Fertility Of Female Mice Research Articles

H3K4 Methylation Promotes Expression of Mitochondrial Dynamics Regulators to Ensure Oocyte Quality in Mice.

Significantly decreased H3K4 methylation in oocytes from aged mice indicates the important roles of H3K4 methylation in female reproduction. However, how H3K4 methylation regulates oocyte development remains largely unexplored. In this study, it is demonstrated that oocyte-specific expression of dominant negative mutant H3.3-K4M led to a decrease of the level of H3K4 methylation in mouse oocytes, resulting in reduced transcriptional activity and increased DNA methylation in oocytes, disturbed oocyte developmental potency, and fertility of female mice. The impaired expression of genes regulating mitochondrial functions in H3.3-K4M oocytes, accompanied by mitochondrial abnormalities, is further noticed. Moreover, early embryos from H3.3-K4M oocytes show developmental arrest and reduced zygotic genome activation. Collectively, these results show that H3K4 methylation in oocytes is critical to orchestrating gene expression profile, driving the oocyte developmental program, and ensuring oocyte quality. This study also improves understanding of how histone modifications regulate organelle dynamics in oocytes.

Microcystin-LR inhibits early pregnancy by impairing the vascular network of luteum: Involvement of the MEK/ERK/SP1/VEGFR2 axis.

Microcystin-leucine-arginine (MC-LR) reduces the fertility of female mice, but the mechanism is unknown. We studied the effect of MC-LR on early pregnancy and elucidated its possible mechanism. The number of embryo beds and embryo volume decreased in pregnant mice at 6 or 8 days after fertilization after acute exposure to MC-LR. The corpus luteum secretes estrogen and progesterone, which are involved in embryo implantation and maintenance of early pregnancy. MC-LR exposure reduced luteal blood vessel branches and inhibited hormone synthesis. Functional blood vessels are essential to the maintenance of luteal structure and function. Reduced migration and tube-forming were also detected in human umbilical vascular endothelial cells (HUVECs) treated with MC-LR. MC-LR significantly decreased the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in vivo and in vitro, which was responsible for the inhibited construction of the vascular network. The MEK/ERK/SP1 signal pathway mediated the decrease in VEGFR2 expression, and the agonists of phosphorylated extracellular regulated protein kinases (p-ERK) alleviated the anti-angiogenic effect of MC-LR. In conclusion, we demonstrated the toxicity of MC-LR on construction of vascular network in corpus luteum, which could provide a new perspective on female infertility or miscarriage caused by environmental factors.

FGF21 negatively affects long-term female fertility in mice

ObjectiveObesity and associated liver disease are a growing public health concern. Pharmacological agents to treat non-alcoholic fatty liver disease are limited. FGF21, a hormone secreted by the liver and potent metabolic modulator, is a promising therapeutic target for this indication with several analogs currently in clinical development. However, concerns about a negative effect of FGF21 on female fertility have not been fully addressed. MethodsAfter induction of obesity, female C57BL/6N mice received a 7-day course of subcutaneously administered FGF21. Control groups received either high-fat diet (HFD) or a normal diet (ND). The mothers were then mated with lean males for 12 weeks. The estrous cycle was recorded for two weeks after breeding. The metabolic phenotype, liver steatosis and reproductive organs were assessed at sacrifice 14 weeks after treatment. ResultsA short-course treatment of FGF21 leads to weight reduction during treatment but has no long-term impact on liver steatosis. A treatment with FGF21 leads to a reduction in the number of pregnancies (0 vs 1, p = 0.019) and no viable pup was born to a mother previously treated with FGF21. The FGF21 treatment affected the number of cycles (1 vs 3, p = 0.048) and amount in diestrus (54 vs 75%, p = 0.008) 12 weeks after the treatment. Additionally, the number of corpora lutea (0.8 vs 3.0, p = 0.016), and mature follicles (0 vs 1, p = 0.037) was reduced compared to the ND group while uterine histology remained unaffected. ConclusionA short-term treatment with FGF21 has a long-term effect on female fertility in mice. This represents a potential safety concern for FGF21 analogs currently in clinical development. Reproductive health outcomes should be included in upcoming clinical trials.

