Intrauterine exposure to 2,3′,4,4′,5-pentachlorobiphenyl alters spermatogenesis and testicular DNA methylation levels in F1 male mice

Abstract STUDY QUESTION How does paternal exposure to bisphenol A (BPA) affect the fertility of male offspring in mice in future generations? SUMMARY ANSWER Paternal exposure to BPA adversely affects spermatogenesis, several important sperm functions and DNA methylation patterns in spermatozoa, which have both multigenerational (in F0 and F1) and partial transgenerational (mainly noticed in F2, but F3) impacts on the fertility of the offspring. WHAT IS KNOWN ALREADY BPA, a synthetic endocrine disruptor, is used extensively to manufacture polycarbonate plastics and epoxy resins. Growing evidence suggests that exposure to BPA during the developmental stages results in atypical reproductive phenotypes that could persist for generations to come. STUDY DESIGN, SIZE, DURATION CD-1 male mice (F0) were treated with BPA (5 or 50 mg/kg body weight per day (bw/day)) or ethinylestradiol (EE) (0.4 μg/kg bw/day) for 6 weeks. Control mice were treated with vehicle (corn oil) only. The treated male mice were bred with untreated female mice to produce first filial generation (F1 offspring). The F2 and F3 offspring were produced similarly, without further exposure to BPA. PARTICIPANTS/MATERIALS, SETTING, METHODS Histological changes in the testis along with functional, biochemical and epigenetic (DNA methylation) properties of spermatozoa were investigated. Subsequently, each parameter of the F0–F3 generations was compared between BPA-treated mice and control mice. MAIN RESULTS AND THE ROLE OF CHANCE Paternal BPA exposure disrupted spermatogenesis by decreasing the size and number of testicular seminiferous epithelial cells, which eventually led to a decline in the total sperm count of F0–F2 offspring (P < 0.05). We further showed that a high BPA dose decreased sperm motility in F0–F2 males by mediating the overproduction of reactive oxygen species (F0–F1) and decreasing intracellular ATP (F0–F2) in spermatozoa (P < 0.05). These changes in spermatozoa were associated with altered global DNA methylation patterns in the spermatozoa of F0–F3 males (P < 0.05). Furthermore, we noticed that BPA compromised sperm fertility in mice from the F0–F2 (in the both dose groups) and F3 generations (in the high-dose group only). The overall reproductive toxicity of BPA was equivalent to or higher (high dose) than that of the tested dose of EE. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Further research is required to determine the variables (e.g. lowest BPA dose) that are capable of producing changes in sperm function and fertility in future generations. WIDER IMPLICATIONS OF THE FINDINGS These results may shed light on how occupational exposure to BPA can affect offspring fertility in humans. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant No. NRF-2018R1A6A1A03025159). M.S.R. was supported by Korea Research Fellowship Program through the NRF funded by the Ministry of Science and ICT (Grant No. 2017H1D3A1A02013844). There are no competing interests.

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Fetal Renal DNA Methylation and Developmental Programming of Stress-Induced Hypertension in Growth-Restricted Male Mice

Reproductive Sciences ◽

10.1007/s43032-019-00121-5 ◽

2020 ◽

Vol 27 (5) ◽

pp. 1110-1120 ◽

Cited By ~ 1

Author(s):

Elizabeth DuPriest ◽

Jessica Hebert ◽

Mayu Morita ◽

Nicole Marek ◽

Emily E. K. Meserve ◽

...

Keyword(s):

Dna Methylation ◽

Developmental Programming ◽

Male Mice ◽

Induced Hypertension

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EGCG Prevents High Fat Diet-Induced Changes in Gut Microbiota, Decreases of DNA Strand Breaks, and Changes in Expression and DNA Methylation ofDnmt1andMLH1in C57BL/6J Male Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/3079148 ◽

2017 ◽

Vol 2017 ◽

pp. 1-17 ◽

Cited By ~ 37

Author(s):

