17α-estradiol does not adversely affect sperm parameters or fertility in male mice: implications for reproduction-longevity trade-offs

Isola, José Victor Vieira; Veiga, Gabriel Barreto; Brito, Camila R.C. de; Rincón, Joao Alveiro Alvarado; Garcia, Driele Neske; Zanini, Bianka M; Hense, Jéssica D; Vieira, Arnaldo Diniz; Garratt, Michael; Gasperin, Bernardo; Schneider, Augusto; Stout, Michael B.

doi:10.1007/s11357-022-00601-8

Cited by 14 publications

(7 citation statements)

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“…Our group has been exploring potential mechanisms by which 17α-E2 may improve health span and extend life span in a male-specific manner. We reported that 17α-E2 supplementation reduces calorie intake, body mass, and regional adiposity in combination with significant improvements in a multitude of systemic metabolic parameters in both middle-aged obese and old male mice without inducing deleterious effects ( 19 , 25–29 , 36 ). Given that 17α-E2 elicits sex-specific effects in mice, which could be at least partially mediated through altered mitochondrial activity, we sought to determine if 17α-E2 would elicit similar sex-specific effects in 4-month-old OKC-HET B/W rats fed HFD ± 17α-E2 for 8 weeks.…”

Section: Resultsmentioning

confidence: 97%

A Genetically Heterogeneous Rat Model with Divergent Mitochondrial Genomes

Sathiaseelan

Ahn

Stout

et al. 2023

The Journals of Gerontology: Series A

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We generated a genetically heterogenous rat model by a four-way cross strategy using four inbred strains [Brown Norway (BN), Fischer 344 (F344), Lewis (LEW), and Wistar Kyoto (KY)] to provide investigators with a highly genetically diverse rat model from commercially available inbred rats. We made reciprocal crosses between males and females from the two F1 hybrids to generate genetically heterogeneous rats with mitochondrial genomes from either the BN (OKC-HET B, a.k.a “B” genotype) or WKY (OKC-HET W a.k.a “W” genotype) parental strains. These two mitochondrial genomes differ at 94 nucleotides, more akin to human mitochondrial genome diversity than that available in classical laboratory mouse strains. Body weights of the B and W genotypes were similar. However, mitochondrial genotype antagonistically affected grip strength and treadmill endurance in females only. In addition, mitochondrial genotype significantly affected multiple responses to a high-fat diet and treatment with 17α-estradiol. Contrary to findings in mice in which males only are affected by 17α-estradiol supplementation, female rats fed a high-fat diet beneficially responded to 17α-estradiol treatment as evidenced by declines in body mass, adiposity, and liver mass. Male rats, by contrast, differed in a mitochondrial genotype-specific manner, with only B males responding to 17α-estradiol treatment. Mitochondrial genotype and sex differences were also observed in features of brain-specific antioxidant response to a high-fat diet and 17α-estradiol as shown by hippocampal levels of Sod2 acetylation, JNK, and FoxO3a. These results emphasize the importance of mitochondrial genotype in assessing responses to putative interventions in aging processes.

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Section: Resultsmentioning

confidence: 97%

A Genetically Heterogeneous Rat Model with Divergent Mitochondrial Genomes

Sathiaseelan

Ahn

Stout

et al. 2023

The Journals of Gerontology: Series A

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“…Samples were then stained using the fast panoptic method. One hundred cells were evaluated on a microscope (Nikon Eclipse E200, Nikon, Tokyo, Japan) at 1003 magnification using immersion oil and differentially counted as normal, or with defects on tail, head and midpiece [24].…”

