How Telomere Dysfunction Affects Female Fertility (A Mouse Study)

In a new study, researchers aimed to reveal a link between telomere dysfunction, ovarian aging and infertility using a mouse model of accelerated-reproductive senescence.

Telomeres are the protective caps at the ends of chromosomes that prevent DNA damage and maintain genomic stability. However, telomeres shorten with each cell division and eventually reach a critical length that triggers cellular senescence or death. Telomere length (TL) and telomerase activity (TA), the enzyme that replenishes telomeric repeats, are influenced by genetic and environmental factors and vary among tissues and individuals.

“Telomere attrition has been identified as one of the molecular determinants of aging [7].”

Telomere dysfunction has been implicated in various age-related diseases, including infertility. Ovarian aging is the main cause of infertility in women, as it leads to a decline in both the quantity and quality of oocytes. Previous studies have shown that TL and TA are reduced in oocytes and granulosa cells of women with diminished ovarian reserve or poor response to ovarian stimulation. Moreover, TL and TA have been associated with ovarian reserve markers and pregnancy outcomes in assisted reproductive technologies.

To better understand the molecular mechanisms underlying ovarian aging and infertility, researchers Alba M. Polonio, Marta Medrano, Lucía Chico-Sordo, Isabel Córdova-Oriz, Mauro Cozzolino, José Montans, Sonia Herraiz, Emre Seli, Antonio Pellicer, Juan A. García-Velasco, and Elisa Varela from The Health Research Institute La Fe (IIS La Fe), IVIRMA Rome, New Jersey and Madrid, Centro Anatomopatológico, Yale School of Medicine, University of Valencia, and Rey Juan Carlos University conducted a new study using a mouse model of accelerated aging: the Senescence-Accelerated Mouse Prone 8 (SAMP8). On May 23, 2023, their research paper was published in Aging’s Volume 15, Issue 11, entitled, “Impaired telomere pathway and fertility in Senescence-Accelerated Mice Prone 8 females with reproductive senescence.”

The Study

The SAMP8 mouse model, which has previously been suggested as an Alzheimer’s disease model of aging, also exhibits a shortened estrous cycle, elevated follicle-stimulating hormone (FSH) levels, and reduced fertility in females at just seven months of age. SAMP8 mice have a shorter lifespan compared to senescence-accelerated mouse resistant 1 (SAMR1) mice. SAMR1 mice do not exhibit reproductive senescence. Thus, the researchers deemed the SAMR1 mouse model an appropriate control group to study the SAMP8 mouse model as a model of ovarian aging and infertility. 

“In the current study, we sought to investigate whether the SAMP8 mice, which show accelerated-reproductive senescence, have alterations in their telomere pathway. This question has not yet been explored in relation to reproduction in this model.”

In this study, the team compared the TL and TA in blood and ovary samples from the SAMP8 female mice at seven months of age (when they show signs of reproductive senescence) with age-matched control SAMR1 mice. They also evaluated the ovarian follicle development, the expression of telomerase subunits (TERT and TERC), and the reproductive outcomes after ovarian stimulation in both groups of mice. In sum, the researchers measured survival rates (in male and female mice), alteration in the telomere pathway at seven months of age, TERT and TERC expression levels, TA on the TL of granulosa cells in developing follicles, and impairment/alterations in the telomere pathway in oogenesis and embryo development.

The results revealed that SAMP8 females had a reduced median lifespan compared to SAMP8 males and SAMR1 males and females. In blood, SAMP8 females had lower mean TL and higher accumulation of short telomeres than the other mice. In ovary, SAMP8 females had lower TA and TERT expression. Furthermore, SAMP8 females had fewer primordial, primary, secondary, and antral follicles than control females, indicating a diminished ovarian reserve. After ovarian stimulation, SAMP8 females had a lower number of oocytes than controls of the same age. Their results suggested that oogenesis and embryo development is impaired in SAMP8 mice at seven months compared to age-matched controls, and this coincides with alterations in the telomere pathway.


“Thus, SAMP8 females represent a bona fide model for the analysis of fertility, not only because it shows similar phenotype to middle-aged women as stated earlier [43], but also because the alterations in the telomere pathway are found in women with fertility disorders [37, 38, 40, 41] and this pathway links reproduction with longevity.”

The researchers concluded that SAMP8 females have impaired telomere pathway and fertility, reflecting signs of reproductive senescence described in middle-aged women. They suggested that the SAMP8 model could be useful in studying the role of telomere dysfunction in ovarian aging and infertility. In addition, this mouse model could be used to test potential therapeutic interventions to improve female reproductive health.

“Understanding the molecular pathways underlying aging and fertility, provides a basis for further studies focused on several topics. First, the analysis of embryo alterations, which can be better assessed in mice than in humans. Second, how reproductive lifespan improvement may ameliorate elderly health. And third, the mechanisms underlying follicle recruitment and development, which are not completely known.”

Click here to read the full research paper published by Aging.