Multigenerational Effects of an Environmentally Relevant Phthalate Mixture on Reproductive Parameters and Ovarian miRNA Expression in Female Rats.

Phthalates are endocrine-disrupting chemicals used in many consumer products. Our laboratory previously developed an environmentally relevant phthalate mixture consisting of 6 phthalates and found that it disrupted female fertility in mice. However, it was unknown if maternal exposure to the mixture affects reproductive parameters and ovarian post-transcription in the F1 and F2 generation of female rats. Thus, we tested the hypothesis that maternal exposure to the phthalate mixture affects folliculogenesis, steroidogenesis, and ovarian microRNA (miRNA) in the F1 and F2 generations of female rats. Pregnant female rats were divided into 4 groups and orally dosed daily from gestational day 10 to postnatal day 21 with corn oil (control group), 20 μg/kg/day, 200 μg/kg/day, or 200 mg/kg/day of the phthalate mixture. Maternal exposure to the phthalate mixture impaired folliculogenesis in the F1 and F2 generations of female rats and affected steroidogenesis in the F1 generation of female rats compared to control. Further, the phthalate mixture altered ovarian expression of some genes related to the cell cycle and steroidogenesis compared to control in the F1 and F2 generations of female rats. The mixture also increased ovarian expression of rno-mir-184 that is involved with the oocyte maturation process. Collectively, our data show that maternal exposure to the phthalate mixture affects folliculogenesis and steroidogenesis in the F1 and F2 generations of female rats and alters ovarian miRNA expression in the F1 generation of female rats.

HIF1α is dispensable for oocyte development and female fertility in mice.

BackgroundIt has been thought that oocyte may develop in a low oxygen environment, as changes in follicle structure and formation of a fluid-filled antrum. The survival of hypoxic tissues is controlled by hypoxia-inducible factors (HIFs) that are activated in a low oxygen state. HIF1α is expressed in mature mouse oocytes and continues to be expressed after fertilization, from the 2-cell to blastocyst stage. However, the physiological roles of HIF pathway during oogenesis and embryogenesis have still not been elucidated in detail.MethodsMutant mice with oocyte-specific HIF1α deletion were generated by crossing Hif1αfl/fl mice with transgenic mice expressing Gdf9-promoter-mediated Cre recombinase. Breeding assay was carried out to detect female fertility. In vitro fertilization and embryo culture were used to assess early embryo development. Oocyte meiotic progression was also examined. Quantitative RT-PCR was used for analyzing of candidate genes expression.ResultsWe successfully generated mutant mice with oocyte-specific deletion of HIF1α. Oocytes loss of HIF1α did not affect female fertility, ovulation and early embryo development. Moreover, oocytes can mature in vitro, and form well-organized spindle in the absence of HIF1α. In addition, pronounced differences in Hif2α and Hif3α mRNA expression were not observed in HIF1α-deleted oocytes. These results revealed that HIF pathway in oocytes is not essential for female fertility.

Thada Is Dispensable for Female Fertility in Mice.

Genome-wide association studies (GWAS) have identified THADA as one of the susceptibility genes for polycystic ovary syndrome (PCOS). Single nucleotide polymorphisms (SNPs) in the THADA gene showed significant over-transmission in PCOS and strong correlations with testosterone level. However, there was insufficient evidence to verify the effect of THADA in vivo on female reproductive system. In this study, we investigated the impacts of Thada ablation on ovarian function and reproductive outcomes with knockout (KO) mice. The results showed that the Thada deletion was insufficient to affect ovarian folliculogenesis, steroidogenesis, and female fertility. Additionally, we stressed the mice with high-fat-high-sugar diet (HFHS). In this case, the KO mice still merely had a negligible impact on ovarian function. These findings indicated that Thada deficiency was dispensable for female fertility in mice, which enriched our knowledge about in vivo functions of PCOS susceptibility genes.

