PM2.5 is still an environmental issue of global concern, closely related to human health. PM2.5 carries a large number of chemical substances, bacteria, viruses, etc., which can enter human lungs with respiration, and even enter alveoli and blood, causing oxidative stress, inflammatory reaction and DNA damage in the human body. In addition to harming the respiratory system, digestive system and cardiovascular system, PM2.5 can also adversely affect human reproduction and normal development. It has been confirmed that exposure to PM2.5 can reduce the concentration and activity of male sperm, thereby interfering with sperm-egg binding. PM2.5 exposure to women during pregnancy can increase the incidence of high blood pressure, cause significant changes in germ cells, and increase the probability of premature birth, low birth weight and birth defects in the fetus. Furthermore, there may also be negative influences during the later development, such as obesity, asthma, frail and poor brain development. This review aims to explore the impact of PM2.5 on human reproduction, the health of pregnant women and fetuses, and the development of offspring, to provide some help for the health protection of PM2.5 and the prevention of related diseases.

• PM2.5

• Human reproduction

• Reproductive health

Liu Z, Ge P, Chen M (2022) Research on the Impact of PM2.5 on Human Reproductive Health in Recent Years: A Review. JSM Environ Sci Ecol 10(1): 1078.

PM2.5: Fine particulate matter; IARC: Agency for Research on Cancer; DNA: DeoxyriboNucleic Acid; Pb: lead; Cd: cadmium; Cu: copper; Hg: mercury; As: arsenic; MAPK: Mitogen-activated protein kinase ;ROS: oxygen species ;BTB: blood testosterone barrier; RNA: Ribonucleic Acid; CytC: Cytochrome C; Mn: Manganese; Ni: Nickel; Zn: Zinc; Caspase: Cysteine-requiring Aspartate Protease Caspase; NOS: i- nitric oxide synthase; Apaf1 : apoptotic protease-activating factor-1; FLIPS: FLICE-like inhibitory proteins; FADD: Fas associated death domain; PKR: intracellular protein kinase RNA; Eif-2: eukaryotic translation initiation factor-2; ATF4: activating transcription factor-4; CHOP: CEBP-homologous protein; PTB:Preterm Birth; HDCP: hypertensive disorder complicating pregnancy; PE: Preeclampsia; mtDNA: Mitochondrial DNA; LTL: telomere length

With the rapid development of modern industry and economy, the adverse effects of air pollution on human health have become increasingly obvious, which needs global attention and common governance [1]. PM2.5 is an important air pollutant, and PM2.5 concentration is an important index of air pollution [2-3]. It was reported that PM2.5-dominated pollution days accounted for more than 60 percent of the total pollution days in China in 2015 [4]. The smaller the particle size, the larger the specific surface area, the more harmful substances, viruses and bacteria carried by the particles, and the greater the adverse impact on human health [5]. The 2015 Global Burden of Disease, Injury and Risk Factors study identified PM2.5 as the fifth most important cause of abnormal deaths, 7.2% of global deaths (about 4.2 million people) are caused by exposure to PM2.5 [6]. 90% of people living in cities and towns are exposed to PM2.5 concentrations above 10µg/ m3 , which is estimated to have reduced their life expectancy by 0.98 years [7]. In China, PM2.5 exposure levels were positively correlated with disease risk, each 10 µg/m3 per cent increase in ambient PM2.5 exposure was associated with a 0.30% increase in cardiovascular and respiratory diseases and a 0.22% increase in non-accidental mortality [8].

PM2.5 can carry a large number of chemical substances, bacteria, viruses and soon to the alveoli and deposit in the alveoli. These harmful substances reach the various organs of the body through the blood circulation, which may cause serious diseases of multiple systems [9,10]. These come from transportation sources (diesel, gasoline vehicles), industrial sources (coal, oil and biomass burning in industrial production), domestic sources (cooking, heating and tobacco smoke), as well as secondary organic aerosols and long-distance transport sources [11]. Carbon particles make up 40 to 60 percent of PM2.5 by weight. At present, black carbon is an important urban air pollutant and has been classified as a 2B carcinogen by the International IARC. It is associated with respiratory and cardiovascular diseases and can cause damage to the nervous system, cardiovascular system and reproductive system. Organic matter and heavy metals are also the main components of cell toxicity of particulate matter [12- 15]. Most of the organic pollutants in the fine particulate matter come from combustion sources. Cytotoxicity studies have found that polycyclic aromatic hydrocarbons and their derivatives can reduce cell viability, and some of their components, which can cause DNA damage, oxidative stress and inflammatory responses, are important sources of inducing and carcinogenic chemicals under human exposure to PM2.5 [16-18]. Heavy metals such as Pb, Cd, Cu, Hg, As etc. can cause cell death, bone and nerve damage, and even have genetic toxicity can cause bone, nerve damage, and even have genetic toxicity.

