Startseite Impacts and potential mechanisms of fine particulate matter (PM2.5) on male testosterone biosynthesis disruption
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Impacts and potential mechanisms of fine particulate matter (PM2.5) on male testosterone biosynthesis disruption

  • Shaokai Zheng ORCID logo , Nannan Zhao , Xiaojun Lin und Lianglin Qiu EMAIL logo
Veröffentlicht/Copyright: 1. September 2023
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Reviews on Environmental Health
Aus der Zeitschrift Reviews on Environmental Health Band 39 Heft 4

Abstract

Exposure to PM2.5 is the most significant air pollutant for health risk. The testosterone level in male is vulnerable to environmental toxicants. In the past, researchers focused more attention on the impacts of PM2.5 on respiratory system, cardiovascular system, and nervous system, and few researchers focused attention on the reproductive system. Recent studies have reported that PM2.5 involved in male testosterone biosynthesis disruption, which is closely associated with male reproductive health. However, the underlying mechanisms by which PM2.5 causes testosterone biosynthesis disruption are still not clear. To better understand its potential mechanisms, we based on the existing scientific publications to critically and comprehensively reviewed the role and potential mechanisms of PM2.5 that are participated in testosterone biosynthesis in male. In this review, we summarized the potential mechanisms of PM2.5 triggering the change of testosterone level in male, which involve in oxidative stress, inflammatory response, ferroptosis, pyroptosis, autophagy and mitophagy, microRNAs (miRNAs), endoplasmic reticulum (ER) stress, and N6-methyladenosine (m6A) modification. It will provide new suggestions and ideas for prevention and treatment of testosterone biosynthesis disruption caused by PM2.5 for future research.

Keywords: PM2.5 ; testosterone biosynthesis; toxic mechanism; male

Introduction

The rapid urbanization and industrialization have accompanied with a growing number of air pollution. Ambient fine particulate matter (aero dynamic diameter ≤2.5 μm, PM2.5) is believed to be the most hazardous air pollution and has become a major public health problem, attracting accumulating attention in bioscience research [1]. PM2.5 is a complex mixture of suspending particles originated from traffic exhaust emission, coal combustion and open heating sources [2]. The main chemical composition of PM2.5 includes metal elements, inorganic ions, polycyclic aromatic hydrocarbons (PAHs) and endocrine disrupting chemicals [3]. However, the constituents of PM2.5 varies with location, season, and source, which indicated that PM2.5 adverse effects on health are complex and extensive. Due to the particles with small size, large surface area and complicated toxic substance, PM2.5 is very easily to enter and accumulate in human various organs and has a marked adverse health on the human [4, 5]. For decades, the relationship between PM2.5 exposure and reproductive dysfunctions in male has attracted an increasing public attention. The epidemiological and experimental evidence have suggested that PM2.5 exposure can impair sperm quality and the level of sex hormones via testicular damage [6, 7].

Over the past decades, there has been a worldwide decline on male sperm quality and an increase on the incidence of infertility [8]. Testosterone is the main male androgen, which is essential for secondary sexual development, metabolism, and spermatogenesis. In the absence of testosterone, males are infertile because of spermatogenesis dysfunction [9]. Testosterone contributes to the maintain of the blood-testis barrier (BTB) [10, 11], which provides nutrients and safe space for the development, survival, and maturation of germ cells [12]. The BTB is one of the tightest blood-tissue barriers in the mammalian animals, constituted by tight junction, gap junction, ectoplasmic specialization, and desmosomes [13]. The tight structure of the BTB can prevent the environmental toxicants from entering. Toxicological studies have shown that the decreasing of testosterone impairs the BTB components in mice [14, 15], which means that testosterone biosynthesis disruption may accelerate PM2.5 accumulation in testis via reducing the integrity of the BTB to impair Leydig cells which is the center of testosterone synthesis and secretion in male. When the level of testosterone reduced, the developing spermatids detached from Sertoli cells in the seminiferous epithelium, which demonstrated that testosterone is important for keeping the BTB function [16]. In addition, PM2.5 can also accumulate in testis and directly damage the BTB through reducing the BTB-related proteins [17, 18]. Thus, PM2.5 may directly or indirectly disrupt the complete structure of the BTB to accelerate Leydig cell damage via multiple toxic mechanisms. The absence of testosterone results in abnormal attachment and release of germ cells via caused the dysfunction of Sertoli cells, which suggested the occurrence of infertility.

Testosterone biosynthesis is vulnerable to exposure to various toxic substances. Recently, several studies have demonstrated that PM2.5 exposure is inversely associated with testosterone biosynthesis [14, 19, 20]. Leydig cells are the major site of testosterone biosynthesis and secretion in male. Testosterone production depends on the function of Leydig cells, which is tightly regulated via complex testosterone biosynthesis pathways (Figure 1) [21]. Testosterone is biosynthesized by various enzymes from cholesterol. First, cholesterol is transported to the inner mitochondrial membrane by StAR and then is converted to pregnenolone by CYP11A1. Pregnenolone is converted to testosterone through two pathways. On the one hand, pregnenolone is converted to androstenediol catalyzed by CYP17A1, AKR1C3 and CYP17B1/2. On the other hand, pregnenolone is converted to androstenedione catalyzed by HSD3B1/2 and CYP17A1. Thereafter, both androstenediol and androstenedione are converted to testosterone via HSD3B1/2 and HSD17B2/3, respectively. Thus, PM2.5 may impair testosterone biosynthesis via targeting Leydig cell. However, there is less reports on whether PM2.5 exposure impairs Leydig cells function and its underlying mechanisms.

Figure 1: Testosterone biosynthesis pathways are shown.
Figure 1:

Testosterone biosynthesis pathways are shown.

A growing number of evidence has shown that PM2.5 impairs male testosterone biosynthesis (Table 1). After the human body inhales small particles matter (such as PM10, PM2.5 and PM0.1), it will enter the systemic circulation and organs of the body, and even reach the testis [18]. We summarized epidemiological and experimental studies and found that most studies have shown that PM2.5 decreased the testosterone level and is accompanied with reproductive impairment such as infertility, the decrease of sperm production and the increase of sperm abnormalities, although several articles have proposed opposite results on the change of testosterone level. Nevertheless, its potential molecular mechanism has not been fully clear. Further studies are needed for further exploring the potential mechanisms of PM2.5-induced decline of testosterone level. In the review, we focus on reviewing the existing epidemiological and experimental studies and summarize potential molecular mechanisms. We propose a hypothesis that the process of PM2.5 exposure impairing male testosterone biosynthesis involved in multiple mechanisms.

Table 1:

Summary of epidemiological and experimental studies on the relationship between PM2.5 exposure and testosterone biosynthesis.

Subject Location PM2.5 exposure Effects on testosterone biosynthesis Reference
Fischer male rat (beginning at birth) Tokyo, Japan Inhalation, 5.63 mg/m3, 6 h/day, 5 days/week for 90 days (diesel exhaust particle) Testosterone↑, impairs sperm quality and production [22]
BALB/c male mice Tokyo, Japan Dorsal subcutaneous injection, 24.7, 74.0 or 220 µg/mouse, 10 times for 5 weeks (diesel exhaust particle) Testosterone↑, decreases sperm productions and viabilities, increases sperm abnormalities [23]
Men Poland Inhalation, arithmetic mean for a period of 90 days before semen collection Testosterone↓, increases sperm abnormalities [7]
Sprague-Dawley (SD) male rats Beijing, China Intratracheal instillation, 1.8, 5.4, 16.2 mg/kg.bw, 10 times for 30 days Testosterone↓, impairs sperm quality [14]
C57Bl/6J male mice Baltimore, USA Inhalation, 12.8 µg/m3, 6 h/day, 5 days/week for 4 months Testosterone↓, decreases sperm count [24]
Male college students Chongqing, China Inhalation, 54.8 µg/m3, from January 1, 2013, to December 31, 2015 Testosterone↑, decreases sperm quality, sperm count and sperm normal morphology [25]
Male C57BL/6 mice Shanghai, China Inhalation, 153.05 µg/m3, 8 h/day, 7 days/week for 125 days Testosterone↓, decreases sperm concentration and motility [26]
Male C57BL/6 mice Shijiazhuang, China Inhalation, 671.87 µg/m3, 6 h/day, 7 days/week for 16 weeks Testosterone↓, decreases sperm density and motility [6]
Sprague-Dawley (SD) male rats Zhengzhou, China Intratracheal instillation, 1.5 mg/kg.bw, 5 days/week for 4 weeks Testosterone↓, decreases sperm quality [1]
Offspring male C57BL/6 mice (sacrificed at 8 weeks old) Beijing, China Intratracheal instillation, 4.8, 43.2 mg/kg.bw, every three days, 6 times in all (maternal exposure) Testosterone↓ [27, 28]
Male adults Beijing, China Inhalation, 63.6 mg/m3, from February 2014 to December 2019 Testosterone↓ [20]
Male Wistar-Kyoto (WKY) rats North Carolina, USA Intratracheal instillation, 5 mg/kg.bw, 1 time Testosterone↓ [29]

Search strategy

A careful literature search was carried out on April 2023 for eligible articles using the PubMed database according to the PRISMA criteria. Only studies in English were included. This review includes studies which used healthy participants, patients, animals in vivo, and cell cultures in vitro. We search the following terms for the search using the Advanced Search Builder: (relevant mechanism [Title/Abstract]) AND ((PM2.5[Title/Abstract]) OR (particulate matter [Title/Abstract]) OR (PM [Title/Abstract])) and (relevant mechanisms [Title/Abstract]) AND (testosterone [Title/Abstract]). The search terms of relevant mechanisms include endoplasmic reticulum stress, ER stress, autophagy, mitophagy, ferroptosis, inflammatory response, inflammation, miR, N6-methyladenosine (m6A) RNA modification, m6A, pyroptosis, ROS and oxidative stress.

Potential mechanisms of PM2.5-induced testosterone biosynthesis disruption

PM2.5 exposure can cause testosterone biosynthesis disruption, while the alteration of testosterone level is associated with various reproductive system toxicity in male. The mechanisms in PM2.5-induced testosterone biosynthesis disruption are various and complex. Therefore, we discuss the potential mechanisms from the following mechanisms: oxidative stress, inflammatory response, ferroptosis, pyroptosis, autophagy and mitophagy, microRNAs (miRNAs), endoplasmic reticulum (ER) stress, and N6-methyladenosine (m6A) modification (Figure 2). Above mechanisms are supported by existing epidemiological and experimental studies.

Figure 2: Potential mechanisms and its adverse outcomes of PM2.5-induced testosterone biosynthesis disruption on male.
Figure 2:

Potential mechanisms and its adverse outcomes of PM2.5-induced testosterone biosynthesis disruption on male.