Mild calorie restriction, but not 17α-estradiol, extends ovarian reserve and fertility in female mice.

Calorie restriction (CR) (25-40%) is the most commonly studied strategy for curtailing age-related disease and has also been found to extend reproductive lifespan in female mice. However, the effects of mild CR (10%), which is sustainable, on ovarian aging has not yet been addressed. 17α-estradiol (17α-E2) is another intervention shown to positively modulate healthspan and lifespan in mice but its effects on female reproduction remain unclear. We evaluated the effects of mild CR (10%) and 17α-E2 treatment on ovarian reserve and female fertility over a 24-week period, and compared these effects with the more commonly employed 30% CR regimen. Both 10% and 30% CR elicited positive effects on the preservation of ovarian reserve, whereas 17α-E2 did not alter parameters associated with ovarian function. Following refeeding, both 10% and 30% increased fertility as evidenced by greater pregnancy rates. In aligned with the ovarian reserve data, 17α-E2 also failed to improve fertility. Collectively, these data indicate that 10% CR is effective in preserving ovarian function and fertility, while 17α-E2 does not appear to have therapeutic potential for delaying ovarian aging.

P140Cap Controls Female Fertility in Mice Acting via Glutamatergic Afference on Hypothalamic Gonadotropin-Releasing Hormone Neurons.

p140Cap, encoded by the gene SRCIN1 (SRC kinase signaling inhibitor 1), is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. p140Cap knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus cycle, reduced ovulation, and defective production of luteinizing hormone and estradiol during proestrus. We investigated the role of p140Cap in the development and maturation of the hypothalamic gonadotropic system. During embryonic development, migration of Gonadotropin-Releasing Hormone (GnRH) neurons from the nasal placode to the forebrain in p140Cap KO mice appeared normal, and young p140Cap KO animals showed a normal number of GnRH-immunoreactive (-ir) neurons. In contrast, adult p140Cap KO mice showed a significant loss of GnRH-ir neurons and a decreased density of GnRH-ir projections in the median eminence, accompanied by reduced levels of GnRH and LH mRNAs in the hypothalamus and pituitary gland, respectively. We examined the number of kisspeptin (KP) neurons in the rostral periventricular region of the third ventricle, the number of KP-ir fibers in the arcuate nucleus, and the number of KP-ir punctae on GnRH neurons but we found no significant changes. Consistently, the responsiveness to exogenous KP in vivo was unchanged, excluding a cell-autonomous defect on the GnRH neurons at the level of KP receptor or its signal transduction. Since glutamatergic signaling in the hypothalamus is critical for both puberty onset and modulation of GnRH secretion, we examined the density of glutamatergic synapses in p140Cap KO mice and observed a significant reduction in the density of VGLUT-ir punctae both in the preoptic area and on GnRH neurons. Our data suggest that the glutamatergic circuitry in the hypothalamus is altered in the absence of p140Cap and is required for female fertility.

Addition of a carboxy-terminal tail to the normally tailless gonadotropin-releasing hormone receptor impairs fertility in female mice.

Gonadotropin-releasing hormone (GnRH) is the primary neuropeptide controlling reproduction in vertebrates. GnRH stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis via a G-protein-coupled receptor, GnRHR, in the pituitary gland. In mammals, GnRHR lacks a C-terminal cytosolic tail (Ctail) and does not exhibit homologous desensitization. This might be an evolutionary adaptation that enables LH surge generation and ovulation. To test this idea, we fused the chicken GnRHR Ctail to the endogenous murine GnRHR in a transgenic model. The LH surge was blunted, but not blocked in these mice. In contrast, they showed reductions in FSH production, ovarian follicle development, and fertility. Addition of the Ctail altered the nature of agonist-induced calcium signaling required for normal FSH production. The loss of the GnRHR Ctail during mammalian evolution is unlikely to have conferred a selective advantage by enabling the LH surge. The adaptive significance of this specialization remains to be determined.