Studies on the toxicology of PM2.5 have been focused on the respiratory system and cardiovascular system, in recent years, the research on reproductive toxicity has been gradually paid attention to and is considered as an important part of the research on human toxicity of PM2.5 [19-21]. PM2.5 enter the human body along with the respiratory system and breaks through the bloodtestosterone barrier and blood-brain barrier [22]. Even at low concentrations, PM2.5 still poses a public health risk [23]. PM2.5 causes defects in the process of reproduction, leading to a decline in the reproductive capacity of exposed people. Studies have found that fertility rates in Both China and the United States have decreased with the increase of PM2.5 concentration in the air [24,25]. Exposure to PM2.5 during sperm production in men leads to a decrease in sperm content in semen and an increase in semen abnormalities [26]. Exposure of pregnant women to PM2.5 can cause pathological changes in placental tissue, affecting reproductive health. Pregnant women are also at increased risk of related diseases that affect fertility [27,28]. PM2.5 exposure causes birth defects in offspring, premature birth, low birth weight and other problems [29]. The overall environment of the world is stable, and the human population is developing rapidly with food health, social welfare and human health. It is estimated that by 2050, the world population will reach 9.6 billion [30]. China’s population is also on the rise. Therefore, it is very important to ensure the safety of childbirth and the healthy growth of newborns, protect the reproductive health of the population and prevent and cure genetic diseases for the healthy and sustainable development of China’s population. At present, many scientists have made research achievements on the impact of PM2.5 on population growth in recent years. But the results are relatively sporadic and lack of systematic summary, some on premature death, some on adverse birth outcomes, and some on effects of fertility [31-33]. When PM2.5 enters the human body, it breaks the barrier structure, induces inflammatory response, causes oxidative stress, affects hormone receptors, leads to cell apoptosis and so on. Understanding these has important reference value for treating the affected population and preventing the harm caused by PM2.5.

Search for keywords PM2.5, reproductive health, etc., in SCIE, AMS and Elsevier databases. Articles on male/male, female/female, fetus/infant, toxic effects of PM2.5 exposure and reproductive health were obtained, and 136 articles were selected and screened. The relationship between PM2.5 and fertility damage was analyzed and summarized. PM2.5 affects the fertility of the human population as a whole by damaging the reproductive capacity of different populations. This paper discusses the effects of PM2.5 exposure on reproductive health of male and female adults, as well as the effects of PM2.5 exposure on fetal and infant health. Studies of each population group have been classified by damage and mechanism studies. The toxicological effects and possible mechanisms of PM2.5 on the human population and fertility status were summarized. This review is expected to help implement some prevention and control measures, reduce the impact of specific pollution sources on fertility, and provide some reference for follow-up research on reproductive health.

Sperm quality and germ cell structure

Male reproductive health is an important aspect of studying the effects of PM2.5 exposure on fertility. A survey of 6,475 ordinary males aged 15 to 49 in Taiwan Province from 2001 to 2014 was conducted [34]. It was found that exposure at both times resulted in lower semen concentration in men. Peking University Third Hospital analyzed 8945 semen samples of young men living in Beijing for a long time from 2015 to 2018. The screened semen was collected from healthy donors free from bad habits (smoking, alcoholism, etc.). It was found that PM2.5 concentration ninety days before collection had an impact on the concentration and activity of the collected sperm [35]. A similar study in a southern Chinese province showed that exposure to PM2.5 may adversely affect semen quality during sperm production, with men’s sperm counts significantly reduced after two weeks of exposure to high levels of PM2.5 [36]. A growing number of studies have shown that PM2.5 exposure adversely affects semen quality.

Hansen et al. [37] not only directly observed the reduction of sperm number and activity caused by PM2.5, but also observed that under exposure to higher concentration of PM2.5, the percentage of abnormal sperm number in total sperm significantly increased, and the risk of structural changes in germ cells increased. Cao et al., [38] studied the possible mechanism of sprem quality problems caused by PM2.5, and found that under PM2.5 exposure, particles enter the body with the respiratory system and break through the blood testosterone barrier, thereby increasing the risk of changes in reproductive cell tissue structure. In the study, experiments on male mice showed changes in epididymis morphology and reduced connectivity between testicular tissues. Qiu et al., [39] Similar study have been conducted that long-term exposure to PM2.5 did not change the weight of the testis and epididymis, but its tissue structure was alienated, vacuolation of sertoli cells and dislocation of immature germ cells in seminal tubules. Long-term exposure to PM2.5 results in structural alienation of the testis and epididymis tissues, vacuolation of sertoli cells and dislocation of immature germ cells in seminal tubules. These studies indicate that the change of germ cell structure can affect the growth and development ability of sperm.

DNA and Hormone secretion

Yang et al. [40] used PM2.5 concentrated samples collected in Shanghai for a 125-day exposure experiment on 12 male mice. It is found that PM2.5 exposure affects all stages of sperm production, and has an impact on the concentration and activity of semen. The experimental group was exposed to concentrated PM2.5, while the control group was exposed to clean filtered air. The control group found that the germ cell structure of the mice in the experimental group was damaged. The study also found that PM2.5 exposure affected the expression of the corresponding mRNA for testosterone production, thereby reducing testosterone production. Exposure to PM2.5 can affect the production of reproductive hormones, or the gonads’ ability to secrete hormones and reduce chronic cell division by affecting the cell cycle and genetics. MAPK signal transduction pathway is the main toxic mechanism of PM2.5 induced sperm injury, which results in significantly reduced fertility and sperm quality of male rats after exposure to PM2.5 [41]. Liu et al. [42]’s study further explored possible toxicological mechanisms. It was found that PM2.5 exposure caused oxidative stress and increased cellular reactive ROS in testicular germ cells. It disrupts the BTB and affects MAPK in germ cells, as well as RNA transcription and factors that regulate antioxidant responses. With the increase of PM2.5 concentration, ROS also increases, which intensifies the oxidative stress response of germ cells and damages sperm production. Xu et al. [43] collected PM2.5 samples from Beijing for exposure experiments on male mice and mouse spermatocytes. The changes of cell structure and abnormal apoptosis of spermatocyte were observed under PM2.5 exposure. The above study also found that the mitochondrial function of germ cells was impaired and the gene expression of some proteins was also affected by exposure to PM2.5. As shown in Figure 1,

