Fuel Fine Particulate Matter Induces Ovary Dysfunction via Metal

Letter Cite This: Environ. Sci. Technol. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/journal/estlcu

Fuel Fine Particulate Matter Induces Ovary Dysfunction via Metal Elements Imbalance and Steroid Biosynthesis Signaling Pathway Inhibition Leilei Xia,†,‡,∇ Caihong Zhang,†,∇ Dan Li,§,∇ Lihua Yang,‡,∥ Wei Sun,⊥ Shengyun Cai,† Qi Meng,† Jizi Shen,† Ye Wang,*,‡,# and Mingjuan Xu*,† †

Department of Obstetrics and Gynecology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China § Shanghai Key Laboratory of Atmospheric Particle Pollution and Prevention (LAP3), Department of Environmental Science and Engineering, Fudan University, Shanghai 200433, China ∥ Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou 221004, China ⊥ Laboratory Animal Center, Second Military Medical University, Shanghai 200433, China # Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China

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‡

S Supporting Information *

ABSTRACT: Fuel fine particulate matter (FPM) is an important component of ambient pollution, has wide biological activity, and can cause a variety of diseases. Epidemiological studies have reported that FPM can decrease human fertility rates, retard embryonic growth, cause adverse effects on pregnancy outcomes, and result in male reproductive damage. However, the effects of FPM on female ovary function and associated mechanisms are still unclear. In this research, different concentrations of gasoline and diesel FPM were chosen to treat female mice in vivo. Fuel FPM can significantly inhibit ovarian function and follicle maturation. The hypothalamus−pituitary−ovary axis was inhibited significantly, with an increase in follicle-stimulating hormone and luteinizing hormone levels and a decrease in estradiol levels, as well as ovary weight loss, which was similar to the symptoms of premature ovarian failure in humans. Fuel FPM can induce the accumulation of copper and lead in the ovary and decrease the levels of zinc, magnesium, and manganese. Simultaneously, the steroid biosynthesis signaling pathway was downregulated, which can contribute to ovarian dysfunction. This study provided a new perspective for understanding the ovarian toxicity of fuel FPM and associated mechanisms, which will aid in the development of new methods to treat ovarian dysfunction induced by FPM.

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sources.11 The fuels, gasoline and diesel, are widely used in vehicles and are important sources of air pollutants, such as fine particulate matter (FPM).12,13 The influence of FPM is increasing.14 The aerodynamic diameter of gasoline and diesel exhaust FPM are smaller than 2.5 μm (2.5 μm particulate matter, [PM2.5]), and most is ultrafine particulate matter with dimensions lower than 0.1 μm.15 The smaller-sized particles more easily transverse through various biological barriers in the human body and can be taken up by and influence different kinds of cells.16,17 The respiratory system is directly exposed to air containing FPM, and injuries and inflammation can be observed after long exposures to FPM.18,19

INTRODUCTION Currently, fertility and reproductive health is decreasing, which is an important public health concern.1 In addition to spermatogenesis disorders in males, ovary dysfunction in females contributes to the decline in natural fertility. Ovary dysfunction is a challenge for successful fertilization and has been observed at increasing rates in females.2,3 Premature ovarian failure,4 polycystic ovary syndrome,5 and infertility6 are the most common diseases of the female reproductive system. The function of the ovary is regulated and influenced by physiological and psychological factors, and environmental conditions.7−10 In addition to mental stress, viral infection, and nutritional imbalance, environmental pollution greatly influences the female reproductive system. With the rapid development of our society, as well as rapid progress in traffic and new materials, energy requirements have increased quickly. Fuel and coal are still the main energy © XXXX American Chemical Society

Received: November 29, 2018 Accepted: December 5, 2018 Published: December 5, 2018 A

DOI: 10.1021/acs.estlett.8b00625 Environ. Sci. Technol. Lett. XXXX, XXX, XXX−XXX

Letter

Environmental Science & Technology Letters

Figure 1. Gasoline and diesel FPM influence the maturation of follicles and ovarian structure changes. (A−F) Follicle counts of different stages. Gasoline and diesel FPM decreased the number count of primordial follicles (A), primary follicles (B), preantral follicles (C), and antral follicles (D) but increased the number count of atretic follicles (E). The total follicles (F) were also decreased tightly. (**P < 0.01, ***P < 0.005, Student’s t test). (G, H) Representative HE staining images of mouse ovaries from the gasoline and diesel FPM treatment groups. The HE staining image of the control group is in Figure S2. (Black arrow: primodrial follicle. Purple arrow: primary follicle. Green arrow: preantral follicle. Blue arrow: preantral follicle. Red arrow: aterial follicle).

