Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes

Endocrine-disrupting chemicals (EDCs), among which methoxychlor (MXC), have been reported to affect the male reproductive system. This study evaluates the possible deleterious effects of MXC on imprinted genes. After administration of the chemical in adult male mice or in pregnant mice we analyzed by pyrosequencing possible methylation defects in two paternally imprinted (H19 and Meg3 (Gtl2)) and three maternally imprinted (Mest (Peg1), Snrpn, and Peg3) genes in the sperm and in the tail, liver, and skeletal muscle DNAs of the adult male mice and of the male offspring. MXC treatment of adult mice decreased the percentages of methylated CpGs of Meg3 and increased those of Mest, Snrpn, and Peg3 in the sperm DNA. MXC treatment of pregnant mice decreased the mean sperm concentrations by 30% and altered the methylation pattern of all the imprinted genes tested in the F1 offspring. In the latter case, MXC effects were transgenerational but disappeared gradually from F1 to F3. MXC did not affect imprinting in the somatic cells, suggesting that it exerts its damaging effects via the process of reprogramming that is unique to gamete development. A systematic analysis at the CpG level showed a heterogeneity in the CpG sensitivity to MXC. This observation suggests that not only DNA methylation but also other epigenetic modifications can explain the transgenerational effects of MXC. The reported effects of EDCs on human male spermatogenesis might be mediated by complex imprinting alterations analogous to those described in this study.

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Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm

Reproduction ◽

10.1530/rep-09-0340 ◽

2010 ◽

Vol 139 (2) ◽

pp. 373-379 ◽

Cited By ~ 192

Author(s):

Christelle Stouder ◽

Ariane Paoloni-Giacobino

Keyword(s):

Reproductive System ◽

Methylation Status ◽

Endocrine Disrupting Chemicals ◽

Sperm Concentration ◽

Female Offspring ◽

Methylation Pattern ◽

Male Reproductive System ◽

Imprinted Genes ◽

Pregnant Mice ◽

Embryo Sex

Endocrine-disrupting chemicals (EDCs), among which is the antiandrogen vinclozolin (VCZ), have been reported to affect the male reproductive system. In this study, VCZ was administered to pregnant mice at the time of embryo sex determination, and its possible effects on the differentially methylated domains (DMDs) of two paternally (H19 and Gtl2) and three maternally (Peg1, Snrpn, and Peg3) imprinted genes were tested in the male offspring. The CpGs methylation status within the five gene DMDs was analyzed in the sperm, tail, liver, and skeletal muscle DNAs by pyrosequencing. In the sperm of controls, the percentages of methylated CpGs were close to the theoretical values of 100 and 0% in paternally or maternally imprinted genes respectively. VCZ decreased the percentages of methylated CpGs of H19 and Gtl2 (respective values 83.1 and 91.5%) and increased those of Peg1, Snrpn, and Peg3 (respective values 11.3, 18.3, and 11.2%). The effects of VCZ were transgenerational, but they disappeared gradually from F1 to F3. The mean sperm concentration of the VCZ-administered female offspring was only 56% of that of the controls in the F1 offspring, and it was back to normal values in the F2 and F3 offspring. In the somatic cells of controls, the percentages of methylated CpGs were close to the theoretical value of 50% and, surprisingly, VCZ altered the methylation of Peg3. We propose that the deleterious effects of VCZ on the male reproductive system are mediated by imprinting defects in the sperm. The reported effects of EDCs on human male spermatogenesis might be mediated by analogous imprinting alterations.

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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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Hypothalamic Expression of Neuropeptide Y (NPY) and Pro-OpioMelanoCortin (POMC) in Adult Male Mice Is Affected by Chronic Exposure to Endocrine Disruptors

Metabolites ◽

10.3390/metabo11060368 ◽

2021 ◽

Vol 11 (6) ◽

pp. 368

Author(s):

Marilena Marraudino ◽

Elisabetta Bo ◽

Elisabetta Carlini ◽

Alice Farinetti ◽

Giovanna Ponti ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Neuropeptide Y ◽