Figure 1: Signaling pathways of testicular cell survival and apoptosis. There are three main gene pathways involved in sperm cell apoptosis, namely external pathway, internal pathway and mitochondrial pathway. Mitochondria play an important role in early apoptosis of germ cells. Exposure to PM2.5 affects hormone levels, which leads to inhibition of Cysteine-requiring Aspartate Protease Caspase (Caspase) 2 expression. It also affects the expression of MAPK, resulting in a decrease in i- Nitric Oxide Synthase (NOS) content and an increase in Cytochrome C (CytC) content. CytC can promote the effect of enzyme and enhance the oxidation effect of cells. Other interfering factors lead to changes in the content ratio of apoptotic Bcl-2 family and anti-apoptotic Bcl-2family, which also leads to increased CytC content. An increase in CytC leads to an increase in a apoptotic protease-activating factor-1Apaf-1 (Apaf-1), which stimulates caspase 3 expression and activates apoptosis. PM2.5 expression also leads to apoptosis of external pathways. Adversely affected Sertoli cells produce cellular gene expression products that bind to Spermatogenic cells receptors. The above process can promote the absorption of FLICE-like inhibitory protein FLIPS (FLIPS) and Caspase by Fas associated death domain (FADD) to increase the content of DISC, thus activating the expression of apoptotic genes. The internal pathway of PM2.5 exposure to germ cell apoptosis is mainly related to endoplasmic reticulum stress response. Caspase 12 lyses and thus participates in the influence of mitochondria due to changes in intracellular Ca2+ concentration. Except for Ca2+,intracellular protein kinase RNA (PKR)-like ER kinase (PERK) is affected, resulting in the production of eukaryotic translation initiation factor-2Eif-2 (Eif-2)that activate activating transcription factor-4 (ATF4) and CEBP-homologous protein CHOP (CHOP), leading to increased apoptosis levels.

There are three main gene pathways involved in sperm cell apoptosis, namely external pathway, internal pathway and mitochondrial pathway.

The influence of PM2.5 components

Huang et al. [44] collected and analyzed semen from 1081 men in Wuhan, China from 2014 to 2015, and it was found that heavy metal elements in PM2.5 would lead to a decrease in sperm concentration and sperm activity. Although the concentration of heavy metals in PM2.5 is generally less than 10 percent, it has strong physiological toxicity [45]. such as Cd, Pb, Mn, Ni, Zn and so on. Ingested into the body with respiration, them even passes through the respiratory barrier, enters the bloodstream and enters the circulatory system, further spread to the whole body [46]. Due to its long half-life, heavy metals can accumulate in the human body, affect the development and function of the male reproductive system, and aggravate the pathological changes of testicular tissue, including twisting of seminiferous tubules, stromal atrophy and spermatocyte apoptosis, etc. Heavy metals in PM2.5 can lead to sperm necrosis, few or no sperm, and a decrease in the number of interstitial cells. What’s more, they can affect the secretion of male hormones and destroy the growth of spermatogenic cells, Sertoli cells and mesenchymal cells. All of these result in a loss of fertility and an increased risk of diseases such as dysfunction, impotence, cancer, obesity, metabolic syndrome, diabetes and more [47,48]. In addition, There are some organic compounds containing methyl benzene, aniline, phenol, alkyl, nitro compounds in the air belong to endocrine disruptors, these organic compounds will break through the blood testis barrier, harm to reproductive cells [49,50]. Omar et al. [49] found that part of organic matter in PM2.5, as endocrine disruptors, affects male reproductive health and leads to reduced male hormone secretion. Mantzouki et al. [51] found that men with impaired fertility were exposed to PM2.5, and the increase in phenolic organic matter content was significantly associated with lower sperm content, or even more serious symptoms of azoospermia. Part of the organic matter in PM2.5, present in PM2.5, which has been proven to be toxic at the level of the reproductive system, causing increased reactive oxygen species levels and apoptosis rates in the reproductive cells, disrupting the balance of steroids, changing the expression of sex hormones, causing fertilization failure, and causing short-term infertility [52,53]. Some organic matter can also affect genetic material and cause aneuploidy of sperm chromosomes [54].