Fine Particulate Matter Exposure. Female C57BL/6 mice used in this research were approximately 6 weeks old. The mice were randomly divided into seven groups, and each group contained eight mice. Three diesel exposure groups and three gasoline exposure groups were exposed to diesel or gasoline FPM at low, medium, and high concentrations of 5 μg/mouse, 25 μg/mouse, and 50 μg/mouse, respectively. The high concentration is representing a daily dose of 25 μg/mouse approximately equating to inhalational exposure to 500 μg/m3 PM2.5, which represents the serious pollution level. The mice in the control group were treated with blank solvent in the same volume. All of the mice were treated for 6 weeks, and the FPM or blank solvent was administered every 2 days.25,26 Then, the mice were sacrificed, and the ovaries were collected for different assays by various methods. The fine particulate matter was dissolved in 0.9% saline with 0.05% Tween 80 by using an ultrasonic mixer (Bilon, Shanghai, China) for more than 30 min, and the final concentrations of the low, medium, and high groups were 0.5, 2.5, and 5 μg/μL, respectively. Each mouse was treated with FPM suspensions at a volume of 10 μL by intratracheal instillation. Furthermore, the size distribution of the FPM in the solvent by Malvern laser particle size analyzer (Zetasizer Nano ZS). Before the fuel FPM was delivered to the mice by the intratracheal instillation, all mice were anaesthetized by breathing isoflurane (VIP3000, Matrx, USA).27 The mice in the different groups were also weighed every 3 days.

An increasing number of epidemiological studies on the reproductive system and fetal development have reported that FPM can inhibit the production of sperm in males,20 cause low birth weight in newborns,21 decrease fertility,22 and lead to adverse pregnancy outcomes,23 which suggested that FPM may damage ovarian functions. However, the influences of FPM on ovarian function are still unclear. In this study, we systemically studied the reproductive toxicity of two kinds of fuel FPM, namely, gasoline and diesel FPM, and explored the associated mechanisms.

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MATERIALS AND METHODS

Preparation of Gasoline and Diesel Fine Particulate Matter. As reported in our previous paper, the fine particles in gasoline and diesel were prepared with a wick burner under a semienclosed cylindrical glass cover with a sufficient particlefree air supply and a stainless-steel environmental chamber equipped with magnetic fans fixed at the bottom of the chamber, which ensured mixing of the chamber’s contents. Each combustion experiment lasted for 10 min, and the combustion experiments for each fuel type were conducted at least in triplicate. Three different sampling systems were used to collect the FPM emitted from the combustion of the fuel oils. The gasoline used in this research was the 97 octane gasoline standard product, and the diesel used in this research was the light diesel oil standard product.24 B


Letter


Figure 2. Serum hormone concentrations of the hypothalamic−pituitary−ovarian axis of mice treated with fuel FPM. (A) Serum E2 level. Gasoline FPM induced a decrease in medium and high concentrations group compared to control. Diesel FPM induced a decrease in all exposure groups. (B) A decrease in ovary weight in fuel FPM group was observed after treatment with FPM. (C) Serum LH level. Gasoline FPM induced an increase in low and medium concentration FPM compared to control. The LH level of the high concentration group was not significantly different from that of control, and it was lower than that of the low and medium concentration group. Diesel FPM induced an increase in serum LH in all exposure groups compared to control. The LH level of the high concentration group was lower than that of medium concentration group. (D) Serum FSH level. Gasoline FPM induced an increase in medium and high concentrations group. FSH of high concentration group was lower than that of medium concentration group. Diesel FPM induced an increase in the all exposure concentration groups. FSH level of high concentration group was lower than that of medium concentration group. (*P < 0.05, ***P < 0.005, ###P < 0.005, Student’s t test, N = 8).

