Assessment spermatogenic cell apoptosis and the transcript levels of metallothionein and p53 in Meretrix meretrix induced by cadmium

Gao, Yilu; Hong, Jiameng; Guo, Yukun; Chen, Mengxu; Chang, Alan K.; Xie, Lei; Xiao, Ying

doi:10.1016/j.ecoenv.2021.112230

Cited by 24 publications

(19 citation statements)

References 55 publications

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“…Another three genes manifested 2-fold decrease of their testis expression when comparing Tcte1 −/− vs. Tcte1 +/− (but not to WT): Aqp2 (aquaporin-2 involved in osmotic transportation of the water), with well-known role in spermatogenesis, female endometrium cycle and urinary incontinenece; [Klein et al , 2013; Ramli et al , 2019], Mt3 (metallothionein-3, committed in homeostasis and detoxification of toxic metals, also in testis) important in apoptosis regulation of Bax and Caspase pathways [Gao et al , 2021; Honda et al , 2010]), and Rps27rt (ribosomal protein) (Figure 5; Supplementary file 11). It was also found that Rps27rt may interact indirectly with Usp39 and mitochondrial respiratory complex linking the mitochondrial energy processing with apoptosis (Supplementary file 11).…”

Section: Resultsmentioning

confidence: 99%

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Tcte1knockout influence on energy chain transportation, apoptosis and spermatogenesis – implications for male infertility

Olszewska

Malcher

Stokowy

et al. 2022

Preprint

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STUDY QUESTION: Is Tcte1 mutation causative for male infertility? SUMMARY ANSWER: Collected data underline the complex and devastating effect of the single-gene mutation on testicular molecular network, leading to male reproductive failure. WHAT IS KNOWN ALREADY: Latest data revealed mutations in genes related to axonemal dynein arms as causative for morphology and motility abnormalities in spermatozoa of infertile males, including dysplasia of fibrous sheath (DFS) and multiple morphological abnormalities in the sperm flagella (MMAF). The nexin-dynein regulatory complex (N-DRC) coordinates the dynein arm activity, and is built from DRC1-DRC7 proteins. DRC5 (TCTE1) - one of N-DRC element, has been already reported as a candidate for abnormal sperm flagella beating, however, only in restricted manner with no clear explanation of respective observations. STUDY DESIGN, SIZE, DURATION: Using CRISPR/Cas9 genome editing technique, mouse knockout line of Tcte1 gene was created on the basis of C57Bl/6J strain. Then, the mouse reproductive potential, semen characteristics, testicular gene expression level, sperm ATP and testis apoptosis level measurements have been performed, followed by visualization of N-DRC proteins in sperm, and protein modeling in silico. Also, a pilot genomic sequencing study of samples from human infertile males (n=248) was applied for screening of TCTE1 variants. PARTICIPANTS/MATERIALS, SETTING, METHODS: To check the reproductive potential of KO mice, adult animals were crossed for delivery of three litters per caged pair, but no longer than for 6 months, in various combinations of zygosity. All experiments were performed for wild type (WT - control group), heterozygous Tcte1+/-, and homozygous Tcte1-/- male mice. Gross anatomy was performed on testis and epididymis, followed by semen analysis. Sequencing of RNA (RNAseq; Illumina) has been done for mice testis tissues. STRING interactions have been checked for protein-protein interactions, based on changed expression level of corresponding genes identified in the mouse testis RNAseq experiments. Immunofluorescence in situ staining was performed to detect the N-DRC complex proteins: Tcte1 (Drc5), Drc7, Fbxl13 (Drc6), and Eps8l1 (Drc3) in mouse spermatozoa. To determine the ATP amount in spermatozoa, the luminescence level was measured. Also, immunofluorescent in situ staining was performed to check the level of apoptosis via caspase 3 visualization on mouse testis samples. DNA from whole blood samples of infertile males (n=137 non-obstructive azoospermia or cryptozoospermia, n=111 samples with spectrum of oligoasthenoteratozoospermia, including n=47 with asthenozoospermia) has been extracted to perform genomic sequencing (WGS, WES or Sanger). Protein prediction modeling of human identified variants and the exon 3 structure deleted in mouse knockout has been also performed. MAIN RESULTS AND THE ROLE OF CHANCE: No progeny at all was found for homozygous males with revealed oligoasthenoteratozoospermia, while heterozygous animals (fertile) manifested oligozoospermia, suggesting haploinsufficiency. RNA-sequencing of the testicular tissue showed the influence of Tcte1 mutations on the expression pattern of 21 genes responsible for mitochondrial ATP processing, linked with apoptosis, or spermatogenesis. In Tcte1-/- males the protein revealed only residual amounts in sperm head nucleus, and was not transported to sperm flagella, as other N-DRC components. Decreased ATP level (2.4-fold lower) was found in spermatozoa of homozygous mice, together with disturbed tail:midpiece ratio, leading to abnormal sperm tail beating. Casp3-positive signals (indicating apoptosis) were observed in spermatogonia only, at similar level in all three mouse genotypes. Mutation screening of human infertile males revealed 1 novel and 5 ultrarare heterogeneous variants (predicted as disease causing) in 6.05% of patients studied. Protein prediction modeling of identified variants revealed changes in the protein surface charge potential, leading to disruption in helix flexibility or its dynamics, thus, suggesting the disrupted TCTE1 interaction with its binding partners located within the axoneme.

