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The potential harm of air pollution to human health, especially reproductive health, is a growing concern. Numerous epidemiological and animal studies have shown that PM2.5 exposure is associated with decreased sperm quality and abnormal sperm morphology. In addition, paternal exposure to environmental pollution factors, such as diethylhexyl phthalate (DEHP) and DDT, is known to affect the post-phenotype through epigenetic effects, and may be transmitted across generations.
The study, "Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism," reported in Cell Discovery on April 23, explored the cross-generational and intergenerational effects of PM2.5 (fine particulate matter) in the real-world environment on male-specific primary hypogonadism. Studies have found that paternal exposure to PM2.5 in the real environment can lead to a transgenerational effect of primary hypogonadism in male offspring, which is sex-specific. The study validated this phenotype with external models and found that small RNAs (sRNAs) play a key role in mediating these transgenerational effects. In particular, miR6240 and piR016061, two sRNAs present in F0-generation PM2.5-exposed spermatozoa, regulate intergenerational transmission by targeting Lhcgr and Nsd1 genes. In addition, piR033435 and piR006695 indirectly regulate the methylation level of F1 spermatozoa by binding to the 3' untranslated region of Tet1 mRNA. The decrease in Tet1 expression leads to hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, which impairs the function of Leydig cells and ultimately leads to primary hypogonadism across generations. These findings not only provide insights into the mechanisms by which environmental pollutants such as PM2.5 affect reproductive health in offspring through the paternal pathway, but also highlight the importance of preconception interventions by paternal fathers in mitigating the adverse effects of environmental pollutants on reproductive health. This research is of great significance for public health and environmental policy-making, and provides a scientific basis for reducing the impact of environmental pollution on reproductive health.
Highlights
Cross-generational effect validation: This study is the first to validate the cross-generational effects of PM2.5 in a real-world setting on male-specific primary hypogonadism. Through in-depth research on intergenerational and intergenerational effects, the potential impact that PM2.5 exposure may have on male reproductive health in offspring has been revealed. Sex-specific findings: The results of the study showed that the transgenerational effects exhibited sex-specificity, with primary hypogonadism observed only in offspring males. This finding is important for understanding the impact of environmental pollution on the reproductive systems of different sexes. Regulatory role of sRNA: The critical role of sRNA in mediating transgenerational effects has been verified by external models. In particular, sRNAs such as miR6240 and piR016061 play an important role in regulating key genes in intergenerational transmission, providing a new perspective for understanding epigenetic regulation. Methylation regulation of Tet1 gene: It was found that piR033435 and piR006695 indirectly regulated the methylation level of PM spermatozoa in F1 generation by binding to the 3' untranslated region of Tet1 mRNA. This finding reveals that sRNA is involved in the formation of phenotypes after environmental exposure by regulating gene expression and methylation levels. Importance of paternal interventions: The findings highlight the importance of preconception interventions for paternal generations in mitigating the adverse effects of environmental pollutants on reproductive health. This finding provides a new way of thinking about the development of personalized reproductive health interventions.
模式图(Credit: Cell Discovery)
Strategies
In this study, animal models were used for experiments, and mice were selected as research subjects. The experiment was divided into two phases: exposure and reproduction of the first generation (F0) and second generation (F1) mice.
Exposure method: F0 generation mice were exposed to PM2.5 in the real environment through the respiratory tract to simulate real environmental pollution. Mice are exposed to PM2.5 by suspending PM2.5 in the air using an aerosol generator.
Determination of reproductive parameters: The F1 generation mice were measured in reproductive parameters, including testicular weight, sperm quality and testosterone level. A comprehensive assessment of the reproductive system is carried out through anatomical and laboratory testing methods.
sRNA sequencing and analysis: sRNA from sperm from F0 generation mice was extracted for high-throughput sequencing. The expression patterns of sRNAs in intergenerational transmission were analyzed, and sRNAs with significant regulatory effects on key genes were screened.
Methylation level detection: DNA methylation level in the sperm of F1 generation mice was determined by methylation-sensitive PCR method. The relationship between methylation level and gene expression was analyzed, and the role of methylation regulation in transgenerational effects was explored.