The results of the above-mentioned animal experiments and cytotoxicity experiments show that the reproductive toxicity caused by PM2.5 exposure will lead to a decrease in the concentration and activity of semen sperm. Oxidative and inflammatory reactions upset the balance between oxidation and anti-oxidation in cells, resulting in mitochondrial and DNA damage. It is clear that PM2.5 exposure can lead to impaired male reproductive function, which has adverse effects on the development of a healthy and sustainable population in China. These studies also have limitations. Although PM2.5 exposure in the environment has proven to damage the quality and production of male sperm, PM2.5 components vary significantly in different spatio-temporal environments, which makes it difficult to draw a systematic conclusion on reproductive toxicity. There is a lack of in vitro data on reproductive toxicology of PM2.5 exposure, mainly from in vivo data.

Stillbirths, Miscarriages and Preterm Birth

Pregnant women are very sensitive to the environment during pregnancy. Any risk that exists during pregnancy can lead to adverse effects on the birth population [55]. Exposure to PM2.5 will have an adverse effect on the outcome of pregnancy, and may cause miscarriage or even severe stillbirth [56-58]. Yang et al. [59] evaluated PM2.5 exposure in 95,354 births from 2011 to 2013. They analysis determined the correlation of exposure to PM2.5 to stillbirths with adverse pregnancy outcomes. It found that exposure to PM2.5 increases the risk of stillbirth throughout pregnancy. Gaskins et al. [60] found that the proportion of miscarriage in the adverse pregnancy results was very large. Long-term exposure to PM2.5 has a significant impact on abortion, but there are few studies on short-term exposure to abortion, and further research is needed. Liu et al. [61] Conducted a cohort study in Ningbo and found that the pregnant women were evaluated using PM2.5 exposure at the corresponding time. The results showed that exposure to PM2.5 is positively correlated with the risk of PTB throughout pregnancy. In addition to the long-term exposure to PM2.5 that will increase the risk of PTB, short-term PM2.5 exposure is also positively correlated with the risk of PTB. Li et al. [62] also found long-term exposure to PM2.5 has greater harm on pregnancy outcomes and a large impact on increasing risk of chronic pregnancy disease. But there may also be a link between short-term exposure and PTB. It is important to protect the air quality of pregnant women. Exposure to PM2.5, even at low concentration and for a short period of time, has adverse effects. Exposure to PM2.5 from different sources has different effects on pregnant women, as does the exposure of women at different times of pregnancy. Li et al. [63] considered the difference between the results of more than half a million pregnancies in Hubei province and pm2.5 exposure in urban and rural areas. There is still a positive correlation between PM2.5 exposure and PTB risk in various regions, but among different regions, the risk of urban PTB is significantly higher than that in rural areas. This is related to the relatively large proportion of traffic sources and industrial sources among the sources of urban PM2.5. Given the impact of the environment on reproductive health, pregnant women should be kept away from emission sources. Liu et al. [64] Cohort analysis found that PM2.5 exposure was positively correlated with preterm birth, especially in the first trimester of pregnancy, the impact of PM2.5 exposure is the most significant. Alman et al. [65] concluded exposure to PM2.5 during the first and second trimesters was significantly associated with PTB. Wang et al. [66] conducted a study assessing PM2.5 exposure in 469,975 singleton fetuses born in Guangzhou, China, from 2015 to 2017. It was found that exposure to PM2.5 in the mid and late trimester of pregnancy is an important period for pregnant women to have premature delivery. Severe PTB is more correlated with PM2.5 exposure. The sensitivity of exposure to PM2.5 varies at different stages of pregnancy, so it is obviously an important means of prevention and treatment to avoid exposure of pregnant women to higher concentration of PM2.5 during relatively sensitive periods.

HDCP

Pregnant women are more sensitive to the environment, and the oxidative stress response resulting from exposure to PM2.5 leads to a higher incidence of HDCP [67]. PM2.5 concentration is closely related to the risk of gestational diabetes, which is also often associated with HDCP. PE is a hypertensive disorder during pregnancy that, along with gestational diabetes, leads to an increased risk of adverse health outcomes for pregnant women and the fetus. Gestational diabetes also increases the risk of a birth defect. [68-73]. PE is a major contributor to maternal morbidity and mortality worldwide and has a high likelihood of adverse birth outcomes [74-76]. Sun et al. [77] evaluated PM2.5 exposure at birth in 6297 cases in Zhejiang, China, from 2013 to 2017. It was found that long-term exposure of pregnant women to PM2.5 during pregnancy led to an increased risk of pregnancy-induced hypertension and PTB. Xue et al. [78] conducted a relevant cohort study to analyze the relationship between maternal exposure to PM2.5 and gestational hypertension and found the large correlation between PM2.5 estimates and gestational hypertension. Savitz et al. [79] conducted a cohort study that also found that PM2.5 exposure was associated with the risk of pregnancy-induced hypertension and PE. Assibey et al. [80] through the use of winter PM2.5 concentration studies, it is found that high-density PM2.5 environmental exposure is correlated with HDCP. His other study analyzed the PM2.5 concentration in each pregnancy month and before pregnancy, it was found that an increase in PM2.5 concentration also leads to an increase in the risk of PE. All of these studies have shown a significant association between PM2.5 exposure and increased HDCP risk. But,the concentration data of PM2.5 exposure in the above study lacked individual differences and ignored the differences in actual PM2.5 exposure of each individual. Xia et al. [27] Conducted a survey of 198 pregnant women living in Shanghai from 2017 to 2018. Each pregnant woman is equipped with close-fitting air sampling equipment to obtain environmental PM2.5 exposure conditions. It was found that during the first and second trimester of pregnancy, PM2.5 exposure would lead to changes in blood pressure parameters through inflammatory responses, and many components in PM2.5 were found to be related to blood pressure parameters. Madhloum et al. [81] studied the results of exposure to PM2.5 during different pregnancy periods. Through the discovery of the insulin in the fetus’ plasma at birth, the change of PM2.5 concentration will also affect the concentration of insulin. This indicates that pregnant women exposed to PM2.5 have an increased risk of high blood pressure, which increases the risk of adverse fertility outcomes. High blood pressure in pregnant women also has a degree of heritability, which increases the adverse effects on reproduction and on future generations. After a pregnant woman suffers from pregnancy-induced hypertension, her risk of PTB will increase significantly [82]. The results of Mandakh et al. [83] showed that PE risk was significantly correlated with PM2.5 exposure during pregnancy, and the correlation between PE risk and exposure window period was also different. In women with HDCP, their fertility is impaired, which has a negative impact on the continued health of the population.