Oxidative stress

Numerous studies have reported that oxidative stress mediated PM2.5-induced toxicity and testosterone biosynthesis disruption. Oxidative stress is the crucial mediator of PM2.5-related toxicity. Oxidative stress can activate other mechanisms, such as inflammation, autophagy, ferroptosis, and pyroptosis [30], [31], [32], which suggested that it is the central mediator of PM2.5-induced toxicity. Thus, oxidative may play an upstream role to trigger other mechanisms or directly target Leydig cells and their testosterone biosynthesis pathway. It has been reported that PM2.5 exposure promoted oxidative stress through inhibiting the expression of sirtuin1(SIRT1), a type III protein deacetylase [33]. SIRT1 is necessary for testosterone biosynthesis via regulating multiple molecules in Leydig cells. The knockout of SIRT1 resulted in a sharp decrease in testosterone in SIRT1−/− mice compared to control mice [34]. The SIRT1-mediated deacetylation of molecules such as Nrf2, p53, NF-kappa B and FOXO3, which performed important roles on driving oxidative stress [35]. All the above studies have suggested that SIRT1 may act as a critical molecular to regulate oxidative stress. The aromatic hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates the excessive reactive oxygen species (ROS) after exposure to PM2.5 [36]. Recently, it has been evidenced that the long-term exposure to triclosan decreases the testosterone level through the activation of AHR in mouse neocortical neurons [37]. AHR also plays an important role on inhibiting testosterone secretion induced by polychlorinated naphthalene mixture in porcine ovaries [38].

Inflammatory response

Some studies have demonstrated that inflammatory response may mediate the testosterone biosynthesis disruption [6, 39, 40]. Toll-like receptor 4 (TLR4) is a typeⅠtransmembrane receptor protein. The extracellular domain recognizes pathogens while the cytoplasmic domain like IL-1 receptor family. NF-kappa B, which is the downstream target of TLR4, involves in initiating inflammatory response [41]. Prior evidence demonstrated that TLR4/NF-kappa B signaling pathway mediates inflammatory response caused by PM2.5 in vitro and in vivo [42], [43], [44]. Interestingly, related research discovered that TLR4 could activate NF-kappa B and lead to the reduction of testosterone concentration via decreasing the expression of testosterone synthesis genes, including StAR, CYP11A1, 3β-HSD, CYP17A1 and 17β-HSD, in male piglets and pig Leydig cells [45]. Notch signaling pathway is highly conserved in animals, which includes Notch receptors (Notch 1–4) and their ligands (Delta1-3 and Jagged1-2) [46]. Studies have shown that PM2.5 modulates airway inflammation by Notch signaling pathway [47, 48]. The knockdown of Notch receptors has shown that the expression of testosterone biosynthesis-related genes and proteins such as CYP11A1, StAR and HSD3B were lower in Leydig cells [49]. It has been demonstrated that NLRP3 inflammasome modulates the initiation of inflammation induced by PM2.5 [50], [51], [52]. A recent publication has noted that NLRP3 inflammasome involves in testicular damage and decrease testosterone level [53]. COX-2/PGE2 signaling pathway is another inflammatory mediator, which is associated with inflammation caused by PM2.5 exposure [54]. The increase of COX-2 and PGE2 level have been described during reproductive damage in male rats [55]. Mitochondria are highly dynamic organelles via fission and fusion to modulate their function [56]. DRP1 can promote fission during mitochondria dynamics. After treatment with urban particulate matter (PM), DRP1 highly expressed and mediated inflammatory response in EA. hy926 cells [57]. Previous studies have found that CREB activated DRP1 and led to decrease in StAR in Leydig cells [58], while DRP1 could increase inflammation [59]. PM2.5 not only targets Leydig cells, but also targets hypothalamic-pituitary-gonadal (HPG) axis [29]. PM2.5 is attributed to suppress HPG axis by inducing hypothalamic inflammation and result the downregulation of testosterone level in a mouse model [24].

Ferroptosis

Ferroptosis is an iron-dependent programmed cell death, characterized by the imbalance of the redox state in cell [60]. Iron plays a critical role in the initiation of ferroptosis. Interestingly, as one of the major mental components of PM2.5, iron can overload and trigger ferroptosis in cells and animals [61, 62]. Ferroptosis contributed to targeting CYP11A1 and caused the deficiency of testosterone biosynthesis after treatment with cadmium in Leydig cells [63]. Thus, we hypothesize that ferroptosis may involve in the disruption of testosterone level by PM2.5 exposure. Accumulating studies have unveiled that the inhibition of Nrf2 is related with PM2.5 exposure-induced ferroptosis [64]. The mechanism of most classic ferroptosis inducers is the inhibition of the antioxidant system. Nrf2 can bind to the antioxidant response element of genes and mediate antioxidant responses in tissues and cells [65]. Nrf2 has been reported to alleviate ferroptosis [66]. Compared with wild-type mice/Leydig cells, the concentration of testosterone was reduced in knockout of Nrf2 mice/Leydig cells, accompanied with reduced antioxidant capacity and the expression of CYP11A1 and StAR [67]. The molecular mechanisms of ferroptosis are also associated with the system Xc−/GSH/GPX4 signaling pathway, PUFA-phospholipid peroxidation, TF/TFR signaling pathway, and p53 signaling pathway [68]. Currently, research on PM2.5-induced ferroptosis is limited.

Pyroptosis

Pyroptosis also is a pro-inflammatory programmed cell death associated with caspases and cytokines. The characteristics of pyroptosis include DNA damage, chromatin, swelling, bubble-like protrusions, and membrane blebbing [69]. In canonical pathway of pyroptosis, cytosolic pattern recognition receptors (PRRs) assemble inflammasomes, which can cleave pro-caspase-1 to caspase-1 [70]. On the one hand, activated caspase-1 can cleaves GSDMD to form N-GSDMD [71, 72]. On the other hand, caspase-1 also cleaves pro-IL-1β and pro-IL-18 to activate IL-1β and IL-18 [73, 74]. Active IL-1β and IL-18 are released from the cell membrane pores, which are formed by N-GSDMD, and result in pyroptosis [75, 76]. In the non-canonical pathway, intracellular lipopolysaccharide (LPS) activates caspase-4/5/11, which can also cleave GSDMD into N-GSDMD [71]. Active caspase-4/5/11 and N-GSDMD can mediate the cleavage and secretion of IL-1β and IL-18 via NLRP3 inflammasome/caspase-1 signaling pathway [77, 78]. The activation of NLRP3 inflammasome is one of the mechanisms to mediate PM2.5-induced toxicity [50, 52]. Emerging data have suggested that PM2.5 causes pyroptosis via NLRP3 inflammasome/caspase-1 in various tissues and cells [79], [80], [81]. The activation of NLRP3 inflammasome has also been associated with testicular impairment and the decrease of testosterone level via reducing the expression of testosterone biosynthesis genes such as CYP11A1, CYP17A1, HSD3B, HSD17B and StAR [82], [83], [84]. The activation of pyroptosis not only involves in NLRP3 inflammasome, but also link with other inflammasomes, which suggests that they maybe regulate pyroptosis caused by PM2.5. At present, studies on the activation of pyroptosis are mostly focused on the NLRP3 inflammasome [74], while studies on the other inflammasomes are rare. In addition, the non-canonical pathway of pyroptosis in testosterone biosynthesis disruption caused by PM2.5 is still unclear.

Autophagy and mitophagy

Autophagy is a complex self-degradative process, which has been considered as an important mechanism of PM2.5-induced toxicity. However, the functional role and underlying mechanisms of autophagy in testosterone biosynthesis are still unclear. There are three types of autophagy, including macro-autophagy, micro-autophagy, and chaperone-mediated autophagy, while macro-autophagy is the best studied [85]. Macro-autophagy process involves key steps: phagophore formation; completion of autophagosome; fusion of autophagosome with lysosome to form autolysosome, which mediates degradation of protein aggregates, organelles, and ribosomes [86]. Several studies have demonstrated that PM2.5-mediated oxidative stress is responsible for autophagy triggered by PM2.5 in vivo and in vitro [87], [88], [89]. Autophagy provides a protective effect to inhibit PM2.5-induced apoptosis, necrosis, and cytotoxicity [90, 91]. mTOR, AMPK, PI3K-AKT, MAPK, and cAMP signaling pathways have been demonstrated to regulate autophagy [85, 86]. Interestingly, the inhibition of autophagy can improve conversely oxidative stress and inflammation caused by PM2.5 [92, 93]. PM2.5 cause the increase of LC3B-Ⅱ/Ⅰ(means the formation of autophagosomes) and the upregulation of P62 (means the block of autophagosomes), which suggests that the importance of autophagic flux in PM2.5-induced toxicity [94, 95]. Recently, a study has shown that PM2.5-induced male reproductive injury is accompanied by the downregulation of serum testosterone and the activation of autophagy [1]. When the body is invaded by external substance, autophagy is a double-edged sword. It can resist the damage of external obstacles to the body, but excessive autophagy may have adverse effects and promote cell death. An increasing body of studies has illustrated that activation of autophagy enhances testosterone secretion and increases StAR, HSD3B2, CYP17A1 and CYP11A1 in Leydig cells and testicular tissue [96], [97], [98], which have demonstrated that autophagy may resist and reduce the toxicants damage on testosterone biosynthesis. Based on the above findings, we can propose a hypothesis that autophagy may play a protective effect to inhibit PM2.5-induced testosterone biosynthesis disruption. However, there is no research about the association between testosterone biosynthesis and autophagy caused by PM2.5. Mitophagy is a selective autophagy, given its significance for PM2.5-mediated toxicity [99, 100], which has also been observed in the exploration of testosterone biosynthesis [101].

MicroRNAs (miRNAs)

MicroRNAs (miRNAs) are sensitive to environmentally hazardous substances and involve in negatively regulating of the expression of target genes. Importantly, numerous studies have reported that miRNAs are altered and participate in PM2.5-induced toxicity in diverse human diseases [102], [103], [104], [105]. However, there are limit microRNAs to be identified as PM2.5-sensitive. Potential miRNAs, which are verified to involve in pathological processes in different tissues and cells caused by PM2.5 and may be associated with testosterone biosynthesis, are illustrated in Table 2. miR-21 previously found to be positively associated with serum levels of testosterone in patients with breast cancer or polycystic ovary syndrome (PCOS) [106]. However, there is less study to demonstrate the relationship between miR-21 and testosterone level in male. Recent studies have verified that PM2.5 exposure induced miR-21 alteration that could trigger vascular endothelial and bronchial epithelial dysfunction [107, 108]. Interestingly, it has demonstrated that testicular vascular damage plays an important role in regulating testosterone such as testicular blood flow, vascular permeability, and endothelial surface [109], which has suggested that testicular vessels may be another mechanism of the impact of PM2.5 on testosterone level. The increased expression of miR-29a is relevant with the decreased androgen production by downregulating the expression of HSD3B1 in Leydig cells [110]. Microarray analysis and real-time PCR analysis revealed that miR-29a positively expressed in associated with PM2.5 exposure in human [111]. MiR-146a has recently been shown to be negatively associated with serum testosterone and its related pathways including Toll-like receptor signaling pathway, apoptosis, cell adhesion molecules and NF-kappa B signaling pathway [112]. MiR-146a is found to play an important role in pathological processes caused by PM2.5 exposure [113]. Above results confirm the possible contribution of aberrant alteration of miRNA expression to PM2.5-induced testosterone biosynthesis disruption in male.

Table 2:

Potential miRNAs involve in PM2.5-induced testosterone biosynthesis disruption in vivo and in vitro model.