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Section: Resultsmentioning

confidence: 99%

“…important in apoptosis regulation of Bax and Caspase pathways [Gao et al, 2021;Honda et al, 2010]), and…”

Section: Sequencing Of Rna (Rnaseq) and String Pathway Analysismentioning

confidence: 99%

Tcte1knockout influence on energy chain transportation, apoptosis and spermatogenesis – implications for male infertility

Olszewska

Malcher

Stokowy

et al. 2022

Preprint

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“…Among these mechanisms, oxidative stress is considered to play an important role (Matovic et al, 2015;Ren et al, 2019;Chen et al, 2020). The enrichment of cadmium to a certain level within an aquatic animal will lead to the production of a large amount of ROS (Gao et al, 2021;Wang et al, 2021). The increased extent of lipid peroxidation we observed in M. meretrix ovary manifested itself as increased ROS, MDA, DPC and PCO levels and decreased T-AOC and MT mRNA levels (Figure 1 & Figure 6A).…”

Section: Toxic Effects Of Cadmium On Ovarymentioning

confidence: 99%

“…The excess ROS can also cause the cross-linking of proteins, nucleic acids and other macromolecules, making them unable to carry out their normal functions in the ovarian cells, thereby adding further stress to the survival of the ovarian cells. The appearance of MDA, the final product of lipid peroxidation, could lead to the denaturation of the cell membrane (Gao et al, 2021). PCO is an irreversible protein modification that occurs under the action of oxidation, and such change in protein structure will result in the loss of the protein function (Fedorova et al, 2014).…”

Section: Toxic Effects Of Cadmium On Ovarymentioning

confidence: 99%

Cadmium-induced toxicity in Meretrix meretrix ovary is characterized by oxidative damage with changes in cell morphology and apoptosis-related factors

et al. 2022

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Cadmium (Cd) is one of the most common pollutants in the environment. It can cause irreversible tissue damage and apoptosis in invertebrates. This study investigated the relationship between Cd exposure and oxidative damage and apoptosis in the ovarian cell of the clam Meretrix meretrix. The clams were exposed to different concentrations of Cd2+ (0, 1.5, 3, 6 and 12 mg L−1) for 5 days, and the accumulated level of Cd2+ in the ovarian tissue, and the degree of oxidative damage, changes in morphology and the response of apoptosis-related factors in the ovarian cell were determined. The bioaccumulation of Cd2+ and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), protein carbonylation (PCO), and DNA-protein crosslinking (DPC) in the ovary were found to increase significantly when the clams were exposed to increasing concentrations of Cd2+. The structure of the ovarian tissue was severely damaged, and the ovarian cells displayed an irregular arrangement. The results of AO/EB staining and flow cytometry showed that the apoptotic rate of the ovarian cells increased with increasing Cd2+ concentrations. The activities of caspase-3, -8, -9, and the mRNA levels of p53, Bax and Caspase-3 in the ovary were also significantly increased. Furthermore, the level of p53 mRNA was positively correlated with the levels of MDA, PCO, DPC and ROS, but negatively correlated with the levels of total antioxidant capacity (T-AOC) and Bcl-2 mRNA. Taken together, these results indicated that Cd2+ exposure would result in oxidative damage and apoptosis for the ovarian cells, suggesting that Cd2+ toxicity could negatively affect the reproductive capacity of M. meretrix, thus threatening the reproductive development of the shellfish.

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“…Numerous studies have shown that Cd induced various adverse effects on biological systems [ 15 , 16 ]. Studies have proved that Cd causes prostate cancer in rodents, triggers reproductive disorders in males and females, and decreases fertility [ 17 , 18 , 19 , 20 ]. Huang et al (2021) suggested that Cd exposure regulates nerve cell proliferation and death, and induces neuroinflammation, which affects the normal development of the fetal brain [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Cd-Induced Cytotoxicity in Normal Human Skin Keratinocytes: Implication for Human Health

Cui

Xie

et al. 2022

IJMS

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Cadmium (Cd) is one of the toxic heavy metals found widely in the environment. Skin is an important target organ of Cd exposure. However, the adverse effects of Cd on human skin are still not well known. In this study, normal human skin keratinocytes (HaCaT cells) were studied for changes in cell viability, morphology, DNA damage, cycle, apoptosis, and the expression of endoplasmic reticulum (ER) stress-related genes (XBP-1, BiP, ATF-4, and CHOP) after exposure to Cd for 24 h. We found that Cd decreased cell viability in a concentration-dependent manner, with a median lethal concentration (LC50) of 11 µM. DNA damage induction was evidenced by upregulation of the level of γ-H2AX. Furthermore, Cd induced G0/G1 phase cell cycle arrest and apoptosis in a dose-dependent manner and upregulated the mRNA levels of ER stress biomarker genes (XBP-1, BiP, ATF4, and CHOP). Taken together, our results showed that Cd induced cytotoxicity and DNA damage in HaCaT cells, eventually resulting in cell cycle arrest in the G0/G1 phase and apoptosis. In addition, ER stress may be involved in Cd-induced HaCaT apoptosis. Our data imply the importance of reducing Cd pollution in the environment to reduce its adverse impacts on human skin.

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Assessment spermatogenic cell apoptosis and the transcript levels of metallothionein and p53 in Meretrix meretrix induced by cadmium

Cited by 24 publications

References 55 publications

Tcte1knockout influence on energy chain transportation, apoptosis and spermatogenesis – implications for male infertility

Tcte1knockout influence on energy chain transportation, apoptosis and spermatogenesis – implications for male infertility

Cadmium-induced toxicity in Meretrix meretrix ovary is characterized by oxidative damage with changes in cell morphology and apoptosis-related factors

Mechanisms of Cd-Induced Cytotoxicity in Normal Human Skin Keratinocytes: Implication for Human Health

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