyrene (B[a]P), a ubiquitous pollutant of polycyclic aromatic hydrocarbons (PAHs), can act as a reproductive toxicant; however, the adverse effect of B[a]P on telomeres in male reproductive cells has never been studied, and the related mechanisms remain unclear. In this study, we explored the effects of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), the active metabolite of B[a]P, on telomere dysfunction in mouse spermatocyte-derived cells (GC-2) and also the potential role of telomerase in BPDE-induced spermatogenic cell damage. The results showed that BPDE induced cell viability inhibition, senescence, and apoptosis in GC-2 cells in a dose-dependent manner. Shortened telomeres, telomere-associated DNA damage, reduced telomerase activity, and TERT expression were also observed in BPDE-treated cells, accompanied with the activation of DNA damage response pathway (ATM/Chk1/p53/p21). Moreover, by establishing the TERT knockdown and re-expression cell models, we found that TERT regulated telomere length and the expression of DNA damage response-related proteins to influence senescence and apoptosis in GC-2 cells. These in vitro findings were further confirmed in vivo in the testicular cells of rats orally administrated with B[a]P for 7 days. B[a]P treatment resulted in histological lesions, apoptosis, and senescence in the testes of rats, which were accompanied by shortened telomeres, reduced levels of TERT protein, and increased expression of DNA damage response-related proteins. In conclusion, it can be concluded that TERT-mediated telomere dysfunction contributes to B[a]P- and BPDE-induced senescence and apoptosis through DNA damage response in male reproductive cells.
Show more [+] Less [-]Ascorbic acid inhibits cadmium-induced disruption of the blood-testis barrier by regulating oxidative stress-mediated p38 MAPK pathways
2018
Chen, Na | Su, Ping | Wang, Mei | Li, Ya-Min
Ascorbic acid (AA), one of the best-known reactive oxygen species (ROS) scavengers, exhibits numerous functions such as antioxidant, anti-cancer, and anti-inflammatory effects. Increasing evidence demonstrates that oxidative stress plays an important role in testicular toxicity. In the present study, we investigated the protective effect of AA against cadmium (Cd)-induced blood-testis barrier (BTB) disruption. Sprague-Dawley (SD) rats were divided into four groups: the Cd-treated group received a single dose (s.c.) of 2 mg/kg BW cadmium chloride; the AA antagonism group received an injection of AA at a dose of 400 mg/kg BW (200 mg 24 h prior to Cd treatment and 200 mg 24 h following Cd treatment); and the control groups received an equal volume of saline or an equal dose of AA. As expected, ROS expression was upregulated in the Cd-treated rats, accompanied by an increase in malondialdehyde (MDA). Interestingly, AA suppressed Cd-induced oxidative stress by decreasing the levels of ROS and MDA and increasing the activity of superoxide dismutase (SOD) and catalase (CAT). In addition, AA also reduced BTB disruption by inhibiting TGF-β3 activation and p38 MAPK phosphorylation. Significant decreases in occludin and claudin-11 expression were observed in the Cd-treated rats, whereas AA administration attenuated this effect. Moreover, testicular histopathology and transmission electron microscopy further demonstrated the protective effects of AA against Cd-induced BTB damage. In conclusion, the results of the present study suggest that AA protects BTB destruction via the inhibition of oxidative stress and the TGF-β3/p38 MAPK signalling pathway in the testis of Cd-exposed rats.
Show more [+] Less [-]Frog (Pelophylax bergeri, Günther 1986) endocrine disruption assessment: characterization and role of skin poly(ADP-ribose) polymerases
2018
Guerriero, Giulia | Brundo, Maria Violetta | Labar, Sofiane | Bianchi, Anna Rita | Trocchia, Samantha | Rabbito, Dea | Palumbo, Giancarlo | Abdel-Gawad, Fagr Kh | De Maio, Anna
Model of the our research was the adult male amphibian anura, Pelophylax bergeri, poikilotherm species not considered threatened by the IUCN, sampled in representative sites at different degree. In the first phase, a biochemical characterization of the ADP-ribosylation on the skin of barcoded amphibian anura collected from Matese Lake (clean reference site in CE, Italy) was carried out. Two PARP isoforms were evidence: the first of 66 kDa is localized into nucleus and activated by DNA damage; the second of 150 kDa is in cytoplasm, as demonstrated by biochemical and immunohistochemical analysis. Subsequently, the PARP activity, the quantitative expression of androgen receptor gene, and the levels of arsenic and chromium in skin and testis of frog and soil, water, and sediment collected from sites at different degrees of pollution were measured. A significant variation of PARP activity and androgen receptor expression levels was detected in both tissues of barcoded frogs from Sarno and Scafati, along Sarno River (SA, Italy), suggesting that a PARP activation is correlated to pollution and to steroid-regulated physiology disruption.
Show more [+] Less [-]Genotoxicity of carbon tetrachloride and the protective role of essential oil of Salvia officinalis L. in mice using chromosomal aberration, micronuclei formation, and comet assay
2018
The present work was conducted to evaluate the genotoxic effect of carbon tetrachloride (CCl₄) in mouse bone marrow and male germ cells. The safety and the modulating activity of sage (Salvia officinalis L.) essential oil (SEO) against the possible genotoxic effect of CCl₄ were also evaluated. A combination of in vivo mutagenic endpoints was included: micronucleus (MN), apoptosis using dual acridine orange/ethidium bromide (AO/EB) staining, comet assay, chromosomal aberrations (CAs), and sperm abnormalities. Histological examination of testis tissues was also studied. The extracted SEO was subjected to gas chromatography-mass spectrometry (GC-MS) for identifying its chemical constituents. Safety/genotoxicity of SEO was determined after two consecutive weeks (5 days/week) from oral treatment with different concentrations (0.1, 0.2, and 0.4 mL/kg). For assessing genotoxicity of CCl₄, both acute (once) and subacute i.p. treatment for 2 weeks (3 days/week) with the concentrations 1.2 mL/kg (for acute) and 0.8 mL/kg (for subacute) were performed. For evaluating the protective role of SEO, simultaneous treatment with SEO plus CCl₄ was examined. In sperm abnormalities, mice were treated with the subject materials for five successive days and the samples were collected after 35 days from the beginning of treatment. Based on GC-MS findings, 22 components were identified in the chromatogram of SEO. The results demonstrated that the three concentrations of SEO were safe and non-genotoxic in all the tested endpoints. Negative results were also observed in bone marrow after acute and subacute treatment with CCl₄. In contrast, CCl₄ induced testicular DNA damage as evidenced by a significant increase of CAs in primary spermatocytes, sperm abnormalities, and histological distortion of testis. A remarkable reduction in these cells was observed in groups treated with SEO plus CCl₄ especially with the two higher concentrations of SEO. In conclusion, SEO is safe and non-genotoxic under the tested conditions and can modulate genetic damage and histological alteration induced by CCl₄ in the testes.
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