Model Dose/duration Trend of miRNAs which may be associated with testosterone biosynthesis Effects Reference
HBE cells 3 μg/cm2, 24 h Up: miR-375 Inflammation [114]
Elderly men 3.83 μg/m3, 7-day Down: miR-1, miR-126, miR-146a, miR-155, miR-21, miR-222, miR-9 Cardiovascular disease [115]
BEAS-2B cells 3, 12 μg/m3, 24,48,72 h Up: miR-21 Genotoxicity in lung cells [116]
BEAS-2B cells 10 μg/cm3, 24 h Up: miR-1246, Lung injury [117]
Human Time windows (1 day, 1 week, 1 month, 3 months, 6 months, and 1 year) Up: miR-126-3p, miR-19b, miR-93, miR-223, miR-142, miR-23a, miR-150, miR-15a, Let-7a Cardiovascular disease [118]
SD rats 0.25, 2.5, and 25 mg per 3 days Up: Let-7b, miR-466b

Down: Let-7e		 Neural diseases [119]
SD rats, HUVEC cells 4 mg/kg.bw in SD rats per 3 days for 4 weeks, 80 μg/mL in HUVEC cells for 24 h Up: miR-21 Vascular endothelial dysfunction [107]
C57BL/6 mice 1 and 5 mg/kg.bw every other day for 4 weeks Down: miR-574 Neural diseases [120]
A549 cells 5, 50 μg/mL for 24 h Down: Let-7a, miR-34a Lung cancer [121]
BALB/c mice 2.5, 10 and 20 mg/kg.bw for 1, 7, 14 days Up: miR-139, miR-146 Lung inflammation [122]
College students 53.1 μg/m3 Down: miR-21, miR-146a, miR-1, miR-119a Cardiovascular disease [123]
Students 21.31 μg/m3 Up: miR-29a, miR-92a Health risks [124]
Elderly men 11.67 μg/m3 Up: miR-199b, miR-223 Blood pressure [105]
HBE and BEAS-2B cells 10, 20, 30 μg/mL for 24 h Down: miR-204 Carcinogenesis [125]
EA.hy926 cells 2.5, 10 μg/cm2 for 24 h Down: miR-128, miR-28 Cardiovascular disease [126]
C57BL/6 mice 900.21 μg/m3 for 8 weeks, 671.87 μg/m3 for 16 weeks Up: miR-96, miR-182, miR-183 Testicular damage [6]
HBECs, MLE-12, RAW264.7 cells 300 μg/cm3 for 24 h Up: miR-29b Inflammatory responses [127]
Wistar rats 1 mL of 1,2,2 mg/mL at day 0, 3, 7 Down: miR-125b, miR-21 Inflammatory responses [128]
SD rats, AC16 cells 1.8, 5.4 and 16.2 mg/kg.bw every 3 days for 1 month in rat, 25 50 100 µg/mL in cells for 24 h Down: miR-205 Cardiovascular diseases [129]
NCI-H23 and Bet1A cells 5 μg/ml for 15 or 28 days Down: miR-125a Lung cancer [130]
BALB/c mice, 16HBE cells 2.5, 10, 20 mg/kg.bw in mice, 25, 50, 100 μg/ml for 24–48 h in cells Down: miR-139 Lung cancer [131]
HBE cells 50 μg/ml for 24 h Down: miR-145 Lung injury [132]
HBE cells 50, 100 μg/ml for 24 h Down: miR-222 Lung injury [133]
Balb/c mice, A549 cells 20 mg/kg.bw in mice, 100 μg/ml for 24 h in cells Down: miR-193b

Up: miR-100, miR-125b		 Lung cancer [134]
C57BL/6 mice 87 μg/m3 for 8 weeks Up: miR-10b, miR-466b Alzheimer’s disease [135]
ApoE−/− mice 157 μg/m3 for 8 weeks Up: miR-326 Atherosclerosis [136]
C57BL/6J mice 0.6 mg/mouse once a week for 2 or 3 months Up: miR-149 Pulmonary fibrosis [137]

Endoplasmic reticulum stress

As the organelles with the largest surface area in cells, the endoplasmic reticulum (ER) plays a key role in the synthesis, folding, and modifications of secreted proteins, which are synthesized in ER membrane-bound ribosomes and then injected into the ER lumen for next processes [138]. Although the protein-folding capacity of ER is exquisitely regulated, diverse external factors can disrupt this process and lead to ER stress due to the accumulation of unfolded/misfolded proteins in ER lumen [139]. The activation of ER stress initiates the unfolded protein response (UPR) to restore ER homeostasis through an adaptive mechanism [140]. In mammalian cells, inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6) and PRKR-like ER kinase (PERK) are three ER transmembrane proteins which operate as ER stress sensors and initiate the adaptive mechanism [141]. Under conditions of inactivation of ER stress, the molecular chaperone glucose-regulated protein 78 (GRP78, alias BIP, HSPA5) binds with these sensors and persists them in an inactivated state. Once the event of the activation of ER stress occurs, GRP78 has a higher affinity to bind misfolded/unfolded proteins while dissociates from the sensors [142]. The discrete sensors enable induction of UPR. The moderate ER stress restores ER homeostasis, and thus causes cells to adapt to stress and survival. However, excessive, and unresolved ER stress can accelerate cell death. Previous studies have reported that PM2.5 could induce ER stress and thus break the balance of ER homeostasis to result in function disorder in various systems [143], [144], [145]. Although numerous studies have demonstrated that ER stress also closely involved in testosterone biosynthesis disruption under adverse conditions in Leydig cells [146, 147], it is unclear whether PM2.5 cause testosterone disorder through the relevant mechanism of ER stress. Thus, it is of interest to evaluate the involvement of ER stress and explore its related UPR pathway during the period of PM2.5-mediated testosterone biosynthesis disruption (Figure 3).

Figure 3: Related toxicity mechanisms involved in the UPR pathway activated by PM2.5-induced ER stress in mammals.
Figure 3:

Related toxicity mechanisms involved in the UPR pathway activated by PM2.5-induced ER stress in mammals.

N6-methyladenosine (m6A) RNA modification

m6A RNA modification refers to the addition of a methylation at position N6 of adenosine in almost type of eukaryotes RNAs [148, 149]. m6A modification is the most abundant and common of RNA modifications and an average of 1–2 m6A modification in each 1000 nucleotides [150]. m6A modification has been identified to involved in regulating RNA translation, stability, splicing and translocation, folding and export [151, 152]. m6A modification frequently occurs around the 3′ untranslated regions (UTRs) and near stop codons in mRNAs [153]. In addition, most m6A modifications are enriched in a conserved motif RRACH (R=A/G, H=A/C/U) [154]. The m6A modification is catalyzed by methyltransferase complex (also called “writers”, including METTL3/14/16, RBM15, VIRMA, ZC3H13 and WTAP), removed by demethylases (also called “erasers”, including ALKBH5, and FTO), and recognized by a group of binding proteins (also called “readers”, including YTHDC1, HNRNPA2B1, HNRNPC, and YTHDF1/2/3) [155]. Several studies have suggested that m6A modification plays a significant role in testicular injury and the decrease of testosterone concentration caused by exogenous toxicants via regulating the expression of testosterone biosynthesis-related enzymes in vivo and in vitro models [156, 157]. PM2.5 can alter m6A modification level and the expression of RNA modulator gene [158]. Currently, only m6A writer METTL3 and METTL16 have been identified to participate in PM2.5-induced injury [159, 160], while it is lack of research on m6A erasers, readers, and other writers.

Conclusions

PM2.5 can lead to many adverse effects on male reproductive system, especially in developing countries which face to the challenge of air pollution. Testosterone plays an important role in maintaining male reproductive health, especially for fertility. Although PM2.5 has a negative impact on male testosterone biosynthesis, few studies have focused on the potential mechanisms. In this review, we aim to explore the potential mechanisms of PM2.5 toxic effects on testosterone level carefully and accurately according to scientific studies. We summarized relevant mechanisms, including oxidative stress, inflammatory response, ferroptosis, pyroptosis, autophagy and mitophagy, miRNAs, ER stress, and m6A modification, which might provide the basis for prevention and treatment of male testosterone level disruption caused by PM2.5. In the future, researchers should pay more attention on the toxic mechanisms of PM2.5 to testosterone biosynthesis. It is wish that under the theoretical framework of this review, researchers can find more exact mechanisms of these effects.

Highlights

PM2.5 causes male testosterone biosynthesis disruption according to existing epidemiological and experimental studies.

Testosterone biosynthesis is closely regulated via complex pathways involving multiple catalytic enzymes.

PM2.5-induced testosterone biosynthesis disruption may lead to various adverse outcome on male health.

Potential toxic mechanisms of PM2.5 are oxidative stress, inflammatory response, ferroptosis, pyroptosis, autophagy and mitophagy, miRNAs, ER stress, and m6A modification.

Corresponding author: Lianglin Qiu, School of Public Health, Nantong University, 9 Seyuan Rd., Nantong, 226019, P.R. China, E-mail:

Funding source: Major Projects of Natural Sciences of University in Jiangsu Province of China

Award Identifier / Grant number: 18KJB330004

Funding source: a project fund of Basic Scientific Research program of Nantong City

Award Identifier / Grant number: JC2019021, JC2020032

Funding source: Natural Science Foundation of Jiangsu Province

Award Identifier / Grant number: BK20221374

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: No. 8130245

Funding source: an innovation project of graduate student scientific research in Jiangsu province

Award Identifier / Grant number: KYCX22_3377

Funding source: Scientific Research Starting Foundation for The Doctoral researcher of Nantong University

Award Identifier / Grant number: No. 14B14

Acknowledgments

The authors acknowledge that there are no conflicts of interest or financial disclosures related to this paper.

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: Conceptualization, S.K.; writing of original draft, S.K.; prepared figures and table, N.Z. and X.J.; review and editing, L.Q.

  4. Competing interests: All authors declare there are no competing interests.

  5. Research funding: This work was supported by National Natural Science Foundation of China (No. 81302452), Natural Science Foundation of Jiangsu Province (BK20221374), Major Projects of Natural Sciences of University in Jiangsu Province of China (18KJB330004), a project fund of Basic Scientific Research program of Nantong City (JC2019021, JC2020032), an innovation project of graduate student scientific research in Jiangsu province (KYCX22_3377) and Scientific Research Starting Foundation for The Doctoral researcher of Nantong University (No. 14B14).