Section: Semen Analysismentioning

confidence: 99%

Dasatinib and quercetin increase testosterone and sperm concentration in mice

Garcia

Hense

Zanini

et al. 2023

PhysInt

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Cellular senescence is a defense mechanism to arrest proliferation of damaged cells. The number of senescent cells increases with age in different tissues and contributes to the development of age-related diseases. Old mice treated with senolytics drugs, dasatinib and quercetin (D+Q), have reduced senescent cells burden. The aim of this study was to evaluate the effects of D+Q on testicular function and fertility of male mice. Mice (n = 9/group) received D (5 mg kg−1) and Q (50 mg kg−1) via gavage every moth for three consecutive days from 3 to 8 months of age. At 8 months mice were breed with young non-treated females and euthanized. The treatment of male mice with D+Q increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology. Sperm motility, seminiferous tubule morphometry, testicular gene expression and fertility were not affected by treatment. There was no effect of D+Q treatment in β-galactosidase activity and in lipofuscin staining in testes. D+Q treatment also did not affect body mass gain and testes mass. In conclusion, D+Q treatment increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology, however did not affect fertility. Further studies with older mice and different senolytics are necessary to elucidate the effects in the decline of sperm output (quality and quantity) associated with aging.

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“…The copyright holder for this preprint this version posted June 14, 2024. ; https://doi.org/10.1101/2024.06.14.599053 doi: bioRxiv preprint 3 reproduction and feminization [6,13,14]. A previous study showed that 17α-estradiol elicits similar genomic binding and transcriptional activation through Esr1 (estrogen receptor α, ERα) to that of 17β-estradiol, suggesting a potential side effect on reproduction and feminization [15].…”

Section: Introductionmentioning

confidence: 99%

“…The safety of 17α-estradiol is key for translation into clinical treatment, and the side effects on reproduction and potential feminization by 17α-estradiol treatment need to be considered. However, contradictory results have been reported regarding its side effects on reproduction and feminization [6, 13, 14]. A previous study showed that 17α-estradiol elicits similar genomic binding and transcriptional activation through Esr1 (estrogen receptor α, ERα) to that of 17β-estradiol, suggesting a potential side effect on reproduction and feminization [15].…”

Section: Introductionmentioning

confidence: 99%

The effects of 17α-estradiol treatment on endocrine system revealed by single-nucleus transcriptomic sequencing of hypothalamus

Li,

Wu,

et al. 2024

Preprint

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In this study, we investigated the role of 17α-estradiol in lifespan extension and its potential side effects for long-term administration. Pooled hypothalami from aged male Norway brown rats treated with 17α-estradiol (O.T), aged male controls (O), and young male controls (Y) were subjected to single-nucleus transcriptomic sequencing (snRNA-seq). To evaluate the effects of 17α-estradiol in anti-aging in neurons, supervised clustering on neurons by neuropeptides and their receptors were used to evaluate the responses of each neuron subtype during aging and after 17α-estradiol treatment. The elevated cellular metabolism, stresses and decreased synaptic activity in neurons initiated by aging were remarkably attenuated by 17α-estradiol. Assessment of changes in neuron populations showed that neurons related to food intake, reproduction, blood pressure, stress response and electrolyte balance were sensitive to 17α-estradiol treatment. 17α-estradiol treatment not only increased Oxytocin (Oxt), but also increased the activity of hypothalamic-pituitary-gonadal (HPG) axis, evidenced by significantly elevated levels of plasma Gnrh, bioavailable testosterone, and decreased estradiol. Elevated Gnrh1 was verified to be one of the causal effects mediating the role of 17α-estradiol in energy homeostasis, neural synapse, and stress response. Notably,Crhneurons displayed most prominently senescent phenotype among all checked neuron subtypes in O.T, which may be a potential side effect of 17α-estradiol treatment. Therefore, HPG axis and energy metabolism may be key targets of 17α-estradiol in male lifespan extension. Additionally, supervised clustering of neurons was shown to be a useful method to assess the responses to treatment among different neuron subtypes in the hypothalamus.

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17α-estradiol does not adversely affect sperm parameters or fertility in male mice: implications for reproduction-longevity trade-offs

Cited by 14 publications

References 50 publications

A Genetically Heterogeneous Rat Model with Divergent Mitochondrial Genomes

A Genetically Heterogeneous Rat Model with Divergent Mitochondrial Genomes

Dasatinib and quercetin increase testosterone and sperm concentration in mice

The effects of 17α-estradiol treatment on endocrine system revealed by single-nucleus transcriptomic sequencing of hypothalamus

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