The maturation of oocytes is regulated by endocrine system. The follicle stage can sensitively reflect the oocytes’ maturation and damage status.28 To explore the influence of gasoline and diesel FPM on follicle maturation, in vivo mouse fuel FPM exposure experiments were performed. To simulate the natural exposure method of FPM, the mice were treated with the FPM by intratracheal instillation, and the size distribution of fuel FPM in the solvent was consistent with the aerodynamic diameter (Figure S1). The results of the follicle count assay showed that gasoline FPM can decrease the count of primordial follicles at medium and high concentrations, and diesel FPM can decrease the primordial follicle number only at high concentration (Figure 1A). Primordial follicles store oocytes and lead to basic follicle development. The minor effects of fuel FPM on the primordial follicles indicated that oocyte storage was tolerant to the fuel FPM, except at high concentrations. Primordial follicles develop into primary follicles, and primary follicles participate in the initial step of follicle maturation progress.29 Our research showed that gasoline FPM can decrease the count of primary follicles at both medium and high concentrations and that diesel FPM can significantly decrease the count of primary follicles at all of the concentration groups, even in the low concentration group (Figure 1B). Then, the preantral follicles and antral follicles were counted, and the results showed that gasoline and diesel FPM can significantly decrease the count of preantral and

All animals were fed in independent ventilated animal cages (IVCs) and housed in specific pathogen-free (SPF) animal rooms at 22 ± 2 °C in a 12:12 h dark and light cycle. Food and water were available freely. All the animal experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals and were approved by the Bioethics Committee of Second Military Medical University, and all the experiments were performed following relevant guidelines and regulations of Second Military Medical University.

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RESULTS AND DISCUSSION

Fuel FPM Induces a Follicle Maturation Disorder. According to epidemiological investigation of FPM, an increasing amount of research has suggested that FPM can influence the normal function of male and female reproductive systems and can inhibit the production of sperm and influence sexual function in males.20 FPM can also influence the development of a fetus, most obviously resulting in low birth weight,21 which widely affects the lifespan and disease susceptibility of newborn children. However, the effects of FPM on the female reproductive system and associated mechanisms are still unclear. We aimed to explore the influence of fuel FPM, which is important component of ambient FPM, on the female reproductive system of mice. C


Letter


Figure 3. Metal elements changes in the ovary. (A, B) Gasoline FPM and diesel FPM induced an increase in Cu and Pb concentrations in the ovary. (*P < 0.05, **P < 0.01, ***P < 0.005, Student’s t test, N = 3). (C) Gasoline FPM had no influence on the Al concentration in the ovary. Diesel FPM induced an increase in Al at different concentrations. (*P < 0.05, **P < 0.01, ***P < 0.005, Student’s t test, N = 3). (D−F) Gasoline FPM and diesel FPM induced a decrease in Zn, Mg, and Mn concentrations in the ovary. (*P < 0.05, **P < 0.01, ***P < 0.005, Student’s t test, N = 3).

concentrations compared with the control group (Figure 2C, D). In the gasoline FPM groups, LH increased in the low and medium concentration groups, and FSH increased in the medium and high concentration groups (Figure 2C, D). Interestingly, in both the gasoline and diesel FPM groups, the serum LH and FSH levels of the high concentration groups were all lower than those of the medium concentration groups. FPM can enter the circulation and induce systemic effects. Based on the characteristics of the hypothalamus−pituitary− ovary axis and our experimental design, these results indicated that FPM can also influence the function of the pituitary gland at high concentration. In summary, gasoline and diesel FPM can disrupt the hypothalamus−pituitary−ovary axis and cause ovarian dysfunction. Furthermore, in addition to LH and FSH, growth hormone (GH), thyroid stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH) are also secreted by the pituitary gland, which is an important endocrine organ.32 Therefore, high-concentration FPM may also lead to other effects on the endocrine system and may have more widely influence on the endocrine system, which can be explored in further research. Fuel FPM Induces the Imbalance of Metal Element Accumulation in the Ovary. FPM is a complex mixture, which is related to its origin, and the components include black carbon, metal elements, organic compounds, and microorganisms. In fuel FPM, the metal elements, polycyclic aromatic hydrocarbons, and carbon are the main components. The ovary is sensitive to the metal elements, and the metal elements have broad biological effects in organisms and can affect various proteins, which can regulate vital cellular processes and signaling pathways.33 In this study, we mainly focused on metal element accumulation in the ovary.