  6. Data availability: Not applicable.

References

1. Yang, Y, Feng, Y, Huang, H, Cui, L, Li, F. PM2.5 exposure induces reproductive injury through IRE1/JNK/autophagy signaling in male rats. Ecotoxicol Environ Saf 2021;211:111924. https://doi.org/10.1016/j.ecoenv.2021.111924.Suche in Google Scholar PubMed

2. Jin, X, Su, R, Li, R, Song, L, Chen, M, Cheng, L, et al.. Amelioration of particulate matter-induced oxidative damage by vitamin c and quercetin in human bronchial epithelial cells. Chemosphere 2016;144:459–66. https://doi.org/10.1016/j.chemosphere.2015.09.023.Suche in Google Scholar PubMed

3. Jeong, SC, Cho, Y, Song, MK, Lee, E, Ryu, JC. Epidermal growth factor receptor (EGFR)-MAPK-nuclear factor(NF)-κB-IL8: a possible mechanism of particulate matter(PM) 2.5-induced lung toxicity. Environ Toxicol 2017;32:1628–36. https://doi.org/10.1002/tox.22390.Suche in Google Scholar PubMed

4. Liu, X, Jin, X, Su, R, Li, Z. The reproductive toxicology of male SD rats after PM2.5 exposure mediated by the stimulation of endoplasmic reticulum stress. Chemosphere 2017;189:547–55. https://doi.org/10.1016/j.chemosphere.2017.09.082.Suche in Google Scholar PubMed

5. Hong, Z, Guo, Z, Zhang, R. Airborne fine particulate matter induces oxidative stress and inflammation in human nasal epithelial cells. Tohoku J Exp Med 2016;239:117–25. https://doi.org/10.1620/tjem.239.117.Suche in Google Scholar PubMed

6. Zhou, L, Su, X, Li, B. PM2.5 exposure impairs sperm quality through testicular damage dependent on NALP3 inflammasome and miR-183/96/182 cluster targeting FOXO1 in mouse. Ecotoxicol Environ Saf 2019;169:551–63. https://doi.org/10.1016/j.ecoenv.2018.10.108.Suche in Google Scholar PubMed

7. Radwan, M, Jurewicz, J, Polańska, K. Exposure to ambient air pollution--does it affect semen quality and the level of reproductive hormones? Ann Hum Biol 2016;43:50–6. https://doi.org/10.3109/03014460.2015.1013986.Suche in Google Scholar PubMed

8. Rolland, M, Le Moal, J, Wagner, V, Royère, D, De Mouzon, J. Decline in semen concentration and morphology in a sample of 26,609 men close to general population between 1989 and 2005 in France. Hum Reprod 2013;28:462–70. https://doi.org/10.1093/humrep/des415.Suche in Google Scholar PubMed PubMed Central

9. Hong, Z, Guo, Z, Zhang, R, Xu, J, Dong, W, Zhuang, G, et al.. Mouse spermatogenesis requires classical and nonclassical testosterone signaling. Biol Reprod 2016;94:11. https://doi.org/10.1095/biolreprod.115.132068.Suche in Google Scholar PubMed PubMed Central

10. Smith, LB, Walker, WH. The regulation of spermatogenesis by androgens. Semin Cell Dev Biol 2014;30:2–13. https://doi.org/10.1016/j.semcdb.2014.02.012.Suche in Google Scholar PubMed PubMed Central

11. Yan, HH, Mruk, DD, Lee, WM, Cheng, CY. Blood-testis barrier dynamics are regulated by testosterone and cytokines via their differential effects on the kinetics of protein endocytosis and recycling in Sertoli cells. FASEB J 2008;22:1945–59. https://doi.org/10.1096/fj.06-070342.Suche in Google Scholar PubMed PubMed Central

12. Ma, B, Zhang, J, Zhu, Z, Zhao, A, Zhou, Y, Ying, H, et al.. Luteolin ameliorates testis injury and blood-testis barrier disruption through the Nrf2 signaling pathway and by upregulating Cx43. Mol Nutr Food Res 2019;63:e1800843. https://doi.org/10.1002/mnfr.201800843.Suche in Google Scholar PubMed

13. Qiu, L, Qian, Y, Liu, Z, Wang, C, Qu, J, Wang, X, et al.. Perfluorooctane sulfonate (PFOS) disrupts blood-testis barrier by down-regulating junction proteins via p38 MAPK/ATF2/MMP9 signaling pathway. Toxicology 2016;373:1–12. https://doi.org/10.1016/j.tox.2016.11.003.Suche in Google Scholar PubMed

14. Liu, J, Ren, L, Wei, J, Zhang, J, Zhu, Y, Li, X, et al.. Fine particle matter disrupts the blood-testis barrier by activating TGF-beta3/p38 MAPK pathway and decreasing testosterone secretion in rat. Environ Toxicol 2018;33:711–9. https://doi.org/10.1002/tox.22556.Suche in Google Scholar PubMed

15. Barone, R, Pitruzzella, A, Marino Gammazza, A, Rappa, F, Salerno, M, Barone, F, et al.. Nandrolone decanoate interferes with testosterone biosynthesis altering blood-testis barrier components. J Cell Mol Med 2017;21:1636–47. https://doi.org/10.1111/jcmm.13092.Suche in Google Scholar PubMed PubMed Central

16. O’Donnell, L, McLachlan, RI, Wreford, NG, de Kretser, DM, Robertson, DM. Testosterone withdrawal promotes stage-specific detachment of round spermatids from the rat seminiferous epithelium. Biol Reprod 1996;55:895–901. https://doi.org/10.1095/biolreprod55.4.895.Suche in Google Scholar PubMed

17. Shi, F, Zhang, Z, Cui, H, Wang, J, Wang, Y, Tang, Y, et al.. Analysis by transcriptomics and metabolomics for the proliferation inhibition and dysfunction through redox imbalance-mediated DNA damage response and ferroptosis in male reproduction of mice and TM4 Sertoli cells exposed to PM2.5. Ecotoxicol Environ Saf 2022;238:113569. https://doi.org/10.1016/j.ecoenv.2022.113569.Suche in Google Scholar PubMed

18. Wang, L, Luo, D, Liu, X, Zhu, J, Wang, F, Li, B, et al.. Effects of PM2.5 exposure on reproductive system and its mechanisms. Chemosphere 2021;264:128436. https://doi.org/10.1016/j.chemosphere.2020.128436.Suche in Google Scholar PubMed

19. Wei, D, Li, S, Liu, X, Zhang, L, Liu, P, Fan, K, et al.. Long-term exposure to particulate matter and residential greenness in relation to androgen and progesterone levels among rural Chinese adults. Environ Int 2021;153:106483. https://doi.org/10.1016/j.envint.2021.106483.Suche in Google Scholar PubMed

20. Zheng, P, Chen, Z, Shi, J, Xue, Y, Bai, Y, Kang, Y, et al.. Association between ambient air pollution and blood sex hormones levels in men. Environ Res 2022;211:113117. https://doi.org/10.1016/j.envres.2022.113117.Suche in Google Scholar PubMed

21. Dankers, AC, Roelofs, MJ, Piersma, AH, Sweep, FC, Russel, FG, van den Berg, M, et al.. Endocrine disruptors differentially target ATP-binding cassette transporters in the blood-testis barrier and affect Leydig cell testosterone secretion in vitro. Toxicol Sci 2013;136:382–91. https://doi.org/10.1093/toxsci/kft198.Suche in Google Scholar PubMed

22. Watanabe, N, Oonuki, Y. Inhalation of diesel engine exhaust affects spermatogenesis in growing male rats. Environ Health Perspect 1999;107:539–44. https://doi.org/10.1289/ehp.99107539.Suche in Google Scholar PubMed PubMed Central

23. Izawa, H, Kohara, M, Watanabe, G, Taya, K, Sagai, M. Diesel exhaust particle toxicity on spermatogenesis in the mouse is aryl hydrocarbon receptor dependent. J Reprod Dev 2007;53:1069–78. https://doi.org/10.1262/jrd.19025.Suche in Google Scholar PubMed

24. Qiu, L, Chen, M, Wang, X, Qin, X, Chen, S, Qian, Y, et al.. Exposure to concentrated ambient PM2.5 compromises spermatogenesis in a mouse model: role of suppression of hypothalamus-pituitary-gonads Axis. Toxicol Sci 2018;162:318–26. https://doi.org/10.1093/toxsci/kfx261.Suche in Google Scholar PubMed PubMed Central

25. Zhou, N, Jiang, C, Chen, Q, Yang, H, Wang, X, Zou, P, et al.. Exposures to atmospheric PM10 and PM10-2.5 affect male semen quality: results of MARHCS study. Environ Sci Technol 2018;52:1571–81. https://doi.org/10.1021/acs.est.7b05206.Suche in Google Scholar PubMed

26. Yang, Y, Yang, T, Liu, S, Cao, Z, Zhao, Y, Su, X, et al.. Concentrated ambient PM2.5 exposure affects mice sperm quality and testosterone biosynthesis. PeerJ 2019;7:e8109. https://doi.org/10.7717/peerj.8109.Suche in Google Scholar PubMed PubMed Central

27. Liu, J, Huang, J, Gao, L, Sang, Y, Li, X, Zhou, G, et al.. Maternal exposure to PM2.5 disrupting offspring spermatogenesis through induced sertoli cells apoptosis via inhibin B hypermethylation in mice. Ecotoxicol Environ Saf 2022;241:113760. https://doi.org/10.1016/j.ecoenv.2022.113760.Suche in Google Scholar PubMed

28. Ren, L, Jiang, J, Huang, J, Zang, Y, Huang, Q, Zhang, L, et al.. Maternal exposure to PM2.5 induces the testicular cell apoptosis in offspring triggered by the UPR-mediated JNK pathway. Toxicol Res 2022;11:226–34. https://doi.org/10.1093/toxres/tfab116.Suche in Google Scholar PubMed PubMed Central

29. Alewel, DI, Henriquez, AR, Schladweiler, MC, Grindstaff, R, Fisher, AA, Snow, SJ, et al.. Intratracheal instillation of respirable particulate matter elicits neuroendocrine activation. Inhal Toxicol 2023;35:59–75. https://doi.org/10.1080/08958378.2022.2100019.Suche in Google Scholar PubMed PubMed Central

30. Zheng, S, Jiang, L, Qiu, L. The effects of fine particulate matter on the blood-testis barrier and its potential mechanisms. Rev Environ Health 2024;39:233–49. https://doi.org/10.1515/reveh-2022-0204.Suche in Google Scholar PubMed

31. Yang, RZ, Xu, WN, Zheng, HL, Zheng, XF, Li, B, Jiang, LS, et al.. Involvement of oxidative stress-induced annulus fibrosus cell and nucleus pulposus cell ferroptosis in intervertebral disc degeneration pathogenesis. J Cell Physiol 2021;236:2725–39. https://doi.org/10.1002/jcp.30039.Suche in Google Scholar PubMed PubMed Central

32. Le, X, Mu, J, Peng, W, Tang, J, Xiang, Q, Tian, S, et al.. DNA methylation downregulated ZDHHC1 suppresses tumor growth by altering cellular metabolism and inducing oxidative/ER stress-mediated apoptosis and pyroptosis. Theranostics 2020;10:9495–511. https://doi.org/10.7150/thno.45631.Suche in Google Scholar PubMed PubMed Central

33. Yang, L, Duan, Z, Liu, X, Yuan, Y. N-acetyl-l-cysteine ameliorates the PM2.5-induced oxidative stress by regulating SIRT-1 in rats. Environ Toxicol Pharmacol 2018;57:70–5. https://doi.org/10.1016/j.etap.2017.11.011.Suche in Google Scholar PubMed

34. Khawar, MB, Liu, C, Gao, F, Gao, H, Liu, W, Han, T, et al.. Sirt1 regulates testosterone biosynthesis in Leydig cells via modulating autophagy. Protein Cell 2021;12:67–75. https://doi.org/10.1007/s13238-020-00771-1.Suche in Google Scholar PubMed PubMed Central

35. Yao, H, Rahman, I. Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence. Biochem Pharmacol 2012;84:1332–9. https://doi.org/10.1016/j.bcp.2012.06.031.Suche in Google Scholar PubMed PubMed Central

36. Ren, F, Ji, C, Huang, Y, Aniagu, S, Jiang, Y, Chen, T. AHR-mediated ROS production contributes to the cardiac developmental toxicity of PM2.5 in zebrafish embryos. Sci Total Environ 2020;719:135097. https://doi.org/10.1016/j.scitotenv.2019.135097.Suche in Google Scholar PubMed