mtDNA

The genes of mitochondria are unique and lack the corresponding repair ability. Oxidative stress can cause mtDNA damage .Therefore, through the study of changes in the content of mtDNA, It can be used to show that PM2.5 exposure can cause the accumulation of oxidative stress in uterus [84-87]. Clemente et al. [84] analyzed the sensitivity of mtDNA in the placenta to toxic substances in the environment by using European counterparts in the two groups of Spanish and Belgian people. Analysis of mtDNA was used to investigate the physiological toxicity of PM2.5 exposure. Grevendonk et al. [89] analyzed 293 cord blood samples from 224 pregnant women in Belgium. Exposure of pregnant women to PM2.5 aggravates the oxidative stress of the whole body in the early pregnancy. Examination of genetic material in mitochondria revealed that oxidative stress caused DNA damage. Compared with DNA damage in the nucleus, mtDNA damage may be more serious. Rosa et al. [90] conducted PM2.5 exposure assessments on pregnant women from 2007 to 2011. There is significant correlation between increased PM2.5 exposure and decreased mtDNA content in cord blood. Late pregnancy is the period when mtDNA is most affected by PM2.5 exposure. Brunst et al. [91] assessed exposure to PM2.5 in 167 pregnant women in Israel in 2011-2012 and found similar results. The reduction of mtDNA exposure to PM2.5 during pregnancy is related and has a cumulative effect. Long-term exposure can also cause trauma to the mother, resulting in a decrease in mtDNA in the placenta. During the PM2.5 exposure period, there is this gender difference in the sensitive window period of mtDNA reduction. The sensitive window period for boys is mainly the late pregnancy, and the sensitive window period for girls is the early pregnancy. A study finds Leukocyte LTL as a guarantee of cell division, it can reflect the reproductive potential of cells and is sensitive to environmental exposure. PM2.5 exposure in the first trimester is significantly related to LTL shortening, in addition, it is more obvious in girls [92].

The placenta and bone

The placenta is a very important organ for women during pregnancy. It has a biofilm that separates the fetal circulation from the mother’s body, as well as a large surface area for material exchange. Exposure to PM2.5 will lead to dysfunction of placenta, which will affect the normal growth and development of the fetus. In addition, Placental hormones also play an important role in maternal metabolism, and if placental hormone levels are unbalanced, it can lead to an increased risk of pregnancy complications such as placental abruption [93-95]. Ananth et al. [96] conducted a cohort study on the results between placental abruption and PM2.5 in both long-term and shortterm PM2.5 exposure modes. The study showed that short-term PM2.5 exposure was associated with the risk of acute placental abruption, while long-term exposure led to an increased risk of placental abruption. In addition to showing the adverse effects of PM2.5 on placenta, some studies have also explained the possible toxicological mechanism of PM2.5 exposure to placenta. Yue et al. [28] found that as for the expression of gene substances in placenta, PM2.5 exposure compared with the control group found that gene expression was affected, and PM2.5 exposure would also adversely affect the growth and development of blood vessels in placenta. Leptin an important hormone for fetal growth in the womb, was used to determine placenta health, the increase in Leptin methylation concentration has a great correlation with the risk of adverse outcomes during pregnancy [97]. Exposure to PM2.5 increases oxidative stress and inflammation in placental cells, both of which are the toxic mechanisms responsible for placental abruption [98]. PM2.5 exposure will adversely affect the bones of pregnant women. Exposure to PM2.5 during pregnancy and postpartum has an impact on the mother’s bone recovery and the fetus’s bone development. Systemic inflammation and oxidative stress caused by PM2.5 exposure can inhibit postnatal bone recovery in pregnant women [99,100]. Wu et al. [101] conducted a longitudinal cohort study of people receiving prenatal care from Mexico City. They use the spatio-temporal prediction model to evaluate the PM2.5 exposure of these pregnant women during pregnancy, pre-pregnancy and post-natal time. Studies have found that high levels of PM2.5 exposure are negatively correlated with bone strength. Long-term exposure to PM2.5 increases the loss of bone strength in pregnant women. These results lead to an increased risk of fractures during pregnancy and postpartum osteoporosis.