antral follicles in a dose-dependent manner (Figure 1C, D). Importantly, the atretic follicles increased in both gasoline and diesel FPM at all concentrations (Figure 1E). Simultaneously, the count of total follicles also decreased in gasoline and diesel FPM groups (Figure 1F). The representative HE staining images of ovaries also reflected the follicle maturation disorder (Figure 1G, H), compared to the control group (Figure S2). These results suggested that both gasoline and diesel FPM can significantly inhibit follicle maturation progress, cause a follicle maturation disorder and decrease the ovary reserve function at high concentrations exposure. Fuel FPM Inhibits Ovarian Estrogen Production and Disrupts the Hypothalamus−Pituitary−Ovary Axis. The follicle stage distribution assay suggested that gasoline and diesel FPM can disrupt the normal development of follicles. The hypothalamus−pituitary−ovary axis plays a central role in the regulation of follicle development and oocyte maturation.30 FSH, LH, and E2 are the three important serum hormones that can be used to evaluate ovarian functions. E2 is mainly produced by the ovarian granulosa cell in females, and it is the direct serum biomarker to measure ovary functions.31 In our research, the serum E2 concentration was lower in the gasoline and diesel FPM-treated mice than that in the control group, except in the low concentration of gasoline FPM group (Figure 2A). Additionally, the weight of the ovary tissue was also measured, and it was shown that both gasoline and diesel FPM can induce ovary weight loss, suggesting ovary atrophy and dysfunction (Figure 2B). LH and FSH were secreted by the pituitary gland and can regulate follicle maturation and hormone synthesis, which can be upregulated by a decrease in E2 as a feedback loop.31 The serum LH and FSH were measured, and the results suggested that the two hormones increased significantly in the diesel FPM groups at all D


Letter


Figure 4. Gasoline FPM inhibited the expression of ovarian steroid synthesis signaling pathway genes. (A) KEGG signaling pathway assay of ovaries treated with gasoline FPM. Gasoline FPM can decrease the signaling pathways associated with steroid hormone biosynthesis, ovarian steroidogenesis. Gasoline FPM can increase the signaling pathways associated with natural killer cell-mediated cytotoxicity, intestinal immune network for IgA production, retinol metabolism, and so on. (B) GO analysis of ovaries treated with gasoline FPM. Gasoline FPM can inhibit the steroid metabolic process, steroid biosynthetic process, regulation of hormone levels, and so on. Gasoline FPM can promote the process associated with tissue development, system development, regulation of cell proliferation, and so on.

and can induce abortion, stillbirth, and infertility. Our research has suggested that the accumulation of Cu and Pb in the ovary can play a central role in follicle maturation disorder and hypothalamus−pituitary−ovary axis inhibition in mice treated with fuel FPM. Al only increased in the diesel FPM groups, and there was no obvious difference in the gasoline FPM groups (Figure 3C), which may be the result of low concentrations of Al in gasoline FPM. The concentration of Zn, Mg, Mn, and Na in the ovary all generally decreased (Figure 3D−F, Figure S3A). Metal elements often share the same receptors to enter a cell. The accumulation of Cu and Pb may also influence the uptake and balance of other metals. Zn can improve follicle viability and growth in in vitro culture and can form various zinc-finger transcription factors

When FPM enters the circulation, the components of the FPM are taken up by cells and converted into more complex compounds. Metal elements may contact proteins or influence other similar metal elements that are involved in vital processes. By the ICP-MS method, the main metal elements in the ovary were measured. Cu and Pb contents in the ovary increased in both the gasoline and diesel FPM groups in dosedependent manners (Figure 3A, B). Cu and Pb were highly abundant in the gasoline and diesel FPM and are toxic to the human reproductive system. Cu is contained in various proteins, such as copper chaperones and enzymes. When the concentration of Cu is higher than the physiological level, it has toxic effects. High concentrations of Cu can induce mitochondria dysfunction and reactive oxygen accumulation. Pb is more toxic to reproductive and embryonic development E


Letter


Figure 5. Diesel FPM inhibited the expression of ovarian steroid synthesis signaling pathway genes. (A) KEGG signaling pathway assay of ovaries treated with diesel FPM. Diesel FPM can decrease the signaling pathways associated with steroid hormone biosynthesis, retinol metabolism, and so on. Diesel FPM can increase the signaling pathways associated with ovarian steroidogenesis, graft-versus-host disease, and so on. (B) GO analysis of ovaries treated with diesel FPM. Diesel FPM can inhibit the regulation of hormone levels, and so on. Diesel FPM can promote the process associated with ion transport, system development, regulation of cell proliferation, and so on.