Deletion of Gremlin-2 alters estrous cyclicity and disrupts female fertility in mice†.

Members of the differential screening-selected gene aberrative in neuroblastoma (DAN) protein family are developmentally conserved extracellular binding proteins that antagonize bone morphogenetic protein (BMP) signaling. This protein family includes the Gremlin proteins, GREM1 and GREM2, which have key functions during embryogenesis and adult physiology. While BMPs play essential roles in ovarian follicle development, the role of the DAN family in female reproductive physiology is less understood. We generated mice null for Grem2 to determine its role in female reproduction in addition to screening patients with primary ovarian insufficiency (POI) for variants in GREM2. Grem2-/- mice are viable, but female Grem2-/- mice have diminished fecundity and irregular estrous cycles. This is accompanied by significantly reduced production of ovarian anti-Müllerian hormone (AMH) from small growing follicles, leading to a significant decrease in serum AMH. Surprisingly, as AMH is a well-established marker of the ovarian reserve, morphometric analysis of ovarian follicles showed maintenance of primordial follicles in Grem2-/- mice like wild-type (WT) littermates. While Grem2 mRNA transcripts were not detected in the pituitary, Grem2 is expressed in hypothalami of WT female mice, suggesting the potential for dysfunction in multiple tissues composing the hypothalamic-pituitary-ovarian axis that contribute to the subfertility phenotype. Additionally, screening 106 women with POI identified one individual with a heterozygous variant in GREM2 that lies within the predicted BMP-GREM2 interface. In total, these data suggest that Grem2 is necessary for female fecundity by playing a novel role in regulating the HPO axis and contributing to female reproductive disease.

The transcription factors SIX3 and VAX1 are required for suprachiasmatic nucleus circadian output and fertility in female mice.

The homeodomain transcription factors sine oculis homeobox 3 (Six3) and ventral anterior homeobox 1 (Vax1) are required for brain development. Their expression in specific brain areas is maintained in adulthood, where their functions are poorly understood. To identify the roles of Six3 and Vax1 in neurons, we conditionally deleted each gene using Synapsincre , a promoter targeting maturing neurons, and generated Six3syn and Vax1syn mice. Six3syn and Vax1syn females, but not males, had reduced fertility, due to impairment of the luteinizing hormone (LH) surge driving ovulation. In nocturnal rodents, the LH surge requires a precise timing signal from the brain's circadian pacemaker, the suprachiasmatic nucleus (SCN), near the time of activity onset. Indeed, both Six3syn and Vax1syn females had impaired rhythmic SCN output, which was associated with weakened Period 2 molecular clock function in both Six3syn and Vax1syn mice. These impairments were associated with a reduction of the SCN neuropeptide vasoactive intestinal peptide in Vax1syn mice and a modest weakening of SCN timekeeping function in both Six3syn and Vax1syn mice. Changes in SCN function were associated with mistimed peak PER2::LUC expression in the SCN and pituitary in both Six3syn and Vax1syn females. Interestingly, Six3syn ovaries presented reduced sensitivity to LH, causing reduced ovulation during superovulation. In conclusion, we have identified novel roles of the homeodomain transcription factors SIX3 and VAX1 in neurons, where they are required for proper molecular circadian clock function, SCN rhythmic output, and female fertility.

Physiological and pathological functions of βB2-crystallins in multiple organs: a systematic review.