Marlene Remely ◽

Franziska Ferk ◽

Sonja Sterneder ◽

Tahereh Setayesh ◽

Sylvia Roth ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Dna Damage ◽

Gut Microbiota ◽

High Fat Diet ◽

Dna Methyltransferase ◽

Dna Methyltransferase 1 ◽

Male Mice ◽

High Fat ◽

Methyltransferase 1

Obesity as a multifactorial disorder involves low-grade inflammation, increased reactive oxygen species incidence, gut microbiota aberrations, and epigenetic consequences. Thus, prevention and therapies with epigenetic active antioxidants, (-)-Epigallocatechin-3-gallate (EGCG), are of increasing interest. DNA damage, DNA methylation and gene expression ofDNA methyltransferase 1,interleukin 6, andMutL homologue 1were analyzed in C57BL/6J male mice fed a high-fat diet (HFD) or a control diet (CD) with and without EGCG supplementation. Gut microbiota was analyzed with quantitative real-time polymerase chain reaction. An induction of DNA damage was observed, as a consequence of HFD-feeding, whereas EGCG supplementation decreased DNA damage. HFD-feeding induced a higher inflammatory status. Supplementation reversed these effects, resulting in tissue specific gene expression and methylation patterns ofDNA methyltransferase 1andMutL homologue 1. HFD feeding caused a significant lower bacterial abundance. TheFirmicutes/Bacteroidetesratio is significantly lower in HFD + EGCG but higher in CD + EGCG compared to control groups. The results demonstrate the impact of EGCG on the one hand on gut microbiota which together with dietary components affects host health. On the other hand effects may derive from antioxidative activities as well as epigenetic modifications observed on CpG methylation but also likely to include other epigenetic elements.

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Impact of a folic acid-enriched diet on urinary tract function in mice treated with testosterone and estradiol

AJP Renal Physiology ◽

10.1152/ajprenal.00674.2014 ◽

2015 ◽

Vol 308 (12) ◽

pp. F1431-F1443 ◽

Cited By ~ 7

Author(s):

Kimberly P. Keil ◽

Lisa L. Abler ◽

Helene M. Altmann ◽

Zunyi Wang ◽

Peiqing Wang ◽

...

Keyword(s):

Dna Methylation ◽

Folic Acid ◽

Urinary Tract ◽

Water Balance ◽

Ventral Prostate ◽

Potential Mechanism ◽

Male Mice ◽

Control Male ◽

Modified Dna ◽

Aging Men

Aging men are susceptible to developing lower urinary tract symptoms, but the underlying etiology is unknown and the influence of dietary and environmental factors on them is unclear. We tested whether a folic acid-enriched diet changed urinary tract physiology and biology in control male mice and male mice with urinary dysfunction induced by exogenous testosterone and estradiol (T+E2), which mimics changing hormone levels in aging humans. T+E2 treatment increased mouse urine output, time between voiding events, and bladder capacity and compliance. Consumption of a folic acid-enriched diet moderated these changes without decreasing prostate wet weight or threshold voiding pressure. One potential mechanism for these changes involves water balance. T+E2 treatment increases plasma concentrations of anti-diuretic hormone, which is offset at least in part by a folic acid-enriched diet. Another potential mechanism involves neural control of micturition. The folic acid-enriched diet, fed to T+E2-treated mice, increased voiding frequency in response to intravesicular capsaicin infusion and increased mRNA abundance of the capsaicin-sensitive cation channel transient receptor potential vanilloid subfamily member 1 ( Trpv1) in L6 and S1 dorsal root ganglia (DRG) neurons. T+E2 treatment and a folic acid-enriched diet also modified DNA methylation, which is capable of altering gene expression. We found the enriched diet increased global DNA methylation in dorsal and ventral prostate and L6 and S1 DRG. Our results are consistent with folic acid acting to slow or reverse T+E2-mediated alteration in urinary function in part by normalizing water balance and enhancing or preserving afferent neuronal function.

