The most common epigenetic modification of messenger RNAs (mRNAs) is N⁶-methyladenosine (m⁶A), which is mainly located near the 3′ untranslated region of mRNAs, near the stop codons, and within internal exons. The biological effect of m⁶A is dynamically modulated by methyltransferases (writers), demethylases (erasers), and m⁶A-binding proteins (readers). By controlling post-transcriptional gene expression, m⁶A has a significant impact on numerous biological functions, including RNA transcription, translation, splicing, transport, and degradation. Hence, m⁶A influences various physiological and pathological processes, such as spermatogenesis, oogenesis, embryogenesis, placental function, and human reproductive system diseases. During gametogenesis and embryogenesis, genetic material undergoes significant changes, including epigenomic modifications such as m⁶A. From spermatogenesis and oogenesis to the formation of an oosperm and early embryogenesis, m⁶A changes occur at every step. m⁶A abnormalities can lead to gamete abnormalities, developmental delays, impaired fertilization, and maternal-to-zygotic transition blockage. Both mice and humans with abnormal m⁶A modifications exhibit impaired fertility. In this review, we discuss the dynamic biological effects of m⁶A and its regulators on gamete and embryonic development and review the possible mechanisms of infertility caused by m⁶A changes. We also discuss the drugs currently used to manipulate m⁶A and provide prospects for the prevention and treatment of infertility at the epigenetic level.

Mutations of hemostasis/coagulation-related genes have been speculated to cause recurrent spontaneous abortion (RSA). This study investigated the genetic association between the polymorphisms of factor V (F5), factor II (F2), antithrombin (SERPINC1), protein C (PROC), protein S (PROS1), protein Z (PROZ), factor XIII (F13A1), and carboxypeptidase B2 (CPB2) genes and RSA. The 426 patients with RSA and 444 controls were recruited in this study, and single-nucleotide polymorphisms (SNPs) were analyzed by using SNPscan technology. Genotype and allele frequencies of rs3136520 in F2, rs3024731 in PROZ, and rs1050782 in F13A1 showed statistically significant differences between the 2 groups. TT genotype of rs3136520 (P = .031, odds ratio [OR] = 0.986, 95% confidence interval [CI] = 0.976-0.997) and AA genotype of rs2069906 in PROC (P = .021, OR = 0.114, 95% CI = 0.014-0.902) in their recessive models and AG + GG variants of rs1050782 (P = .007, OR = 0.681, 95% CI = 0.516-0.899) in the dominant model might be associated with the reduced risk of RSA. AT + TT variants of rs3024731 (P = .010, OR = 1.479, 95% CI = 1.098-1.994) may increase disease susceptibility in dominant model. Haplotype analysis of rs3024731 and rs3024735 in PROZ displayed that the AA and TG haplotype were inclined to decrease and increase the risk of RSA, respectively. These results suggested that rs3136520, rs2069906, rs3024731, and rs1050782 may have a significant association with the genetic susceptibility of RSA in Chinese Han women.

3-methyl-4-nitrophenol (PNMC), a degradation product of organophosphorus insecticides and a byproduct of fuel combustion, exerting endocrine-disrupting effects. However, its impact on the meiotic process of oocytes remains unclear. In the present study, we investigated the effects of PNMC on meiotic maturation of mouse oocytes in vitro and related mechanisms. Morphologically, PNMC-exposure affected germinal vesicle breakdown (GVBD) and polar body extrusion (PBE) in mouse oocytes. Proteomic analysis suggested that PNMC-exposure altered oocyte protein expression that are associated with cytoskeleton, mitochondrial function and oxidative stress. Further studies demonstrated that PNMC-exposure disrupted spindle assembly and chromosome alignment, caused sustained activation of spindle assembly checkpoint (SAC), and arrested meiosis in oocytes. Specifically, PNMC-exposure interfered with the function of microtubule organizing centers (MTOCs) by significantly reducing phosphorylated mitogen activated protein kinase (p-MAPK) expression and disrupting the localization of Pericentrin and p-Aurora A, leading to spindle assembly failure. Besides, PNMC-exposure also increased α-tubulin acetylation, decreased microtubule stability. Moreover, PNMC-exposure impaired mitochondrial function, evidenced by abnormal mitochondrial distribution, decreased mitochondrial membrane potential and ATP levels, release of Cytochrome C into the cytoplasm, and elevated ROS levels. As a result, exposure to PNMC caused DNA damage and early apoptosis in oocytes. Fortunately, melatonin was able to promote oocyte maturation by removing the excessive ROS and enhancing mitochondrial function. These results highlight the adverse effects of PNMC on meiotic maturation, and underscore the protective role of melatonin against PNMC-induced damage.