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Unborn Children Exposed to Common Chemical Leads to Fertility Defects

In a trending new study, researchers investigated a common chemical and its multigenerational effects on fertility and ovarian function.

Unborn Children Exposed to Common Chemical Leads to Fertility Defects

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The food, beverages and products that women are exposed to before and during pregnancy can have lifelong consequences for babies in the womb. This concept is known as fetal programming. Introducing endocrine-disrupting chemicals (EDCs; toxins) during critical moments of fetal development can significantly impact the child’s health, development and fertility. These negative impacts may even compound in future generations.

“However, our understanding of the negative effects of chemicals on health in women is less than those in men [24].”


Frying, roasting or baking starchy food at high temperatures produces a Maillard reaction. A problematic result of this reaction is the formation of a chemical compound called acrylamide (ACR). Acrylamide can be found in many common foods, including french fries, chips, bread, crackers, coffee, and so on. Exposure to this chemical during pregnancy has been linked to reduced development and reproductive function.

“Based on the formation of ACR in food during high temperatures and its presence in water and cosmetics [25, 26], this potential EDC may constitute a major problem for human health and could notably affect female fertility by influencing the ovary structure and function.”

While the effects of ACR in-utero have been documented, researchers Nouf Aldawood, Maroua Jalouli, Abdulkarem Alrezaki, Saber Nahdi, Abdullah Alamri, Mohamed Alanazi, Salim Manoharadas, Saleh Alwasel, and Abdel Halim Harrath from King Saud University wondered how exposure to acrylamide impacts health, development and fertility after a second generation. In a new study, the team investigated exposure to this toxin and its effects on ovarian function over the course of two generations of rats. On September 6, 2022, their research paper was published in Aging’s Volume 14, Issue 17, and entitled, “Fetal programming: in utero exposure to acrylamide leads to intergenerational disrupted ovarian function and accelerated ovarian aging.”

The Study

“In our current study, the focus was on the effect of ACR during pregnancy on the ovarian function extended over two successive generations as the ovaries are considered one of the most sensitive organs to toxic substances and exposure during the fetal stage.”

The researchers raised 20 healthy female Wistar-Albino rats and mated them. Between gestation days six and 21 (delivery), five pregnant rats were dosed daily with distilled water (the control group; no ACR), five pregnant study rats were dosed daily with 2.5 mg/kg of ACR, five pregnant study rats were dosed with 10 mg/kg of ACR, and the last five pregnant rats were dosed with 20 mg/kg of ACR. Offspring exposed to ACR, or animals of the first generation (AF1), were collected, as were the offspring of the control group (CF1). Blood samples were collected and ovaries were assessed at four weeks of age. AF1 and CF1 rats were raised until maturity and mated again. All pregnant rats were dosed depending on what/how much their mother received. The AF1 and CF1 rats gave birth to the second generation: the AF2 and CF2 offspring. Again, blood samples were collected and ovaries were assessed at four weeks of age. 


The researchers found that the first generation of offspring from the rats dosed with ACR (AF1) had ovaries that weighed significantly more than those in the control group (CF1). Upon histoarchitecture examination of the ovaries, this weight increase may have been caused by ovarian cysts that were identified within the AF1 rats and indicated a disruption in ovarian function. Interestingly, the results were quite different in AF2 rats. The researchers were surprised to find that prenatal ACR exposure in the second generation decreased ovarian weights and increased estradiol levels, CYP19 mRNA levels and CYP19 protein expression in all three study groups. These findings in the AF2 rats indicated early ovarian aging.

“In this study, we found that the first generation reacted differently from the second generation. Indeed, maternal exposure to ACR caused an ovarian disruption in AF1 as evidenced by severe histopathological damage, development of cysts, and high apoptosis in the stroma cells, and decreased plasmatic estradiol levels and its corresponding CYP19 gene and protein expression. However, it has induced early ovarian aging in AF2 characterized by high estradiol and progesterone levels, upregulation of CYP19, and apoptotic cell death in the stroma.”


“Altogether, the present study suggests that the in utero multigenerational exposure to ACR highly reduced fertility and ovarian function in females of the first generation, while it has induced early ovarian aging in females of the second generation.”

This may be the world’s first study to examine the multigenerational impact of ACR exposure on ovarian function and fertility in female rat offspring. This study provides evidence that in-utero exposure to ACR can lead to ovarian dysfunction and accelerated ovarian aging. Ovarian aging is not only a potential barrier to fertility but also a major risk factor for ovarian cancer. Women should take fetal programming into grave consideration when pregnant. Results from this study have important implications for human health and fertility.

“Moreover, this study provides some interesting evidence for the eventual implication of the epigenetic impacts of endocrine disruptors on female reproduction across generations. Future studies, using genome wide DNA methylation approaches for some specific key biomarkers of ovarian development, such as CYP19, are fundamental to determine how prenatal exposure to endocrine disruptors could drive adverse secondary phenotypic effects among the future generations in both humans and animals.”

Click here to read the full research paper published by Aging.

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