Crystallins, the major constituent proteins of mammalian lenses, are significant not only for the maintenance of eye lens stability, transparency, and refraction, but also fulfill various physiopathological functions in extraocular tissues. βB2-crystallin, for example, is a multifunctional protein expressed in the human retina, brain, testis, ovary, and multiple tumors. Mutations in the βB2 crystallin gene or denaturation of βB2-crystallin protein are associated with cataracts, ocular pathologies, and psychiatric disorders. A prominent role for βB2-crystallins in axonal growth and regeneration, as well as in dendritic outgrowth, has been demonstrated after optic nerve injury. Studies in βB2-crystallin-null mice revealed morphological and functional abnormalities in testis and ovaries, indicating βB2-crystallin contributes to male and female fertility in mice. Interestingly, although pathogenic significance remains obscure, several studies identified a clear correlation between βB2 crystallin expression and the prognosis of patients with breast cancer, colorectal cancer, prostate cancer, renal cell carcinoma, and glioblastoma in the African American population. This review summarizes the physiological and pathological functions of βB2-crystallin in the eye and other organs and tissues and discusses findings related to the expression and potential role of βB2-crystallin in tumors.

Radiation‐induced effects in the Organs of the Reproductive and Endocrine Systems of Mice

In connection with the radioactive contamination of territories as a result of atomic explosions, the activities of enterprises for the extraction, processing and storage of radioactive materials, as well as emergency radioactive contamination, it is urgent to study the biological consequences of chronic exposure to ionizing radiation in low doses. We studied the effect of chronic gamma irradiation (10-30 cGy) on the fertility of female Af line mice, on the cytogenetic state of male germ cells, and also investigated the stability of the genome in thyroid cells. The experiments were carried out on animals from the Scientific Collection of Experimental Animals (http://www.ckp-rf.ru/usu/471933/). It was found that the chronic action of ionizing radiation in low doses leads to an increase in the fertility of female mice (20 and 30 cGy). It was found that 4 months after irradiation, the number of abnormal sperm heads and the level of micronuclei in thyroid cells were the same as in the control. In the long term after irradiation of mice at doses of 20 and 30 cGy, a decrease in the number of cells with double-stranded DNA breaks was found in the thyroid gland. Irradiation of mice at a dose of 10 cGy did not change the level of DNA fragmentation in the thyroid gland. It was shown that irradiation of animals in a chronic mode contributed to a change in the sensitivity of thyroid cells to an additional load of urethane. We found in thyroid cells after exposure to urethane a decrease in DNA double-strand breaks in control mice, whereas in irradiated animals there was an increase in DNA fragmentation in the cells. Thus, the effectiveness of chronic exposure to ionizing radiation at doses of 20 and 30 cGy was found, which was manifested in an increase in fertility in female mice and in a change in the stability of the thyroid gland cell genome. We think that in order to identify biological effects in the field of low doses of ionizing radiation, it is necessary to apply research methods at different levels of the structural organization of the organism.

Mitochondrial Stress Response Gene Clpp Is Not Required for Granulosa Cell Function.

Mitochondrial unfolded protein response (UPRmt) is a highly conserved mechanism, which is activated upon cellular or metabolic stress and aims to help cells maintain homeostasis. CLPP (caseinolytic peptidase P) plays a crucial factor for UPRmt; it promotes the degradation of unfolded mitochondrial proteins. Global germline deletion of Clpp in mice results in female infertility and accelerated follicular depletion. Here, we asked whether CLPP is necessary for granulosa/cumulus cell function. Clppflox/flox mice were generated and crossbred with Cyp19a1-Cre mice to generate mice with granulosa/cumulus cell-specific Clpp deletion (Clpp−/−). Mature (8-week-old) Clpp−/− female mice (8-week-old) were compared to same age wild type (WT) mice. We found that mature Clpp−/− female mice were fertile and produced a similar number of pups per litter compared to WT. Folliculogenesis was not affected by the loss of CLPP in granulosa/cumulus cells as Clpp−/− and WT mice had a similar number of primordial, primary, secondary, early antral, and antral follicles. The number of germinal vesicles (GV) and MII oocytes collected from Clpp−/− and WT female mice were also similar. Our findings demonstrate that fertility in female mice is not affected by granulosa/cumulus cell-specific UPRmt disruption through CLPP deletion.