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Faculty Opinions recommendation of Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717978192.793471011 ◽

2013 ◽

Author(s):

Louiza Belkacemi

Keyword(s):

Diabetes Mellitus ◽

Dna Methylation ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Metabolic Programming ◽

Intrauterine Exposure

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Early-Life Stress Reduces DNA Methylation of the Pomc Gene in Male Mice

Endocrinology ◽

10.1210/en.2013-1868 ◽

2014 ◽

Vol 155 (5) ◽

pp. 1751-1762 ◽

Cited By ~ 81

Author(s):

Yonghe Wu ◽

Alexandre V. Patchev ◽

Guillaume Daniel ◽

Osborne F.X. Almeida ◽

Dietmar Spengler

Keyword(s):

Dna Methylation ◽

Life Stress ◽

Early Life ◽

Binding Protein ◽

Early Life Stress ◽

Neuroendocrine Cells ◽

Mrna Levels ◽

Male Mice ◽

Pomc Mrna ◽

Pomc Gene

Early-life stress (ELS) increases the vulnerability thresholds for stress-related diseases such as major depression and anxiety by inducing alterations in the structure and function of neural circuits and endocrine pathways. We previously demonstrated the contribution of epigenetic mechanisms to the long-term programming of the hypothalamo-pituitary-adrenal axis activity following ELS exposure in male mice. Here, ELS comprising daily separation of pups from their dams on postnatal days 1–10 was observed to up-regulate the expression of the pituitary proopiomelanocortin (Pomc) gene; POMC serves as a prohormone for ACTH, a key mediator of the adrenocortical response to stress. Detailed analysis revealed that the increase in Pomc mRNA levels results from a reduction in DNA methylation at a critical regulatory region of the Pomc gene; interestingly, this change occurs with some delay after ELS and persists for up to 1 year. Using a Pomc-expressing pituitary cell line (AtT20), we confirmed a role for DNA methylation in restraining Pomc expression under resting conditions: specifically, we show that CpG site-specific methylation of the Pomc promoter represses Pomc mRNA transcription. Further, we show high-affinity binding of methyl-CpG binding protein-2 to the distal promoter of Pomc, suggesting that methyl-CpG binding protein-2 acts in association with the chromatin modifiers histone deacetylase 2 and DNA methyltransferase 1 to repress Pomc gene expression. Collectively, these experiments contribute to our understanding of the mechanisms through which environmental cues are translated into stable changes (“cellular memory”) in neuroendocrine cells.

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Sodium Fluoride Affects DNA Methylation of Imprinted Genes in Mouse Early Embryos

Cytogenetic and Genome Research ◽

10.1159/000442067 ◽

2015 ◽

Vol 147 (1) ◽

pp. 41-47 ◽

Cited By ~ 7

Author(s):

Lei Zhao ◽

Sheng Zhang ◽

Xinglan An ◽

Wentao Tan ◽

Bo Tang ◽

...

Keyword(s):

Dna Methylation ◽

Embryonic Development ◽

Mrna Level ◽

Mouse Embryos ◽

Imprinted Genes ◽

Male Mice ◽

Early Embryos ◽

Pregnant Mice ◽

H19 Gene ◽

Early Mouse

Fluorine is reported to affect embryonic development, but the underlining mechanism is unclear. The modification of DNA methylation of the H19 and Peg3 genes is important in embryonic development. Therefore, the effect of fluorine on methylation of H19 and Peg3 during early mouse embryos was studied. It was shown that the H19 gene was significantly downmethylated in E2.5, E3.5, and E4.5 embryos from pregnant mice treated with 120 mg/l NaF in drinking water for 48 h. But methylation of both H19 and Peg3 genes was disrupted when the parent male mice were treated with NaF for 35 days. H19 DNA methylation decreased significantly, while Peg3 was almost completely methylated. However, when pregnant mice, mated with NaF-treated male mice, were again treated with NaF for 48 h, either H19 or Peg3 methylation in the embryos decreased significantly. In addition, the mRNA level of H19 considerably increased in E3.5 and E4.5 embryos from NaF-treated pregnant mice. Further, the expression of DNMT1 decreased significantly after NaF treatment. Conclusively, we demonstrated that fluorine may adversely affect early embryonic development by disrupting the methylation of H19 and Peg3 through downregulation of DNMT1.

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