The use of bisphenol A (BPA) has been restricted due to its endocrine-disrupting effects. As a widely used alternative to BPA today, environmental levels of bisphenol Z (BPZ) continue to rise and accumulate in humans. Oocyte quality is critical for a successful pregnancy. Nevertheless, the toxic impacts of BPZ on the maturation of mammalian oocytes remain unexplored. Therefore, the impacts of BPZ and BPA on oocyte meiotic maturation were compared in an in vitro mouse oocyte culture model. Exposure to 150 μM of both BPZ and BPA disrupted the assembly of the meiotic spindle and the alignment of chromosomes, and BPZ exerted stronger toxicological effects than BPA. Furthermore, BPZ resulted in aberrant expression of F-actin, preventing the formation of the actin cap. Mechanistically, BPZ exposure disrupted the mitochondrial localization pattern, reduced mitochondrial membrane potential and ATP content, leading to impaired mitochondrial function. Further studies revealed that BPZ exposure resulted in oxidative stress and altered expression of genes associated with anti-oxidative stress. Moreover, BPZ induced severe DNA damage and triggered early apoptosis in oocytes, accompanied by impaired lysosomal function. Overall, the data in this study suggest that BPZ is not a safe alternative to BPA. BPZ can trigger early apoptosis by affecting mitochondrial function and causing oxidative stress and DNA damage in oocytes. These processes disrupt cytoskeletal assembly, arrest the cell cycle, and ultimately inhibit oocyte meiotic maturation.

Cetylpyridinium chloride (CPC), a widely utilized quaternary ammonium compound, serves as both an antiseptic and antibacterial agent. Previous studies have highlighted its toxic effects across various cell types, including reproductive toxicity. However, the specific impacts of CPC on female reproduction, particularly on early embryonic development, as well as the underlying mechanisms, remain incompletely understood. In this study, we revealed that environmental concentrations of CPC exposure influenced mouse early embryonic development in vitro in a dose-dependent manner. Transcriptomic sequencing identified 3799 differentially expressed genes (DEGs), suggesting that CPC exposure disrupted gene expression in 2-cell embryos. Functional enrichment analysis further revealed that DEGs were significantly involved in pathways and processes related to mitochondrial function, ROS, and gene transcription. In-depth analysis revealed that CPC exposure impeded zygotic genome activation and degradation of maternal effect genes, thereby disrupting the maternal-to-zygotic transition (MZT). Further investigations demonstrated that CPC exposure reduced ATP levels in 2-cell embryos, elevated mitochondrial membrane potential, markedly increased ROS and DHE levels, and heightened DNA damage, indicating mitochondrial dysfunction and oxidative stress. Moreover, CPC exposure altered histone methylation and acetylation modification patterns, marked by elevated levels of H3K9me3 and acH3K27, and decreased levels of H3K27me3 and acH3K9. Overall, CPC exposure below environmental concentrations disrupts MZT by impairing mitochondrial function and histone modifications, ultimately leading to developmental arrest in mouse preimplantation embryos. These findings highlight the potential reproductive toxicity of CPC on female health.

Fine particulate matter (PM_2.5) may disrupt women's reproductive hormones, posing potential reproductive risks. However, the exact compositions of PM_2.5 responsible for these effects remain unclear. Our investigation explored the long-term impacts of PM_2.5 constituents on reproductive hormones, based on a large longitudinal assisted reproductive cohort study in Anhui, China. We included 24,396 reproductive hormone samples from 19,845 women attending assisted reproductive technologies (ART) between 2014 and 2020. Using high-resolution gridded data (1-km resolution), we calculated the residence-specified PM_2.5 constituents during the year before the month of hormone testing. Relationships between PM_2.5 constituents [organic matter (OM), chloride (Cl^-), sulfate (SO₄^2-), ammonium (NH₄⁺), black carbon, and nitrate] and reproductive hormones were investigated using the linear mixed model with subject-specific intercepts. The constituent-proportion model and the constituent-residual model were also constructed. Additionally, cubic spline analysis was used to examine the potential non-linear exposure-response relationship. We found that per interquartile range (IQR) increment in OM was associated with a 5.31 % (3.74 %, 6.89 %) increase in estradiol, and per IQR increment in Cl^- and NH₄⁺ were associated with 13.56 % (7.63 %, 19.82 %) and 9.07 % (4.35 %, 14.01 %) increases in luteinizing hormone. Conversely, per IQR increment in OM and Cl^- were associated with -7.27 % (-9.34 %, -5.16 %) and -8.52 % (-10.99 %, -5.98 %) decreases in progesterone, and per IQR increment in SO₄^2- was associated with a -9.15 % (-10.31 %, -7.98 %) decrease in testosterone. These associations were held in both proportional and residual models. Moreover, exposure-response curves for estradiol and progesterone with PM_2.5 constituents exhibited approximately U-shaped. These results suggested that specific PM_2.5 constituents might disrupt reproductive hormone homeostasis in women attending ART, providing new evidence for formulating PM_2.5 pollution reduction strategies that could benefit women's reproductive health.