that participate in regulating the proliferation of follicle cells.34,35 Mg is the inhibitor of thrombin generation in bovine ovarian follicular fluid and can also promote the binding of FSH to membrane receptors, suggesting that Mg is necessary for ovary development.36 Mn may have complex regulation effects on the ovary. Some research has reported that Mn was toxic to the brain−pituitary−testicular axis in rats; however, other research suggested that soluble and insoluble forms of inorganic Mn compounds, by extrapolation, cannot be considered reproductive toxicants.37,38 These results suggest that the decrease in Zn, Mg, and Mn may also participate in follicle maturation. Furthermore, the concentration changes of other metals, including Fe, Cr, Cd, Si, and As, had no relationship with the

FPM and therefore may not be influenced by gasoline and diesel FPM (Figure S3). In summary, the imbalance of metal elements induced by gasoline and diesel FPM greatly contributes to a follicle maturation disorder and may influence cell signaling pathways at the molecular level. Fuel FPM Inhibits the Steroid Biosynthesis Signaling Pathway of Ovaries. To explore the mechanism of fuel FPM further, the expression spectrum sequencing of ovary tissue and bioinformation assays were performed. The KEGG pathway assay showed that the steroid hormone biosynthesis signaling pathway was inhibited by both gasoline and diesel FPM (Figures 4A and 5A). A GO assay showed that the genes associated with hormone level regulation were downregulated F


Letter


ovarian failure: a general population registry-based study. Hum. Reprod. 2015, 30, 1229−1238. (5) Azziz, R.; Carmina, E.; Chen, Z.; Dunaif, A.; Laven, J. S.; Legro, R. S.; Lizneva, D.; Natterson-Horowtiz, B.; Teede, H. J.; Yildiz, B. O. Polycystic ovary syndrome. Nat. Rev. Dis. Primers 2016, 2, 16057. (6) Abrao, M. S.; Muzii, L.; Marana, R. Anatomical causes of female infertility and their management. Int. J. Gynecol. Obstet. 2013, 123 (Suppl 2), S18−S24. (7) Brown, H. M.; Russell, D. L. Blood and lymphatic vasculature in the ovary: development, function and disease. Hum. Reprod. Update 2014, 20, 29−39. (8) Rzymski, P.; Tomczyk, K.; Rzymski, P.; Poniedziałek, B.; Opala, T.; Wilczak, M. Impact of heavy metals on the female reproductive system. Ann. Agric. Environ. Med. 2015, 22, 259−264. (9) Xue, T.; Zhu, T. Increment of ambient exposure to fine particles and the reduced human fertility rate in China, 2000−2010. Sci. Total Environ. 2018, 642, 497−504. (10) Chan, K. A.; Tsoulis, M. W.; Sloboda, D. M. Early-life nutritional effects on the female reproductive system. J. Endocrinol. 2015, 224, R45−62. (11) Lin, H. H.; Suk, C. W.; Lo, H. L.; Huang, R. Y.; Enarson, D. A.; Chiang, C. Y. Indoor air pollution from solid fuel and tuberculosis: a systematic review and meta-analysis. Int. J. Tuberc. Lung Dis. 2014, 18, 613−621. (12) Adar, S. D.; Filigrana, P. A.; Clements, N.; Peel, J. L. Ambient Coarse Particulate Matter and Human Health: A Systematic Review and Meta-Analysis. Curr. Environ. Health Rep. 2014, 1, 258−274. (13) Costa, S.; Ferreira, J.; Silveira, C.; Costa, C.; Lopes, D.; Relvas, H.; Borrego, C.; Roebeling, P.; Miranda, A. I.; Teixeira, J. P. Integrating health on air quality assessment–review report on health risks of two major European outdoor air pollutants: PM and NO2. J. Toxicol. Environ. Health, Part B 2014, 17, 307−340. (14) Zhou, X.; Cao, Z.; Ma, Y.; Wang, L.; Wu, R.; Wang, W. Concentrations, correlations and chemical species of PM2.5/PM10 based on published data in China: Potential implications for the revised particulate standard. Chemosphere 2016, 144, 518−526. (15) Galea, K. S.; Hurley, J. F.; Cowie, H.; Shafrir, A. L.; Sánchez Jiménez, A.; Semple, S.; Ayres, J. G.; Coggins, M. Using PM2.5 concentrations to estimate the health burden from solid fuel combustion, with application to Irish and Scottish homes. Environ. Health 2013, 12, 50. (16) Wang, W.; Deng, Z.; Feng, Y.; Liao, F.; Zhou, F.; Feng, S.; Wang, X. PM2.5 induced apoptosis in endothelial cell through the activation of the p53-bax-caspase pathway. Chemosphere 2017, 177, 135−143. (17) Zou, Y.; Jin, C.; Su, Y.; Li, J.; Zhu, B. Water soluble and insoluble components of urban PM2.5 and their cytotoxic effects on epithelial cells (A549) in vitro. Environ. Pollut. 2016, 212, 627−635. (18) Hu, W.; Downward, G. S.; Reiss, B.; Xu, J.; Bassig, B. A.; Hosgood, H. D., 3rd; Zhang, L.; Seow, W. J.; Wu, G.; Chapman, R. S.; Tian, L.; Wei, F.; Vermeulen, R.; Lan, Q. Personal and indoor PM2.5 exposure from burning solid fuels in vented and unvented stoves in a rural region of China with a high incidence of lung cancer. Environ. Sci. Technol. 2014, 48, 8456−8464. (19) Leclercq, B.; Kluza, J.; Antherieu, S.; Sotty, J.; Alleman, L. Y.; Perdrix, E.; Loyens, A.; Coddeville, P.; Lo Guidice, J. M.; Marchetti, P.; Garçon, G. Air pollution-derived PM2. 5 impairs mitochondrial function in healthy and chronic obstructive pulmonary diseased human bronchial epithelial cells. Environ. Pollut. 2018, 243, 1434− 1449. (20) Zhang, J.; Liu, J.; Ren, L.; Wei, J.; Duan, J.; Zhang, L.; Zhou, X.; Sun, Z. PM2.5 induces male reproductive toxicity via mitochondrial dysfunction, DNA damage and RIPK1 mediated apoptotic signaling pathway. Sci. Total Environ. 2018, 634, 1435−1444. (21) Slama, R.; Morgenstern, V.; Cyrys, J.; Zutavern, A.; Herbarth, O.; Wichmann, H. E.; Heinrich, J. Traffic-related atmospheric pollutants levels during pregnancy and offspring’s term birth weight: a study relying on a land-use regression exposure model. Environ. Health Perspect. 2007, 115, 1283−1292.