Behind the Scenes
Correlation between PM2.5 exposure and decreased sperm quality and abnormal sperm morphology: There is a relationship between PM2.5 (inhalable particulate matter, particulate matter with a diameter of 2.5 microns or less) exposure and decreased sperm quality and abnormal sperm morphology. Decreased sperm quality: Some studies suggest that long-term exposure to high levels of PM2.5 pollution may lead to decreased sperm quality in men. This decline includes decreased sperm count, decreased motility, and morphological abnormalities. Abnormal sperm morphology: PM2.5 exposure is thought to be associated with abnormal sperm morphology. This morphological abnormality may include head malformations, tail malformations, etc., which affect the normal structure and function of sperm. Mechanism of reproductive toxicity: Harmful chemicals in PM2.5 (such as heavy metals, polycyclic aromatic hydrocarbons, etc.) may enter the bloodstream after inhalation, affecting the normal function of the reproductive system. These chemicals can affect the development of testicles and sperm, leading to decreased sperm quality and abnormal morphology. Inflammation and oxidative stress: PM2.5 exposure can cause inflammation and oxidative stress, affecting the health of the reproductive system. Inflammation and oxidative stress may directly affect sperm morphology and function. Animal studies: Several animal studies also support the relationship between PM2.5 exposure and decreased sperm quality and abnormal sperm morphology. These studies looked at the effects on the reproductive system by exposing experimental animals to different concentrations of PM2.5 and found a certain degree of adverse effects.
The results of the sex-specific study of the cross-generational effect showed that the cross-generational effect of PM2.5 exposure on the reproductive health of offspring showed obvious sex-specificity, and primary hypogonadism was only observed in offspring males. This finding suggests that there may be differences in the effects of environmental exposure on offspring of different genders, and provides a new perspective for the study of sex differences.
Physiological structure and function differencesThere are significant differences in physiological structure and function between male and female reproductive systems. The male reproductive system includes organs such as the testicles, epididymis, whereas the female reproductive system includes organs such as ovaries, uterus, etc. These differences may result in males and females responding differently to environmental factors. The male reproductive system may be more sensitive to environmental factors because organs such as testicles are directly affected by environmental factors such as temperature, chemicals, etc., and are therefore more likely to develop reproductive health problems after exposure.
Differences in sex hormone levels: There are significant differences in sex hormone levels between males and females, such as testosterone, estradiol, etc. These sex hormones play an important role in regulating the development and function of the reproductive system. Different sex hormone levels may result in different responses to environmental exposures in males and females, affecting the performance of reproductive health in offspring.
Validation and further study of these hypothetical factors requires further experiments and studies to validate. Comparing sex differences through experimental design provides a clearer picture of the differences in responses between males and females to environmental exposures. Further research can also explore the regulatory role of sex hormones in the formation of representations after environmental exposure, as well as the mechanisms by which physiological differences in the reproductive system affect reproductive health.
The experimental results of small RNAs (sRNAs) in intergenerational transmission showed that sRNAs such as miR6240 and piR016061 played a key role in the intergenerational effect. These sRNAs may be important regulators of representative pattern formation after environmental exposure. sRNAs such as miR6240 and piR016061 affect the reproductive health of offspring by targeting the expression of key genes. These sRNAs may affect the development and function of the reproductive system by regulating gene expression levels. Through bioinformatics analysis and experimental verification, the interaction between sRNAs such as miR6240 and piR016061 and key genes was determined. These sRNAs may affect reproductive health performance by binding to specific genes and regulating the transcription or translation of genes. The discovery of sRNAs such as miR6240 and piR016061 revealed an important regulatory mechanism in the formation of representative types after environmental exposure. These sRNAs may be molecular regulators of phenotypic formation after environmental exposure, influencing the reproductive health of offspring by regulating the expression levels of key genes. The study of sRNAs such as miR6240 and piR016061 revealed the mechanism of the impact of environmental exposure on the reproductive health of offspring, and also provided an important molecular biological basis for understanding the formation of representative types after environmental exposure. This finding provides new ideas for the development of targeted reproductive health intervention strategies in the future, such as by regulating the expression level of sRNA, which may reduce the adverse effects of environmental exposure on the reproductive health of offspring.