37. Szychowski, KA, Skóra, B, Wójtowicz, AK. Involvement of sirtuins (Sirt1 and Sirt3) and aryl hydrocarbon receptor (AhR) in the effects of triclosan (TCS) on production of neurosteroids in primary mouse cortical neurons cultures. Pestic Biochem Physiol 2022;184:105131. https://doi.org/10.1016/j.pestbp.2022.105131.Suche in Google Scholar PubMed

38. Barć, J, Gregoraszczuk, EL. Halowax 1051 affects steroidogenesis by down-regulation of aryl hydrocarbon and estrogen receptors and up-regulation of androgen receptor in porcine ovarian follicles. Chemosphere 2016;144:467–74. https://doi.org/10.1016/j.chemosphere.2015.09.026.Suche in Google Scholar PubMed

39. Liu, C, Yang, J, Du, X, Geng, X. Filtered air intervention modulates hypothalamic-pituitary-thyroid/gonadal axes by attenuating inflammatory responses in adult rats after fine particulate matter (PM2.5) exposure. Environ Sci Pollut Res Int 2022;29:74851–60. https://doi.org/10.1007/s11356-022-21102-3.Suche in Google Scholar PubMed

40. Zhang, C, Bian, H, Chen, Z, Tian, B, Wang, H, Tu, X, et al.. The association between dietary inflammatory index and sex hormones among men in the United States. J Urol 2021;206:97–103. https://doi.org/10.1097/JU.0000000000001703.Suche in Google Scholar PubMed

41. Zhu, MM, Wang, L, Yang, D, Li, C, Pang, ST, Li, XH, et al.. Wedelolactone alleviates doxorubicin-induced inflammation and oxidative stress damage of podocytes by IκK/IκB/NF-κB pathway. Biomed Pharmacother 2019;117:109088. https://doi.org/10.1016/j.biopha.2019.109088.Suche in Google Scholar PubMed

42. Woodward, NC, Levine, MC, Haghani, A, Shirmohammadi, F, Saffari, A, Sioutas, C, et al.. Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo. J Neuroinflammation 2017;14:84. https://doi.org/10.1186/s12974-017-0858-x.Suche in Google Scholar PubMed PubMed Central

43. Dai, P, Shen, D, Shen, J, Tang, Q, Xi, M, Li, Y, et al.. The roles of Nrf2 and autophagy in modulating inflammation mediated by TLR4 – NFκB in A549 cell exposed to layer house particulate matter 2.5 (PM2.5). Chemosphere 2019;235:1134–45. https://doi.org/10.1016/j.chemosphere.2019.07.002.Suche in Google Scholar PubMed

44. Zhou, Y, Liu, J, Jiang, C, Chen, J, Feng, X, Chen, W, et al.. A traditional herbal formula, Deng-Shi-Qing-Mai-Tang, regulates TLR4/NF-κB signaling pathway to reduce inflammatory response in PM2.5-induced lung injury. Phytomedicine 2021;91:153665. https://doi.org/10.1016/j.phymed.2021.153665.Suche in Google Scholar PubMed

45. Li, Y, Zhang, Y, Feng, R, Zheng, P, Huang, H, Zhou, S, et al.. Cadmium induces testosterone synthesis disorder by testicular cell damage via TLR4/MAPK/NF-κB signaling pathway leading to reduced sexual behavior in piglets. Ecotoxicol Environ Saf 2022;233:113345. https://doi.org/10.1016/j.ecoenv.2022.113345.Suche in Google Scholar PubMed

46. Wang, H, Zang, C, Liu, XS, Aster, JC. The role of Notch receptors in transcriptional regulation. J Cell Physiol 2015;230:982–8. https://doi.org/10.1002/jcp.24872.Suche in Google Scholar PubMed PubMed Central

47. Xia, M, Harb, H, Saffari, A, Sioutas, C, Chatila, TA. A Jagged 1-Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles. J Allergy Clin Immunol 2018;142:1243–56. https://doi.org/10.1016/j.jaci.2018.03.009.Suche in Google Scholar PubMed PubMed Central

48. Park, JH, Choi, JY, Lee, HK, Jo, C, Koh, YH. Notch1-mediated inflammation is associated with endothelial dysfunction in human brain microvascular endothelial cells upon particulate matter exposure. Arch Toxicol 2021;95:529–40. https://doi.org/10.1007/s00204-020-02942-9.Suche in Google Scholar PubMed

49. Zhao, Y, Liu, H, Yang, Y, Huang, W, Chao, L. The effect and mechanism of Grim 19 on mouse sperm quality and testosterone synthesis. Reproduction 2022;163:365–77. https://doi.org/10.1530/REP-21-0385.Suche in Google Scholar PubMed

50. Chu, C, Zhang, H, Cui, S, Han, B, Zhou, L, Zhang, N, et al.. Ambient PM2.5 caused depressive-like responses through Nrf2/NLRP3 signaling pathway modulating inflammation. J Hazard Mater 2019;369:180–90. https://doi.org/10.1016/j.jhazmat.2019.02.026.Suche in Google Scholar PubMed

51. Jia, G, Yu, S, Sun, W, Yang, J, Wang, Y, Qi, Y, et al.. Hydrogen sulfide attenuates particulate matter-induced emphysema and airway inflammation through nrf2-dependent manner. Front Pharmacol 2020;11:29. https://doi.org/10.3389/fphar.2020.00029.Suche in Google Scholar PubMed PubMed Central

52. Li, M, Hua, Q, Shao, Y, Zeng, H, Liu, Y, Diao, Q, et al.. Circular RNA circBbs9 promotes PM2.5-induced lung inflammation in mice via NLRP3 inflammasome activation. Environ Int 2020;143:105976. https://doi.org/10.1016/j.envint.2020.105976.Suche in Google Scholar PubMed

53. Antonuccio, P, Micali, AG, Romeo, C, Freni, J, Vermiglio, G, Puzzolo, D, et al.. NLRP3 inflammasome: a new pharmacological target for reducing testicular damage associated with varicocele. Int J Mol Sci 2021;22:1319. https://doi.org/10.3390/ijms22031319.Suche in Google Scholar PubMed PubMed Central

54. Song, C, Liu, L, Chen, J, Hu, Y, Li, J, Wang, B, et al.. Evidence for the critical role of the PI3K signaling pathway in particulate matter-induced dysregulation of the inflammatory mediators COX-2/PGE2 and the associated epithelial barrier protein Filaggrin in the bronchial epithelium. Cell Biol Toxicol 2020;36:301–13. https://doi.org/10.1007/s10565-019-09508-1.Suche in Google Scholar PubMed PubMed Central

55. Lu, B, Ran, Y, Wang, S, Li, J, Zhao, Y, Ran, X, et al.. Chronic oral depleted uranium leads to reproductive damage in male rats through the ROS-hnRNP A2/B1-COX-2 signaling pathway. Toxicology 2021;449:152666. https://doi.org/10.1016/j.tox.2020.152666.Suche in Google Scholar PubMed

56. Jin, JY, Wei, XX, Zhi, XL, Wang, XH, Meng, D. Drp1-dependent mitochondrial fission in cardiovascular disease. Acta Pharmacol Sin 2021;42:655–64. https://doi.org/10.1038/s41401-020-00518-y.Suche in Google Scholar PubMed PubMed Central

57. Wang, Y, Xiong, L, Yao, Y, Ma, Y, Liu, Q, Pang, Y, et al.. The involvement of DRP1-mediated caspase-1 activation in inflammatory response by urban particulate matter in EA.hy926 human vascular endothelial cells. Environ Pollut 2021;287:117369. https://doi.org/10.1016/j.envpol.2021.117369.Suche in Google Scholar PubMed

58. Ma, X, Chen, A, Melo, L, Clemente-Sanchez, A, Chao, X, Ahmadi, AR, et al.. Loss of hepatic DRP1 exacerbates alcoholic hepatitis by inducing megamitochondria and mitochondrial maladaptation. Hepatology 2023;77:159–75. https://doi.org/10.1002/hep.32604.Suche in Google Scholar PubMed PubMed Central

59. Li, R, Zhang, J, Wang, Q, Cheng, M, Lin, B. TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway. J Neuroinflammation 2022;19:257. https://doi.org/10.1186/s12974-022-02619-3.Suche in Google Scholar PubMed PubMed Central

60. Dixon, SJ, Lemberg, KM, Lamprecht, MR, Skouta, R, Zaitsev, EM, Gleason, CE, et al.. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012;149:1060–72. https://doi.org/10.1016/j.cell.2012.03.042.Suche in Google Scholar PubMed PubMed Central

61. Wang, Y, Tang, M. PM2.5 induces ferroptosis in human endothelial cells through iron overload and redox imbalance. Environ Pollut 2019;254:112937. https://doi.org/10.1016/j.envpol.2019.07.105.Suche in Google Scholar PubMed

62. Gu, Y, Hao, S, Liu, K, Gao, M, Lu, B, Sheng, F, et al.. Airborne fine particulate matter (PM2.5) damages the inner blood-retinal barrier by inducing inflammation and ferroptosis in retinal vascular endothelial cells. Sci Total Environ 2022;838:156563. https://doi.org/10.1016/j.scitotenv.2022.156563.Suche in Google Scholar PubMed

63. Zeng, L, Zhou, J, Wang, X, Zhang, Y, Wang, M, Su, P. Cadmium attenuates testosterone synthesis by promoting ferroptosis and blocking autophagosome-lysosome fusion. Free Radic Biol Med 2021;176:176–88. https://doi.org/10.1016/j.freeradbiomed.2021.09.028.Suche in Google Scholar PubMed

64. Guohua, F, Tieyuan, Z, Xinping, M, Juan, X. Melatonin protects against PM2.5-induced lung injury by inhibiting ferroptosis of lung epithelial cells in a Nrf2-dependent manner. Ecotoxicol Environ Saf 2021;223:112588. https://doi.org/10.1016/j.ecoenv.2021.112588.Suche in Google Scholar PubMed

65. Dodson, M, de la Vega, MR, Cholanians, AB, Schmidlin, CJ, Chapman, E, Zhang, DD. Modulating NRF2 in disease: timing is everything. Annu Rev Pharmacol Toxicol 2019;59:555–75. https://doi.org/10.1146/annurev-pharmtox-010818-021856.Suche in Google Scholar PubMed PubMed Central

66. Dodson, M, Castro-Portuguez, R, Zhang, DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol 2019;23:101107. https://doi.org/10.1016/j.redox.2019.101107.Suche in Google Scholar PubMed PubMed Central

67. Chen, H, Jin, S, Guo, J, Kombairaju, P, Biswal, S, Zirkin, BR. Knockout of the transcription factor Nrf2: effects on testosterone production by aging mouse Leydig cells. Mol Cell Endocrinol 2015;409:113–20. https://doi.org/10.1016/j.mce.2015.03.013.Suche in Google Scholar PubMed PubMed Central

68. Tang, D, Chen, X, Kang, R, Kroemer, G. Ferroptosis: molecular mechanisms and health implications. Cell Res 2021;31:107–25. https://doi.org/10.1038/s41422-020-00441-1.Suche in Google Scholar PubMed PubMed Central

69. Yu, P, Zhang, X, Liu, N, Tang, L, Peng, C, Chen, X. Pyroptosis: mechanisms and diseases. Signal Transduct Targeted Ther 2021;6:128. https://doi.org/10.1038/s41392-021-00507-5.Suche in Google Scholar PubMed PubMed Central