by both gasoline and diesel FPM (Figures 4B and 5B). Combining the results of the KEGG pathway assay and GO assay suggested that gasoline and diesel FPM can inhibit the steroid biosynthesis signaling pathway and ovarian steroid synthesis. To verify this result, qRT-PCR was performed to measure the expression of genes in steroid biosynthesis, including HSD 17B1, CYP 1B1, HSD 3B6, CYP 11A1, HSD 17B7, HSD 17B2, and HSD 3B1.39 The results showed that gasoline FPM inhibited the expression of all seven steroid biosynthesis genes compared to the control group. Diesel FPM inhibited four of the genes, namely, HSD 17B1, CYP 1B1, CYP 11A1, and HSD 17B7, and the expression of the other three genes was not higher than that of the control group (Figure S4). In general, fuel FPM can inhibit the steroid biosynthesis signaling pathway of ovaries, demonstrating the reproductive toxicity of FPM. However, the complex relationship of the accumulation of Cu and Pb elements and steroid biosynthesis signaling pathway inhibition is still unknown and should be explored in future research.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.estlett.8b00625.

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Figures and tables, plus detailed methods, instrumental settings, and measurement data of examples discussed in the manuscript. (PDF)

AUTHOR INFORMATION

Corresponding Authors

*M. Xu. E-mail: [email protected]. Phone: +8681870948. *Y. Wang. E-mail: [email protected]. Phone: +8681870948. ORCID

Dan Li: 0000-0001-6765-6627 Ye Wang: 0000-0002-5675-2733 Author Contributions ∇

L. Xia, C. Zhang, and D. Li contributed equally to this work

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (Nos. 81472771, 81770421) and the Fund of the Institute of Translational Medicine of Second Military Medical University (No. 2017JZ48).

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Fuel Fine Particulate Matter Induces Ovary Dysfunction via Metal

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