The role of methylation regulation of sRNA on the expression and methylation level of Tet1 gene and its effect on the function of the reproductive system of the offspring were detected by the detection of the expression level and methylation level of Tet1 gene in the exposed and control mice, and the evaluation of the reproductive system function of the offspring. It was found that the expression level of the Tet1 gene changed significantly in F1 mice exposed to PM2.5. Compared with the control group, the expression level of Tet1 gene in the exposed mice may be significantly up-regulated or down-regulated. Similarly, the results showed that the DNA methylation levels of the exposed mice also changed significantly. There may be an increase or decrease in DNA methylation levels, corresponding to changes in Tet1 gene expression levels. The reproductive system function of the offspring mice was further evaluated, and abnormal reproductive system function related to the changes in Tet1 gene expression level and methylation level was found. It is manifested by changes in the weight of reproductive organs, the quality of germ cells, hormone levels, etc. These data reveal the important role of epigenetic modifications in the reproductive health of environmentally exposed offspring. By regulating the expression and methylation level of Tet1 gene, sRNA may lead to abnormal reproductive system function in offspring, which provides a new idea for further study of the effect of environmental exposure on epigenetic regulation.
Potentially Limiting Mouse Model: The study used a mouse model to mimic the effects of human reproductive health. While mice provide a tightly controlled experimental system for biomedical research, mice and humans are physiologically and genetically different, so experimental results may not be fully extrapolated to humans. Environmental Simulation: The PM2.5 exposure in the study was carried out under laboratory conditions, which may not fully replicate the exposure in the natural environment. In the natural environment, people may be exposed to multiple pollutants at the same time, and these pollutants may interact and affect reproductive health in different ways than under laboratory conditions. Longitudinal tracking: This study focused on short-term cross-generational effects and did not conduct long-term follow-up studies. For transgenerational effects, especially epigenetic effects, it is important to understand the effects over time. Long-term tracking can help determine the impact of PM2.5 exposure on future generations across multiple life cycles.
Potential Research Directions: Integrated Environmental Factors: Future research may consider studying PM2.5 alongside other environmental pollutants such as heavy metals and organic pollutants to more comprehensively assess the impact of environmental factors on reproductive health. By simulating exposures closer to the natural environment, it can help to better understand the interaction of different environmental factors and their mechanisms. Long-term and Transgenerational Effects: Research can be extended to longer follow-ups to explore the effects of PM2.5 exposure on multiple generations of offspring. In particular, look at whether these effects will diminish or intensify over time, and whether there are certain critical periods or conditions that can reverse these effects. Epigenetic Regulatory Mechanisms: To explore the specific role of sRNA and other epigenetic factors such as DNA methylation and histone modifications in the phenotyping of PM2.5 exposure. This includes identifying more key molecules, target genes, and their regulatory networks to clarify the role of these molecular regulatory pathways in reproductive health and disease development. Epidemiological Studies and Biomarkers: Epidemiological studies to validate the prevalence of the effects observed in mouse models in the population and explore potential biomarkers. These markers can be used for early diagnosis or to predict the impact of environmental exposures on reproductive health, thereby facilitating the development of prevention and interventions. Intervention Strategy Development: Based on existing mechanistic studies, explore possible intervention strategies, such as antioxidants and molecularly targeted drugs, to mitigate or reverse the adverse effects of environmental exposure on reproductive health. Experimental and clinical studies can help validate the effectiveness and safety of these strategies.
Link to original article
Wei X, Zhang Z, Gu Y, Zhang R, Huang J, Li F, He Y, Lu S, Wu Y, Zeng W, Liu X, Liu C, Liu J, Ao L, Shi F, Chen Q, Lin Y, Du J, Jin G, Xia Y, Ma H, Zheng Y, Huo R, Cao J, Shen H, Hu Z. Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism. Cell Discov. 2024 Apr 23; 10(1):44. doi: 10.1038/s41421-024-00657-0. PMID: 38649348; PMCID: PMC11035589.
https://www.nature.com/articles/s41421-024-00657-0
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