TMEM150B is dispensable for oocyte maturation and female fertility in mouse

Premature ovarian insufficiency (POI) refers to severe decline of ovary function in females which usually leads to infertility. It has been reported that the TMEM150B gene is mostly associated with age at natural menopause, early menopause and POI, but its role in female reproduction remains unknown. In this study, we found Tmem150b was highly expressed in mouse oocytes, but its deletion had no obvious effect on meiotic maturation of oocytes indicated by first polar body emission and spindle morphology. There were also no obvious differences in follicle development and corpus luteum formation between knockout and wild type mice. Finally, knockout of Tmem150b did not affect female fertility and sexual hormone levels. In summary, our results suggest that TMEM150B is not essential for female fertility in mice.

Ablation of TGFBR3 (betaglycan) in oocytes does not affect fertility in female mice.

Ovarian follicle development is regulated by locally produced TGFβ superfamily members. The TGFβ type III receptor (TGFBR3, or betaglycan), which regulates the actions of diverse TGFβ ligands, including inhibins, is expressed in different ovarian cell types. However, its functional roles in the ovary have not been investigated in vivo. Here, we ablated Tgfbr3 in murine oocytes using the Cre-loxP system. Oocyte-specific Tgfbr3 knockout (cKO) females were fertile, producing litters of similar size and frequency as controls. Their ovarian weights and histology were also normal. Though we confirmed efficient recombination of the floxed alleles, we did not detect Tgfbr3 mRNA in purified oocytes from superovulated cKO or control mice. These results challenge earlier observations of betaglycan protein expression in this cell type. Regardless, Tgfbr3 in the murine oocyte is clearly dispensable for female fertility.

Effect of tramadol on ovaries of female mice

Tramadol hydrochloride (TrHC) is considered a synthetic analgesic drug, showing opioid and non- opioid characteristics, the central nervous system is the main system affected by it . It is used to relieve pain, but it can be used to treat other neurotic and psychotic diseases as well(1). These characteristics comes from that TrHC acts on opioid receptors, having a weak agonistic effect, and it affects monoamine receptors by blockage of noradrenaline (NE) and serotonin (5-HT) reuptake, this will lead to the suppression of pain transmission in the nervous system(2,3).Frequent studies concentrated on the effects of TrHC on the functions of the testis with carelessness to its effects on the functions of the ovaries. So the aim of this study was to investigate the effects of tramadol hydrochloride (TrHC) on female reproductive function, ovarian toxicity and examine the morphology of the ovaries of mice exposed to tramadol hydrochloride (TrHC). Forty female mice were divided randomly into two groups of 20: one control group and one (TrHC) treated group. The TrHC treated group received 100mg per kilogram body weight of TrHC for 2months.The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, and progesterone (P)were measured. Evaluation of the ovaries was conducted after staining with hematoxylin-eosin, and immunohistochemical studies. The concentration of reproductive hormones was significantly lower in the (TrHC)-treated group. In addition, the total number of follicles of all types was significantly lower in the (TrHC) -treated group. These results suggest that female reproductive function is inhibited by(TrHC). TrHC may thus significantly reduce the fertility of female mice.