Female germ cell

In addition to affecting women during pregnancy, PM2.5 also adversely affects female germ cells, resulting in impaired female fertility and affecting the overall development of the population. Gaskins et al. [102] subjected female mice to toxicological exposure to PM2.5. It was found that the tissue structure of ovary was changed, and the expression of apoptotic protein was significantly higher than that of the control group. Meanwhile, exposure to PM2.5 also affected hormone levels. An increase in PM2.5 concentration reduces the number of ovarian follicles in the stomach antrum, while a decrease in ovarian reserve affects a woman’s fertility. At present, the research on female germ cells is still in the stage of animal experiments, and the related epidemiological studies are relatively few. Gai et al. [103] observed in the experiment of PM2.5 exposure in female mice that PM2.5 exposure would not only aggravate oxidative stress response, but also aggravate the inflammatory response to ovarian cells with the increase of PM2.5 concentration. In Figure 2, The original experimental cells were observed at a multiple of 100,000.

Figure 2: Comparison of the ultrastructural alterations in mitochondria in ovarian tissues in mice of different groups (original magnification ×10,000) .In the control group are the germ cells of mice that grow normally, the rest are PM2.5 injections, and the experimental group supplemented with vitamin C, vitamin E, aspirin and Ozone. Ultra structural changes of mitochondria in ovarian tissues of different groups were compared. In the PM2.5 exposure group, mitochondria were swollen, mitochondria membrane was damaged, linear particles were disordered and vacuolated. Combined exposure to Ozone and PM2.5 increased the risk of ovarian cell damage, while mixed exposure to the other three substances and PM2.5 reduced the risk. It indicates that in the actual exposure environment, PM2.5 will interact with other environmental pollutants, resulting in a further increase in reproductive toxicity. Through the combined exposure experiment with the addition of relevant antioxidant and inflammatory drugs and PM2.5, it was proved that oxidative stress and inflammatory response of cells exposed to PM2.5 were the important reasons leading to the reproductive toxicity of PM2.5.

In the control group, the mitochondria in the germ cells were intact and arranged regularly in the cells.

Similarly, Guo et al. [104] exposed mice to clean air and PM2.5. The results showed that the oxidative stress response of the oocytes of female mice was significantly higher in mice exposed to PM2.5 than in mice exposed to clean air. The number of oocytes in mice exposed to PM2.5 decreased significantly. The measurement of transcription factors in oocytes found that it also affected the gene expression of germ cells. In the final production results, the number and weight of mice in the PM2.5 exposure group were reduced. Bao et al. ‘s study supplement to a possible mechanism for adverse birth outcomes in mice exposed to PM2.5. Exposure to PM2.5 can lead to cell apoptosis, changes in the morphology of female mouse germ cells, impaired embryo quality, and finally the number of litters of female mice is reduced.

PM2.5 exposure can lead to changes in the tissue structure of female germ cells, genetic material is affected, oxidative stress and inflammation are caused, and the risk of various pregnancy diseases in pregnant women is increased, and it can also lead to adverse pregnancy outcomes. Taking medications related to antioxidants and inflammatory responses can help treat diseases caused by PM2.5 exposure. Reducing female reproductive injury caused by PM2.5 can protect the healthy and sustainable growth of the population.

Numerous epidemiological body provides evidence that high individual exposure to PM2.5 may adversely affect developing fetuses, and reproductive epidemiology provides evidence that fetuses and infants may be more sensitive than adults to a variety of environmental poisons [100,105,106]. For China, the healthy birth of a fetus and the healthy growth of children are all related to the country’s policy of healthy birth and post-natal care. Ensuring a healthy population group is of great significance to the future development of our country. PM2.5 exposure will affect all stages of the growth and development of the fetus in the mother. It will have an adverse effect on the growth of cells involved in the vegetative ectoderm of the fetus, as well as the cells involved in the individual development of the fetus in the future [99]. Child birth defects due to PM2.5 exposure during pregnancy problem has aroused people’s wide attention, such as fetal chromosomal abnormalities, premature birth, low birth weight, long-term complications etc. [107,108].

Obesity and Low Birth Weight

Chiu et al. [109] conducted a growth and development study on 277 full-term children. In the early and mid-trimesters of pregnancy, higher levels of PM2.5 exposure are related to the weight change of girls, while exposure to PM2.5 in the second trimester is associated with increased fat in boys. Kim et al. [110] indicated that PM2.5 exposure can affect the decomposition of carbohydrates, which may be the cause of childhood obesity. The study of Lin et al. [111] found that PM2.5 exposure is related to birth weight and obesity in the subsequent growth and development of children. Exposure to PM2.5 not only affects children’s metabolic development and leads to obesity, but also increased neonatal DNA methylation. Both contribute to childhood obesity. As shown in Figure 3, analyze the relationship between newborn birth weight and pregnant women’s prenatal exposure.

Figure 3: Prenatal environment influences on birth weight. Figure 3a and Figure 3b are both the relationship between prenatal environmental variables and body weight, and it is found that there is a significant correlation between them. Figure 3c and Figure 3d deal with the interference factors, and the percentage change of birth weight with the prenatal environment change is significantly related to the environment. A mother’s weight, blood sugar levels, and environmental exposure are all related to a child’s weight.