Adult Male ◽

Endocrine Disrupting Chemicals ◽

Endocrine System ◽

Male Mice ◽

Hypothalamic Nuclei ◽

Short Term Exposure ◽

Control Food Intake

In the arcuate nucleus, neuropeptide Y (NPY) neurons, increase food intake and decrease energy expenditure, and control the activity of pro-opiomelanocortin (POMC) neurons, that decrease food intake and increase energy expenditure. Both systems project to other hypothalamic nuclei such as the paraventricular and dorsomedial hypothalamic nuclei. Endocrine disrupting chemicals (EDCs) are environmental contaminants that alter the endocrine system causing adverse health effects in an intact organism or its progeny. We investigated the effects of long-term exposure to some EDCs on the hypothalamic NPY and POMC systems of adult male mice that had been previously demonstrated to be a target of some of these EDCs after short-term exposure. Animals were chronically fed for four months with a phytoestrogen-free diet containing two different concentrations of bisphenol A, diethylstilbestrol, tributyltin, or E2. At the end, brains were processed for NPY and POMC immunohistochemistry and quantitatively analyzed. In the arcuate and dorsomedial nuclei, both NPY and POMC immunoreactivity showed a statistically significant decrease. In the paraventricular nucleus, only the NPY system was affected, while the POMC system was not affected. Finally, in the VMH the NPY system was affected whereas no POMC immunoreactive material was observed. These results indicate that adult exposure to different EDCs may alter the hypothalamic circuits that control food intake and energy metabolism.

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EFFECTS OF TESTOSTERONE AND FOLLICLE-STIMULATING HORMONE ON SPERMATOGENESIS IN ADULT MICE DURING TREATMENT WITH OESTRADIOL

Journal of Endocrinology ◽

10.1677/joe.0.0600037 ◽

1974 ◽

Vol 60 (1) ◽

pp. 37-45 ◽

Cited By ~ 12

Author(s):

A. G. DAVIES ◽

M. COUROT ◽

P. GRESHAM

Keyword(s):

Dose Level ◽

Adult Male ◽

Follicle Stimulating Hormone ◽

Male Mice ◽

Human Pituitary ◽

Oestradiol Treatment ◽

Adult Mice ◽

Stimulating Hormone

SUMMARY Adult male mice were treated with oestradiol for 10 weeks and for the last half of this period they were given relatively large daily doses of testosterone and highly purified human pituitary follicle-stimulating hormone (FSH), singly and in combination. Oestradiol treatment reduced and testosterone restored the yields of mature (step 16) spermatids from round (step 7) spermatids, round spermatids from pachytene primary spermatocytes and pachytene from preleptotene spermatocytes. At the dose level used FSH was not effective alone but appeared to augment the effect of testosterone on the yield of round spermatids from preleptotene spermatocytes.

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Effect of neonatal dexamethasone treatment on cognitive abilities of adult male mice and gene expression in the hypothalamus

Vavilov Journal of Genetics and Breeding ◽

10.18699/vj19.514 ◽

2019 ◽

Vol 23 (4) ◽

pp. 456-464

Author(s):

N. P. Bondar ◽

V. V. Reshetnikov ◽

K. V. Burdeeva ◽

T. I. Merkulova

Keyword(s):

Hpa Axis ◽

Adult Male ◽

Early Life ◽

Receptor Gene ◽

Expression Level ◽

Male Mice ◽

Dexamethasone Treatment ◽

Negative Feedback Regulation ◽

Adult Mice ◽

Glucocorticoid Receptor Gene

The early postnatal period is critical for the development of the nervous system. Stress during this period causes negative long-term effects, which are manifested at both behavioral and molecular levels. To simulate the elevated glucocorticoid levels characteristic of early-life stress, in our study we used the administration of dexamethasone, an agonist of glucocorticoid receptors, at decreasing doses at the first three days of life (0.5, 0.3, 0.1 mg/kg, s.c.). In adult male mice with neonatal dexamethasone treatment, an increase in the relative weight of the adrenal glands and a decrease in body weight were observed, while the basal level of corticosterone remained unchanged. Dexamethasone treatment in early life had a negative impact on the learning and spatial memory of adult mice in the Morris water maze. We analyzed the effect of elevated glucocorticoid levels in early life on the expression of the Crh, Avp, Gr, and Mr genes involved in the regulation of the HPA axis in the hypothalami of adult mice. The expression level of the mineralocorticoid receptor gene (Mr) was significantly downregulated, and the glucocorticoid receptor gene (Gr) showed a tendency towards decreased expression (p = 0.058) in male mice neonatally treated with dexamethasone, as compared with saline administration. The expression level of the Crh gene encoding corticotropin-releasing hormone was unchanged, while the expression of the vasopressin gene (Avp) was increased in response to neonatal administration of dexamethasone. The obtained results demonstrate a disruption of negative feedback regulation of the HPA axis, which involves glucocorticoid and mineralocorticoid receptors, at the level of the hypothalamus. Malfunction of the HPA axis as a result of activation of the glucocorticoid system in early life may cause the development of cognitive impairment in the adult mice.

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