70. Van Opdenbosch, N, Lamkanfi, M. Caspases in cell death, inflammation, and disease. Immunity 2019;50:1352–64. https://doi.org/10.1016/j.immuni.2019.05.020.Suche in Google Scholar PubMed PubMed Central

71. Shi, J, Zhao, Y, Wang, K, Shi, X, Wang, Y, Huang, H, et al.. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015;526:660–5. https://doi.org/10.1038/nature15514.Suche in Google Scholar PubMed

72. Kuang, S, Zheng, J, Yang, H, Li, S, Duan, S, Shen, Y, et al.. Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis. Proc Natl Acad Sci USA 2017;114:10642–7. https://doi.org/10.1073/pnas.1708194114.Suche in Google Scholar PubMed PubMed Central

73. Thornberry, NA, Bull, HG, Calaycay, JR, Chapman, KT, Howard, AD, Kostura, MJ, et al.. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 1992;356:768–74. https://doi.org/10.1038/356768a0.Suche in Google Scholar PubMed

74. Hou, J, Hsu, JM, Hung, MC. Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity. Mol Cell 2021;81:4579–90. https://doi.org/10.1016/j.molcel.2021.09.003.Suche in Google Scholar PubMed PubMed Central

75. Xu, B, Jiang, M, Chu, Y, Wang, W, Chen, D, Li, X, et al.. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. J Hepatol 2018;68:773–82. https://doi.org/10.1016/j.jhep.2017.11.040.Suche in Google Scholar PubMed

76. de Vasconcelos, NM, Van Opdenbosch, N, Van Gorp, H, Parthoens, E, Lamkanfi, M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ 2019;26:146–61. https://doi.org/10.1038/s41418-018-0106-7.Suche in Google Scholar PubMed PubMed Central

77. Zhaolin, Z, Guohua, L, Shiyuan, W, Zuo, W. Role of pyroptosis in cardiovascular disease. Cell Prolif 2019;52:e12563. https://doi.org/10.1111/cpr.12563.Suche in Google Scholar PubMed PubMed Central

78. Rühl, S, Broz, P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux. Eur J Immunol 2015;45:2927–36. https://doi.org/10.1002/eji.201545772.Suche in Google Scholar PubMed

79. Li, J, An, Z, Song, J, Du, J, Zhang, L, Jiang, J, et al.. Fine particulate matter-induced lung inflammation is mediated by pyroptosis in mice. Ecotoxicol Environ Saf 2021;219:112351. https://doi.org/10.1016/j.ecoenv.2021.112351.Suche in Google Scholar PubMed

80. Li, J, Zhang, Y, Zhang, L, An, Z, Song, J, Wang, C, et al.. Fine particulate matter exposure exacerbated nasal mucosal damage in allergic rhinitis mice via NLRP3 mediated pyroptosis. Ecotoxicol Environ Saf 2021;228:112998. https://doi.org/10.1016/j.ecoenv.2021.112998.Suche in Google Scholar PubMed

81. Niu, L, Li, L, Xing, C, Luo, B, Hu, C, Song, M, et al.. Airborne particulate matter (PM2.5) triggers cornea inflammation and pyroptosis via NLRP3 activation. Ecotoxicol Environ Saf 2021;207:111306. https://doi.org/10.1016/j.ecoenv.2020.111306.Suche in Google Scholar PubMed

82. Li, Y, Su, Y, Zhou, T, Hu, Z, Wei, J, Wang, W, et al.. Activation of the NLRP3 inflammasome pathway by prokineticin 2 in testicular macrophages of uropathogenic Escherichia coli-induced orchitis. Front Immunol. 2019;10:1872. https://doi.org/10.3389/fimmu.2019.01872 Suche in Google Scholar PubMed PubMed Central

83. Fouad, AA, Abdel-Aziz, AM, Hamouda, AAH. Diacerein downregulates NLRP3/caspase-1/IL-1β and IL-6/STAT3 pathways of inflammation and apoptosis in a rat model of cadmium testicular toxicity. Biol Trace Elem Res 2020;195:499–505. https://doi.org/10.1007/s12011-019-01865-6.Suche in Google Scholar PubMed

84. Arab, HH, Elhemiely, AA, El-Sheikh, AAK, Khabbaz, HJA, Arafa, EA, Ashour, AM, et al.. Repositioning linagliptin for the mitigation of cadmium-induced testicular dysfunction in rats: targeting HMGB1/TLR4/NLRP3 Axis and autophagy. Pharmaceuticals 2022;15:852. https://doi.org/10.3390/ph15070852.Suche in Google Scholar PubMed PubMed Central

85. Parzych, KR, Klionsky, DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxidants Redox Signal 2014;20:460–73. https://doi.org/10.1089/ars.2013.5371.Suche in Google Scholar PubMed PubMed Central

86. Glick, D, Barth, S, Macleod, KF. Autophagy: cellular and molecular mechanisms. J Pathol 2010;221:3–12. https://doi.org/10.1002/path.2697.Suche in Google Scholar PubMed PubMed Central

87. Deng, X, Zhang, F, Rui, W, Long, F, Wang, L, Feng, Z, et al.. PM2.5-induced oxidative stress triggers autophagy in human lung epithelial A549 cells. Toxicol Vitro 2013;27:1762–70. https://doi.org/10.1016/j.tiv.2013.05.004.Suche in Google Scholar PubMed

88. Bai, R, Guan, L, Zhang, W, Xu, J, Rui, W, Zhang, F, et al.. Comparative study of the effects of PM1-induced oxidative stress on autophagy and surfactant protein B and C expressions in lung alveolar type II epithelial MLE-12 cells. Biochim Biophys Acta 2016;1860:2782–92. https://doi.org/10.1016/j.bbagen.2016.05.020.Suche in Google Scholar PubMed

89. Su, R, Jin, X, Zhang, W, Li, Z, Liu, X, Ren, J. Particulate matter exposure induces the autophagy of macrophages via oxidative stress-mediated PI3K/AKT/mTOR pathway. Chemosphere 2017;167:444–53. https://doi.org/10.1016/j.chemosphere.2016.10.024.Suche in Google Scholar PubMed

90. Deng, X, Zhang, F, Wang, L, Rui, W, Long, F, Zhao, Y, et al.. Airborne fine particulate matter induces multiple cell death pathways in human lung epithelial cells. Apoptosis 2014;19:1099–112. https://doi.org/10.1007/s10495-014-0980-5.Suche in Google Scholar PubMed

91. Liu, T, Wu, B, Wang, Y, He, H, Lin, Z, Tan, J, et al.. Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells. Mol Med Rep 2015;12:1914–22. https://doi.org/10.3892/mmr.2015.3577.Suche in Google Scholar PubMed PubMed Central

92. Xu, X, Wang, H, Liu, S, Xing, C, Liu, Y, Aodengqimuge, et al.. TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5). Autophagy 2016;12:1832–48. https://doi.org/10.1080/15548627.2016.1204496.Suche in Google Scholar PubMed PubMed Central

93. Shumin, Z, Luying, Z, Senlin, L, Jiaxian, P, Yang, L, Lanfang, R, et al.. Ambient particulate matter-associated autophagy alleviates pulmonary inflammation induced by Platanus pollen protein 3 (Pla3). Sci Total Environ 2021;758:143696. https://doi.org/10.1016/j.scitotenv.2020.143696IF:10.753Q1.10.1016/j.scitotenv.2020.143696Suche in Google Scholar PubMed

94. Pei, C, Wang, F, Huang, D, Shi, S, Wang, X, Wang, Y, et al.. Astragaloside IV protects from PM2.5-induced lung injury by regulating autophagy via inhibition of PI3K/Akt/mTOR signaling in vivo and in vitro. J Inflamm Res. 2021;14:4707-21. https://doi.org/10.2147/JIR.S312167.Suche in Google Scholar PubMed PubMed Central

95. Zhang, XJ, Chen, S, Huang, KX, Le, WD. Why should autophagic flux be assessed? Acta Pharmacol Sin 2013;34:595–9. https://doi.org/10.1038/aps.2012.184.Suche in Google Scholar PubMed PubMed Central

96. Zhang, J, Ye, R, Grunberger, JW, Jin, J, Zhang, Q, Mohammadpour, R, et al.. Activation of autophagy by low-dose silica nanoparticles enhances testosterone secretion in leydig cells. Int J Mol Sci 2022;23:3104. https://doi.org/10.3390/ijms23063104.Suche in Google Scholar PubMed PubMed Central

97. Li, MY, Zhu, XL, Zhao, BX, Shi, L, Wang, W, Hu, W, et al.. Adrenomedullin alleviates the pyroptosis of Leydig cells by promoting autophagy via the ROS-AMPK-mTOR axis. Cell Death Dis 2019;10:489. https://doi.org/10.1038/s41419-019-1728-5.Suche in Google Scholar PubMed PubMed Central

98. Khedr, NF, Werida, RH. l-carnitine modulates autophagy, oxidative stress and inflammation in trazodone induced testicular toxicity. Life Sci 2022;290:120025. https://doi.org/10.1016/j.lfs.2021.120025.Suche in Google Scholar PubMed

99. Qiu, YN, Wang, GH, Zhou, F, Hao, JJ, Tian, L, Guan, LF, et al.. PM2.5 induces liver fibrosis via triggering ROS-mediated mitophagy. Ecotoxicol Environ Saf 2019;167:178–87. https://doi.org/10.1016/j.ecoenv.2018.08.050.Suche in Google Scholar PubMed

100. Wu, X, Li, J, Wang, S, Jiang, L, Sun, X, Liu, X, et al.. 2-Undecanone protects against fine particle-induced kidney inflammation via inducing mitophagy. J Agric Food Chem 2021;69:5206–15. https://doi.org/10.1021/acs.jafc.1c01305.Suche in Google Scholar PubMed

101. Lu, L, Liu, JB, Wang, JQ, Lian, CY, Wang, ZY, Wang, L. Glyphosate-induced mitochondrial reactive oxygen species overproduction activates parkin-dependent mitophagy to inhibit testosterone synthesis in mouse leydig cells. Environ Pollut 2022;314:120314. https://doi.org/10.1016/j.envpol.2022.120314.Suche in Google Scholar PubMed

102. Mancini, FR, Laine, JE, Tarallo, S, Vlaanderen, J, Vermeulen, R, van Nunen, E, et al.. microRNA expression profiles and personal monitoring of exposure to particulate matter. Environ Pollut 2020;263:114392. https://doi.org/10.1016/j.envpol.2020.114392.Suche in Google Scholar PubMed

103. Chen, H, Xu, Y, Rappold, A, Diaz-Sanchez, D, Tong, H. Effects of ambient ozone exposure on circulating extracellular vehicle microRNA levels in coronary artery disease patients. J Toxicol Environ Health 2020;83:351–62. https://doi.org/10.1080/15287394.2020.1762814.Suche in Google Scholar PubMed PubMed Central

104. Zhou, T, Yu, Q, Sun, C, Wang, Y, Zhong, Y, Wang, G. A pilot study of blood microRNAs and lung function in young healthy adults with fine particulate matter exposure. J Thorac Dis 2018;10:7073–80. https://doi.org/10.21037/jtd.2018.12.42.Suche in Google Scholar PubMed PubMed Central