Prenatal exposure to an environmentally relevant phthalate mixture accelerates biomarkers of reproductive aging in a multiple and transgenerational manner in female mice

Phthalates are known endocrine-disrupting chemicals that are found in many consumer products. Our laboratory previously developed a relevant phthalate mixture consisting of six phthalates and found that it disrupted female fertility in mice. However, it is unknown if prenatal exposure to phthalate mixtures can accelerate reproductive aging and if this occurs in multiple generations. Thus, we tested the hypothesis that prenatal exposure to a mixture of phthalates accelerates biomarkers of reproductive aging in multiple generations of female mice. Pregnant CD-1 mice were orally dosed with vehicle control or a phthalate mixture (20 μg/kg/day-500 mg/kg/day) daily from gestational day 10 to birth. Adult F1 females born to these dams were used to create the F2 and F3 generations by mating them with unexposed males. At 13 months, estrous cyclicity was monitored and ovaries and sera were collected for analysis. In the F1 generation, the mixture decreased testosterone and inhibin B levels, but increased follicle-stimulating hormone and luteinizing hormone levels compared to control. In the F2 generation, the phthalate mixture decreased the percent of antral follicles and testosterone hormone levels compared to control. In the F3 generation, prenatal exposure to the phthalate mixture increased ovarian weight, increased the time in metestrus/diestrus, altered follicle numbers, and decreased the levels of luteinizing hormone compared to control. Collectively, these data suggest that prenatal exposure to a phthalate mixture may accelerate several biomarkers of reproductive aging in a multi- and transgenerational manner in female mice.

A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice.

Reduced fertility is a common clinical feature of the individuals with Fanconi anemia (FA), a rare autosomal recessive disorder due to deficiency in FA pathway during DNA repair. Our previous study reported that the heterozygous pathogenic variants in FANCA (Fanconi anemia complementation group A) induced premature ovarian insufficiency (POI). However, the genotype-phenotype correlation in POI caused by FANCA variants remains considerably uncertain. Herein, a heterozygous non-frameshift Fanca-mutated mouse strain (Fanca+/hypo) carrying a 9-bp deletion (c.3581del9, p.QEA1194-1196del) was generated. The mutant mice exhibited slightly decreased Fanca protein level in ovaries, suggesting the non-frameshift deletion mutant is hypomorphic. Female fertility test showed decreased number of litters, litter sizes and prolonged litter interval time in the female Fanca+/hypo mice compared to wild-type mice. Follicle counting revealed a consistent decreasing pattern of follicle numbers in Fanca+/hypo females compared to that in wild-type mice with aging. Furthermore, embryonic fibroblasts of Fanca+/hypo mice were hyper-responsive to Mitomycin C in vitro, demonstrating a partial loss of function of this hypomorphic Fanca mutant in DNA repair. Collectively, our experimental observations suggest that the hypomorphic Fanca allele is sufficient to reduce female fertility in mice, providing new insights into the genetic counseling of FANCA variants in subfertile women.

Lead exposure activates the Nrf2/Keap1 pathway, aggravates oxidative stress, and induces reproductive damage in female mice

Lead, a common metallic contaminant, is widespread in the living environment, and has deleterious effects on the reproductive systems of humans and animals. Although numerous toxic effects of lead have been reported, the effects and underlying mechanisms of the impacts of lead exposure on the female reproductive system, especially oocyte maturation and fertility, remain unknown. In this study, mice were treated by gavage for seven days to evaluate the reproductive damage and role of Nrf2-mediated defense responses during lead exposure. Lead exposure significantly reduced the maturation and fertilization of oocytes in vivo. Additionally, lead exposure triggered oxidative stress with a decreased glutathione level, increased amount of reactive oxygen species, and abnormal mitochondrial distribution. Moreover, lead exposure caused histopathological and ultrastructural changes in oocytes and ovaries, along with decreases in the activities of catalase, glutathione peroxidase, total superoxide dismutase, and glutathione-S transferase, and increases in the levels of malonaldehyde in mouse ovaries. Further experiments demonstrated that lead exposure activated the Nrf2 signaling pathway to protect oocytes against oxidative stress by enhancing the transcription levels of antioxidant enzymes. In conclusion, our study demonstrates that lead activates the Nrf2/Keap1 pathway and impairs oocyte maturation and fertilization by inducing oxidative stress, leading to a decrease in the fertility of female mice.