PM2.5 exposure will destroy the ideal intrauterine environment, disrupt the metabolic plan of the growing fetus, increase the level of inflammatory cytokines, impair the function of insulin receptors, affect the decomposition of glucose, and increase the possibility of obesity in later childhood [112].

In addition to obesity, low birth weight can also lead to congenital deficiencies in the growth and development of babies. The reduction in birth weight is significantly correlated with PM2.5 exposure during pregnancy [113]. A cohort study on the relationship between PM2.5 and birth weight found After excluding the interference of personal living habits, it was found that higher PM2.5 exposure during pregnancy is related to the reduction of birth weight. However, as the birth weight is greatly reduced, the correlation of PM2.5 will decrease. PM2.5 exposure has an adverse effect on birth weight, but it is not a decisive factor [114]. Guo et al. [115] Studied the relationship between PM2.5 exposure and birth weight change at term. The study also found a link between reduced birth weight and PM2.5 exposure. In the mixed model of all air pollutants, it was not found to be related to birth weight, but in a single PM2.5 exposure model, PM2.5 concentration was negatively correlated with birth weight. Early pregnancy has the greatest impact on birth weight throughout pregnancy. Fleischer et al. [31] analyzed adverse pregnancy outcomes caused by exposure to PM2.5 during pregnancy. It was also found that the PM2.5 concentration in the environment is negatively correlated with birth weight, and the higher the PM2.5 exposure level, the more serious the impact. Slama et al. [116] analyzed the relationship between the birth weight of 1016 children born in the 1990s in Munich, Germany and their exposure to PM2.5 from traffic sources. PM2.5 concentration and absorbance were found to have adverse effects on birth weight, and PM2.5 exposure from traffic sources led to lower birth weight. Janssen et al. [117] cohort analysis was performed on pregnancy outcomes and fetuses of pregnant women exposed to PM2.5. The results found that thyroid hormone in cord blood decreased with increased PM2.5 concentration. Such changes in late pregnancy may affect fetal thyroid function and lead to changes in birth weight. The research of Eliot et al. [118] further explained the possible toxicological mechanism. PM2.5 from the traffic source cause DNA damage, adversely affect the growth and development of the fetus, and cause a decrease in birth weight. Yang et al. [119] research on the main mechanism of adverse effects of PM2.5 exposure on fetal growth. In addition to directly affecting fetal growth and development through inflammatory response, oxidative stress and other mechanisms, PM2.5 also indirectly affects fetal growth through affecting blood glucose level.

Congenital defect disease

Fetal growth restriction is mainly caused by uterine placental dysfunction, resulting in an inadequate supply of nutrients and oxygen, affecting the normal growth of the fetus. Related research has shown that PM2.5 exposure is associated with placental inflammatory response, abnormal trophoblast invasion and reduced placental angiogenesis, which may lead to impaired fetal growth [120-122]. Exposure to PM2.5 causes changes in the arterial wall of young children, thereby increasing the risk of cardiovascular disease, oxidative stress and inflammation are believed to be important links between air pollution and cardiovascular risk caused by atherosclerosis [123,124]. Ntarladima et al. [125] measured carotid intima media thickness, carotid artery opening, elastic modulus, diastolic and systolic blood pressure, and the results showed that the carotid artery density in children exposed to PM2.5 decreased by standard deviation. In further research, Hwang et al. [126] conducted a comparative analysis of the birth environment exposure of 1087 children with heart defects and More than 10000 normal children in Taiwan Province. It is found that babies born prematurely are at greater risk than full-term babies. The greater the concentration of air pollution in the environment, the greater the risk of heart defects. Except for the cardiovascular birth defects, Adel et al. [127] evaluated 216,730 infants from 1997 to 2004, using data from air monitoring stations to assess their pollution exposure. Research results show that exposure to air pollution significantly increases the risk of congenital malformations, especially the special malformations in the reproductive organs and circulatory system. Jordan et al. [128] assessed the relationship between partial congenital defects and PM2.5 exposure. Analysis of spina bifida, critical congenital heart defects and orofacial clefts, found that exposure to PM2.5 is related to these birth defects. Interestingly, Schembari et al. [129] used PM2.5 exposure from traffic sources to compare 2247 children with chromosomal abnormalities in Barcelona from 1994 to 2006 and 2991 normal children in a comparative study. Traffic source PM2.5 exposure does not have an obvious relationship with every congenital defects, but there is a clear correlation between cardiovascular-related congenital diseases and PM2.5 concentration. Stingone et al. [130] conducted PM2.5 exposure assessments on congenital anomalies in nine states of America. The current high levels of PM2.5 exposure are significantly related to a variety of congenital defects. In the sensitive window period of fetal heart development, the oxidative stress response caused by PM2.5 exposure is the main potential mechanism for cardiovascular congenital diseases. Embryonic exposure affects the maternal and/or intrauterine environment and leads to impaired fetal development. During rapid fetal growth, the developing cardiovascular system is particularly susceptible to its environment, fetal exposure can cause changes in epigenetic characteristics that lead to permanent changes in gene expression [131]. The increased risk of congenital defects in children is also detrimental to the healthy development of the population.