105. Rodosthenous, RS, Kloog, I, Colicino, E, Zhong, J, Herrera, LA, Vokonas, P, et al.. Extracellular vesicle-enriched microRNAs interact in the association between long-term particulate matter and blood pressure in elderly men. Environ Res 2018;167:640–9. https://doi.org/10.1016/j.envres.2018.09.002.Suche in Google Scholar PubMed PubMed Central

106. Zhang, C, Liu, K, Li, T, Fang, J, Ding, Y, Sun, L, et al.. miR-21: a gene of dual regulation in breast cancer. Int J Oncol 2016;48:161–72. https://doi.org/10.3892/ijo.2015.3232.Suche in Google Scholar PubMed

107. Dai, J, Chen, W, Lin, Y, Wang, S, Guo, X, Zhang, QQ. Exposure to concentrated ambient fine particulate matter induces vascular endothelial dysfunction via miR-21. Int J Biol Sci 2017;13:868–77. https://doi.org/10.7150/ijbs.19868.Suche in Google Scholar PubMed PubMed Central

108. Xie, W, Ling, M, Xiao, T, Fan, Z, Chen, D, Tang, M, et al.. Tanshinone IIA-regulation of IL-6 antagonizes PM2.5 -induced proliferation of human bronchial epithelial cells via a STAT3/miR-21 reciprocal loop. Environ Toxicol 2022;37:1686–96. https://doi.org/10.1002/tox.23517.Suche in Google Scholar PubMed

109. Damber, JE, Bergh, A, Daehlin, L. Testicular blood flow, vascular permeability, and testosterone production after stimulation of unilaterally cryptorchid adult rats with human chorionic gonadotropin. Endocrinology 1985;117:1906–13. https://doi.org/10.1210/endo-117-5-1906.Suche in Google Scholar PubMed

110. Chen, H, Guo, X, Xiao, X, Ye, L, Huang, Y, Lu, C, et al.. Identification and functional characterization of microRNAs in rat Leydig cells during development from the progenitor to the adult stage. Mol Cell Endocrinol 2019;493:110453. https://doi.org/10.1016/j.mce.2019.110453.Suche in Google Scholar PubMed

111. Motta, V, Angelici, L, Nordio, F, Bollati, V, Fossati, S, Frascati, F, et al.. Integrative Analysis of miRNA and inflammatory gene expression after acute particulate matter exposure. Toxicol Sci 2013;132:307–16. https://doi.org/10.1093/toxsci/kft013.Suche in Google Scholar PubMed PubMed Central

112. Long, W, Zhao, C, Ji, C, Ding, H, Cui, Y, Guo, X, et al.. Characterization of serum microRNAs profile of PCOS and identification of novel non-invasive biomarkers. Cell Physiol Biochem 2014;33:1304–15. https://doi.org/10.1159/000358698.Suche in Google Scholar PubMed

113. Shang, Y, Liu, Q, Wang, L, Qiu, X, Chen, Y, An, J. microRNA-146a-5p negatively modulates PM2.5 caused inflammation in THP-1 cells via autophagy process. Environ Pollut 2021;268:115961. https://doi.org/10.1016/j.envpol.2020.115961.Suche in Google Scholar PubMed

114. Bleck, B, Grunig, G, Chiu, A, Liu, M, Gordon, T, Kazeros, A, et al.. MicroRNA-375 regulation of thymic stromal lymphopoietin by diesel exhaust particles and ambient particulate matter in human bronchial epithelial cells. J Immunol 2013;190:3757–63. https://doi.org/10.4049/jimmunol.1201165.Suche in Google Scholar PubMed PubMed Central

115. Fossati, S, Baccarelli, A, Zanobetti, A, Hoxha, M, Vokonas, PS, Wright, RO, et al.. Ambient particulate air pollution and microRNAs in elderly men. Epidemiology 2014;25:68–78. https://doi.org/10.1097/EDE.0000000000000026.Suche in Google Scholar PubMed PubMed Central

116. Borgie, M, Ledoux, F, Verdin, A, Cazier, F, Greige, H, Shirali, P, et al.. Genotoxic and epigenotoxic effects of fine particulate matter from rural and urban sites in Lebanon on human bronchial epithelial cells. Environ Res 2015;136:352–62. https://doi.org/10.1016/j.envres.2014.10.010.Suche in Google Scholar PubMed

117. Longhin, E, Capasso, L, Battaglia, C, Proverbio, MC, Cosentino, C, Cifola, I, et al.. Integrative transcriptomic and protein analysis of human bronchial BEAS-2B exposed to seasonal urban particulate matter. Environ Pollut 2016;209:87–98. https://doi.org/10.1016/j.envpol.2015.11.013.Suche in Google Scholar PubMed

118. Rodosthenous, RS, Coull, BA, Lu, Q, Vokonas, PS, Schwartz, JD, Baccarelli, AA. Ambient particulate matter and microRNAs in extracellular vesicles: a pilot study of older individuals. Part Fibre Toxicol 2016;13:13. https://doi.org/10.1186/s12989-016-0121-0.Suche in Google Scholar PubMed PubMed Central

119. Chao, MW, Yang, CH, Lin, PT, Yang, YH, Chuang, YC, Chung, MC, et al.. Exposure to PM2.5 causes genetic changes in fetal rat cerebral cortex and hippocampus. Environ Toxicol 2017;32:1412–25. https://doi.org/10.1002/tox.22335.Suche in Google Scholar PubMed

120. Ku, T, Li, B, Gao, R, Zhang, Y, Yan, W, Ji, X, et al.. NF-κB-regulated microRNA-574-5p underlies synaptic and cognitive impairment in response to atmospheric PM2.5 aspiration. Part Fibre Toxicol 2017;14:34. https://doi.org/10.1186/s12989-017-0215-3.Suche in Google Scholar PubMed PubMed Central

121. Wei, H, Liang, F, Cheng, W, Zhou, R, Wu, X, Feng, Y, et al.. The mechanisms for lung cancer risk of PM2.5 : induction of epithelial-mesenchymal transition and cancer stem cell properties in human non-small cell lung cancer cells. Environ Toxicol 2017;32:2341–51. https://doi.org/10.1002/tox.22437.Suche in Google Scholar PubMed

122. Hou, T, Liao, J, Zhang, C, Sun, C, Li, X, Wang, G. Elevated expression of miR-146, miR-139 and miR-340 involved in regulating Th1/Th2 balance with acute exposure of fine particulate matter in mice. Int Immunopharm 2018;54:68–77. https://doi.org/10.1016/j.intimp.2017.10.003.Suche in Google Scholar PubMed

123. Chen, R, Li, H, Cai, J, Wang, C, Lin, Z, Liu, C, et al.. Fine particulate air pollution and the expression of microRNAs and circulating cytokines relevant to inflammation, coagulation, and vasoconstriction. Environ Health Perspect 2018;126:017007. https://doi.org/10.1289/EHP1447.Suche in Google Scholar PubMed PubMed Central

124. Espín-Pérez, A, Krauskopf, J, Chadeau-Hyam, M, van Veldhoven, K, Chung, F, Cullinan, P, et al.. Short-term transcriptome and microRNAs responses to exposure to different air pollutants in two population studies. Environ Pollut 2018;242:182–90. https://doi.org/10.1016/j.envpol.2018.06.051.Suche in Google Scholar PubMed

125. Luo, F, Wei, H, Guo, H, Li, Y, Feng, Y, Bian, Q, et al.. LncRNA MALAT1, an lncRNA acting via the miR-204/ZEB1 pathway, mediates the EMT induced by organic extract of PM2.5 in lung bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2019;317:L87–98. https://doi.org/10.1152/ajplung.00073.2019.Suche in Google Scholar PubMed

126. Wang, Y, Zou, L, Wu, T, Xiong, L, Zhang, T, Kong, L, et al.. Identification of mRNA-miRNA crosstalk in human endothelial cells after exposure of PM2.5 through integrative transcriptome analysis. Ecotoxicol Environ Saf 2019;169:863–73. https://doi.org/10.1016/j.ecoenv.2018.11.114.Suche in Google Scholar PubMed

127. Wang, J, Zhu, M, Ye, L, Chen, C, She, J, Song, Y. MiR-29b-3p promotes particulate matter-induced inflammatory responses by regulating the C1QTNF6/AMPK pathway. Aging (Albany NY) 2020;12:1141–58. https://doi.org/10.18632/aging.102672.Suche in Google Scholar PubMed PubMed Central

128. Chen, H, Zhang, X, Zhang, T, Li, X, Li, J, Yue, Y, et al.. Ambient PM toxicity is correlated with expression levels of specific MicroRNAs. Environ Sci Technol 2020;54:10227–36. https://doi.org/10.1021/acs.est.0c03876.Suche in Google Scholar PubMed

129. Feng, L, Wei, J, Liang, S, Sun, Z, Duan, J. miR-205/IRAK2 signaling pathway is associated with urban airborne PM2.5-induced myocardial toxicity. Nanotoxicology 2020;14:1198–212. https://doi.org/10.1080/17435390.2020.1813824.Suche in Google Scholar PubMed

130. Liu, LZ, Wang, M, Xin, Q, Wang, B, Chen, GG, Li, MY. The permissive role of TCTP in PM2.5/NNK-induced epithelial-mesenchymal transition in lung cells. J Transl Med 2020;18:66. https://doi.org/10.1186/s12967-020-02256-5.Suche in Google Scholar PubMed PubMed Central

131. Wang, Y, Zhong, Y, Zhang, C, Liao, J, Wang, G. PM2.5 downregulates MicroRNA-139-5p and induces EMT in bronchiolar epithelium cells by targeting Notch1. J Cancer 2020;11:5758–67. https://doi.org/10.7150/jca.46976.Suche in Google Scholar PubMed PubMed Central

132. Cai, Y, Li, R, Zheng, K, Wang, B, Qin, S, Li, B, et al.. Effect of c-fos gene silence on PM2.5-induced miRNA alteration in human bronchial epithelial cells. Environ Toxicol Pharmacol 2021;84:103607. https://doi.org/10.1016/j.etap.2021.103607.Suche in Google Scholar PubMed

133. Li, B, Huang, N, Wei, S, Xv, J, Meng, Q, Aschner, M, et al.. lncRNA TUG1 as a ceRNA promotes PM exposure-induced airway hyper-reactivity. J Hazard Mater 2021;416:125878. https://doi.org/10.1016/j.jhazmat.2021.125878.Suche in Google Scholar PubMed PubMed Central

134. Wang, Y, Zhong, Y, Sun, K, Fan, Y, Liao, J, Wang, G. Identification of exosome miRNAs in bronchial epithelial cells after PM2.5 chronic exposure. Ecotoxicol Environ Saf 2021;215:112127. https://doi.org/10.1016/j.ecoenv.2021.112127.Suche in Google Scholar PubMed

135. Fu, P, Zhao, Y, Dong, C, Cai, Z, Li, R, Yung, KKL. An integrative analysis of miRNA and mRNA expression in the brains of Alzheimer’s disease transgenic mice after real-world PM2.5 exposure. J Environ Sci 2022;122:25–40. https://doi.org/10.1016/j.jes.2021.10.007.Suche in Google Scholar PubMed

136. Gao, Y, Zhang, Q, Sun, J, Liang, Y, Zhang, M, Zhao, M, et al.. Extracellular vesicles derived from PM2.5-exposed alveolar epithelial cells mediate endothelial adhesion and atherosclerosis in ApoE-/- mice. FASEB J 2022;36:e22161. https://doi.org/10.1096/fj.202100927RR.Suche in Google Scholar PubMed