Nervous system and other diseases

Perinatal exposure to PM2.5 has been shown to have negative effects on children’s neuropsychological development. Emam et al. [132] analyzed the effects of PM2.5 exposure to the nervous system during prenatal and pregnancy in female mice. Found that PM2.5 exposure can affect the secretion of hypothalamic neurohormones, thereby affecting children’s social behavior and nervous system, which may be the cause of children’s autism. McGuinn et al. [133] conducted a comparative analysis of 855 people with early tendency and 647 children with autism from 2003 to 2004. PM2.5 exposure was assessed before and throughout pregnancy, and in the first year of life. An association was observed between PM2.5 exposure and autism in the first year of life, with higher concentrations increasing the risk. Bose et al. [134] studied the effects of 375 pregnant women and singleborn children in Mexico from 2007 to 2011 and the effects of PM2.5 exposure on children’s sleep quality and nervous system. It find that the development of the nervous system of the fetus in the womb will affect the sleep structure after birth, and Exposure to PM2.5 can lead to less sleep in young children, possibly because of damage to their neuron-development. The sensitive window of influence is mainly concentrated in the early and third trimesters. This may be because PM2.5 will break through the blood-brain barrier and affect the construction of the cerebral nervous system.

Seeni et al. [135] analyzed the results of 223,385 births with only one child born in the United States from 2002 to 2008, and used a model to evaluate PM2.5 exposure during pregnancy. It was found that exposure to PM2.5 in the latter part of pregnancy leads to an increased risk of temporary dyspnea. There is a significant correlation between PM2.5 exposure and the risk of suffocation during the entire pregnancy. As the PM2.5 concentration increases, the possibility of suffocation also increases. Exposure to high levels of PM2.5 in the second trimester also increased the risk of respiratory distress syndrome. Clinical experience has shown that the incidence of neonatal jaundice increases when air quality degrades. A study of 25,782 newborns reported an increase in neonatal bilirubin levels. Bilirubin levels increase linearly with exposure time from 0 to 48h. Improving air quality may be the key to reducing the risk of jaundice in newborns [136].

All of the above studies have shown that PM2.5 exposure can lead to an increased risk of congenital diseases and affect the quality of the birth population. Reducing PM2.5 concentration can reduce the negative impact of environmental exposure on the population policy of healthy birth and nurturing. Research also has certain limitations. The main toxicological mechanisms currently discussed are inflammatory factors, stress response, which destroys the barrier structure as the blood enters the body, affects hormone receptors and cell apoptosis. However, reproductive toxicology involves very complex physiological processes, and the composition of PM2.5 is also complex and diverse, which leads to challenges in the study of specific molecular mechanisms. Long-term Chronic Toxicology Experimental Research and the toxicological study of complex PM2.5 components on the growth and development of young children is still a difficult and important point.

PM2.5 exposure causes oxidative stress in testicular tissue, oxidative damage in testicular cells, increased apoptosis of Sertoli cells, spermatogenic cells and mesenchymal cells, damage to the microbiological environment, and decrease of sperm quality, leading to male infertility. Exposure to air pollutants can disrupt hormones in the body, destroy OS balance, damage embryo and placental tissue, and affect normal embryo implantation. Women preparing for pregnancy should do a good job of air pollution protection before conception, early protection will improve the clinical pregnancy rate, reduce the occurrence of spontaneous abortion. Have immediate and long-term effects on the influence of the child during pregnancy, such as congenital deformity inflammation, premature birth, low birth weight, longterm complications hypertension and obesity, etc. Oxidative stress, DNA methylation, changes in mitochondrial DNA content, endocrine disorders and so on Maybe the mechanism of PM2.5’s effect on offspring. PM2.5 affects the fertility of men and women of the right age, endangers the growth and development of fetuses and adversely affects the growth of children, thus causing adverse effects on human fertility. Understanding the impact of PM2.5 on human fertility is necessary for the long-term and scientific development of human beings, as well as for the current global population problem and the policy of good birth and postnatal care.

In our review report, many countries and regions are involved, and the influence of spatial factors is comprehensively considered. However, in the study of the impact of PM2.5 on human fertility, the single PM2.5 factor may not be the main factor, and other complex environmental factors around it are also important to influence fertility. In addition, different components of PM2.5 in different regions and different periods have different influences on fertility. A more detailed and comprehensive consideration of the impact of PM2.5 on fertility is still a problem waiting to be solved. In toxicity studies, there are differences between in vitro experiments and the real environment of the human body. It is closer to the specific toxicological mechanism of the human body, which will help us better understand the harm of PM2.5 to fertility.

This research was funded by the National Natural Science Foundation of China (grant number 21976094, 22176100); and the National Key Research and Development Project 9(grant number 2018YFC0213802)

Conceptualization, M.C. and Z.L.; formal analysis, P.G.; investigation, Z.L.; resources, M.C; data curation, P.G. and Z.J.; writing—original draft preparation, Z.L.; writing—review and editing, Z.L.; funding acquisition, M.C. All authors have read and agreed to the published version of the manuscript

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