137. Jia, Q, Li, Q, Wang, Y, Zhao, J, Jiang, Q, Wang, H, et al.. Lung microbiome and transcriptome reveal mechanisms underlying PM2.5 induced pulmonary fibrosis. Sci Total Environ 2022;831:154974. https://doi.org/10.1016/j.scitotenv.2022.154974.Suche in Google Scholar PubMed

138. Anelli, T, Sitia, R. Protein quality control in the early secretory pathway. EMBO J 2008;27:315–27. https://doi.org/10.1038/sj.emboj.7601974.Suche in Google Scholar PubMed PubMed Central

139. Zhang, J, Guo, J, Yang, N, Huang, Y, Hu, T, Rao, C. Endoplasmic reticulum stress-mediated cell death in liver injury. Cell Death Dis 2022;13:1051. https://doi.org/10.1038/s41419-022-05444-x.Suche in Google Scholar PubMed PubMed Central

140. Oakes, SA. Endoplasmic reticulum stress signaling in cancer cells. Am J Pathol 2020;190:934–46. https://doi.org/10.1016/j.ajpath.2020.01.010.Suche in Google Scholar PubMed PubMed Central

141. Chen, X, Cubillos-Ruiz, JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer 2021;21:71–88. https://doi.org/10.1038/s41568-020-00312-2.Suche in Google Scholar PubMed PubMed Central

142. Walter, P, Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011;334:1081–6. https://doi.org/10.1126/science.1209038.Suche in Google Scholar PubMed

143. Zhu, S, Li, X, Dang, B, Wu, F, Wang, C, Lin, C. Lycium Barbarum polysaccharide protects HaCaT cells from PM2.5-induced apoptosis via inhibiting oxidative stress, ER stress and autophagy. Redox Rep 2022;27:32–44. https://doi.org/10.1080/13510002.2022.2036507.Suche in Google Scholar PubMed PubMed Central

144. Zhang, M, Wang, Y, Wong, RMS, Yung, KKL, Li, R. Fine particulate matter induces endoplasmic reticulum stress-mediated apoptosis in human SH-SY5Y cells. Neurotoxicology 2022;88:187–95. https://doi.org/10.1016/j.neuro.2021.11.012.Suche in Google Scholar PubMed

145. Zhang, M, Chen, J, Jiang, Y, Chen, T. Fine particulate matter induces heart defects via AHR/ROS-mediated endoplasmic reticulum stress. Chemosphere 2022;307:135962. https://doi.org/10.1016/j.chemosphere.2022.135962.Suche in Google Scholar PubMed

146. Xiong, Y, Li, J, He, S. Zinc protects against heat stress-induced apoptosis via the inhibition of endoplasmic reticulum stress in TM3 leydig cells. Biol Trace Elem Res 2022;200:728–39. https://doi.org/10.1007/s12011-021-02673-7.Suche in Google Scholar PubMed

147. Xiao, Q, Hou, X, Kang, C, Xu, L, Yuan, L, Zhao, Z, et al.. Chlorocholine chloride induced testosterone secretion inhibition mediated by endoplasmic reticulum stress in primary rat Leydig cells. Toxicol Lett 2022;356:161–71. https://doi.org/10.1016/j.toxlet.2021.12.018.Suche in Google Scholar PubMed

148. Fu, Y, Dominissini, D, Rechavi, G, He, C. Gene expression regulation mediated through reversible m⁶A RNA methylation. Nat Rev Genet 2014;15:293–306. https://doi.org/10.1038/nrg3724.Suche in Google Scholar PubMed

149. Jiang, X, Liu, B, Nie, Z, Duan, L, Xiong, Q, Jin, Z, et al.. The role of m6A modification in the biological functions and diseases. Signal Transduct Targeted Ther 2021;6:74. https://doi.org/10.1038/s41392-020-00450-x.Suche in Google Scholar PubMed PubMed Central

150. Krug, RM, Morgan, MA, Shatkin, AJ. Influenza viral mRNA contains internal N6-methyladenosine and 5’-terminal 7-methylguanosine in cap structures. J Virol 1976;20:45–53. https://doi.org/10.1128/JVI.20.1.45-53.1976.Suche in Google Scholar PubMed PubMed Central

151. Liu, Q, Gregory, RI. RNAmod: an integrated system for the annotation of mRNA modifications. Nucleic Acids Res 2019;47:W548–55. https://doi.org/10.1093/nar/gkz479.Suche in Google Scholar PubMed PubMed Central

152. Zhao, BS, Roundtree, IA, He, C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol 2017;18:31–42. https://doi.org/10.1038/nrm.2016.132.Suche in Google Scholar PubMed PubMed Central

153. Meyer, KD, Saletore, Y, Zumbo, P, Elemento, O, Mason, CE, Jaffrey, SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons. Cell 2012;149:1635–46. https://doi.org/10.1016/j.cell.2012.05.003.Suche in Google Scholar PubMed PubMed Central

154. Wang, T, Kong, S, Tao, M, Ju, S. The potential role of RNA N6-methyladenosine in Cancer progression. Mol Cancer 2020;19:88. https://doi.org/10.1186/s12943-020-01204-7IF:41.444Q1.10.1186/s12943-020-01204-7Suche in Google Scholar PubMed PubMed Central

155. Panneerdoss, S, Eedunuri, VK, Yadav, P, Timilsina, S, Rajamanickam, S, Viswanadhapalli, S, et al.. Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression. Sci Adv 2018;4:eaar8263. https://doi.org/10.1126/sciadv.aar8263.Suche in Google Scholar PubMed PubMed Central

156. Chen, Y, Wang, J, Xu, D, Xiang, Z, Ding, J, Yang, X, et al.. m6A mRNA methylation regulates testosterone synthesis through modulating autophagy in Leydig cells. Autophagy 2021;17:457–75. https://doi.org/10.1080/15548627.2020.1720431.Suche in Google Scholar PubMed PubMed Central

157. Zhao, TX, Wang, JK, Shen, LJ, Long, CL, Liu, B, Wei, Y, et al.. Increased m6A RNA modification is related to the inhibition of the Nrf2-mediated antioxidant response in di-(2-ethylhexyl) phthalate-induced prepubertal testicular injury. Environ Pollut 2020;259:113911. https://doi.org/10.1016/j.envpol.2020.113911.Suche in Google Scholar PubMed

158. Ji, D, Hu, C, Ning, J, Ying, X, Zhang, H, Zhang, B, et al.. N6-methyladenosine mediates Nrf2 protein expression involved in PM2.5-induced pulmonary fibrosis. Ecotoxicol Environ Saf 2023;254:114755. https://doi.org/10.1016/j.ecoenv.2023.114755.Suche in Google Scholar PubMed

159. Yuan, Q, Zhu, H, Liu, H, Wang, M, Chu, H, Zhang, Z. METTL3 regulates PM2.5-induced cell injury by targeting OSGIN1 in human airway epithelial cells. J Hazard Mater 2021;415:125573. https://doi.org/10.1016/j.jhazmat.2021.125573.Suche in Google Scholar PubMed

160. Guo, X, Lin, Y, Lin, Y, Zhong, Y, Yu, H, Huang, Y, et al.. PM2.5 induces pulmonary microvascular injury in COPD via METTL16-mediated m6A modification. Environ Pollut 2022;303:119115. https://doi.org/10.1016/j.envpol.2022.119115.Suche in Google Scholar PubMed

Received: 2023-05-17
Accepted: 2023-07-18
Published Online: 2023-09-01
Published in Print: 2024-12-17

© 2023 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. A systematic review on the association between exposure to air particulate matter during pregnancy and the development of hypertensive disorders of pregnancy and gestational diabetes mellitus
  4. Screen time and childhood attention deficit hyperactivity disorder: a meta-analysis
  5. The association between polycystic ovary syndrome and environmental pollutants based on animal and human study; a systematic review
  6. Residues of carcinogenic pesticides in food: a systematic review
  7. The concentration of Lithium in water resources: A systematic review, meta-analysis and health risk assessment
  8. Polychlorinated biphenyls and thyroid function: a scoping review
  9. The European Union assessments of radiofrequency radiation health risks – another hard nut to crack (Review)
  10. Research progresses on the effects of heavy metals on the circadian clock system
  11. Diagnosing and managing heat exhaustion: insights from a systematic review of cases in the desert climate of Mecca
  12. Para-occupational exposure to chemical substances: a systematic review
  13. Association of the ACE2-Angiotensin1-7–Mas axis with lung damage caused by cigarette smoke exposure: a systematic review
  14. Impacts and mechanisms of PM2.5 on bone
  15. Impacts and potential mechanisms of fine particulate matter (PM2.5) on male testosterone biosynthesis disruption
  16. Exposure to perfluoroalkyl and polyfluoroalkyl substances and risk of stroke in adults: a meta-analysis
  17. Prevalence and concentration of aflatoxin M1 and ochratoxin A in cheese: a global systematic review and meta-analysis and probabilistic risk assessment
  18. The effect of polycyclic aromatic hydrocarbon biomarkers on cardiovascular diseases
  19. Biological effects of electromagnetic fields on insects: a systematic review and meta-analysis
  20. Letter to the Editor
  21. Monkeypox and drug repurposing: seven potential antivirals to combat the viral disease
https://doi.org/10.1515/reveh-2023-0064
Schlagwörter für diesen Artikel
PM2.5; testosterone biosynthesis; toxic mechanism; male

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. A systematic review on the association between exposure to air particulate matter during pregnancy and the development of hypertensive disorders of pregnancy and gestational diabetes mellitus
  4. Screen time and childhood attention deficit hyperactivity disorder: a meta-analysis
  5. The association between polycystic ovary syndrome and environmental pollutants based on animal and human study; a systematic review
  6. Residues of carcinogenic pesticides in food: a systematic review
  7. The concentration of Lithium in water resources: A systematic review, meta-analysis and health risk assessment
  8. Polychlorinated biphenyls and thyroid function: a scoping review
  9. The European Union assessments of radiofrequency radiation health risks – another hard nut to crack (Review)
  10. Research progresses on the effects of heavy metals on the circadian clock system
  11. Diagnosing and managing heat exhaustion: insights from a systematic review of cases in the desert climate of Mecca
  12. Para-occupational exposure to chemical substances: a systematic review
  13. Association of the ACE2-Angiotensin1-7–Mas axis with lung damage caused by cigarette smoke exposure: a systematic review
  14. Impacts and mechanisms of PM2.5 on bone
  15. Impacts and potential mechanisms of fine particulate matter (PM2.5) on male testosterone biosynthesis disruption
  16. Exposure to perfluoroalkyl and polyfluoroalkyl substances and risk of stroke in adults: a meta-analysis
  17. Prevalence and concentration of aflatoxin M1 and ochratoxin A in cheese: a global systematic review and meta-analysis and probabilistic risk assessment
  18. The effect of polycyclic aromatic hydrocarbon biomarkers on cardiovascular diseases
  19. Biological effects of electromagnetic fields on insects: a systematic review and meta-analysis
  20. Letter to the Editor
  21. Monkeypox and drug repurposing: seven potential antivirals to combat the viral disease
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Heruntergeladen am 24.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/reveh-2023-0064/html
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