Hydrogen sulfide is a regulator of mammary gland development in prepubescent female mice

Zhang,Jing; Ye,Jiayi; Yuan,Cong; Fu,Qin; Zhang,Fenglin; Zhu,Xiaotong; Wang,Lina; Gao,Ping; Shu,Gang; Wang,Songbo; Liu,Qiang; Jiang,Qingyan

doi:10.3892/mmr.2020.11462

Hydrogen sulfide is a regulator of mammary gland development in prepubescent female mice

Authors:
- Jing Zhang
- Jiayi Ye
- Cong Yuan
- Qin Fu
- Fenglin Zhang
- Xiaotong Zhu
- Lina Wang
- Ping Gao
- Gang Shu
- Songbo Wang
- Qiang Liu
- Qingyan Jiang
View Affiliations

Affiliations: College of Animal Science, Shanxi Agricultural University, Jinzhong, Shanxi 030801, P.R. China, Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
Published online on: August 25, 2020 https://doi.org/10.3892/mmr.2020.11462
Pages: 4061-4069

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to investigate the effects of exogenous H2S on mammary gland development in pubescent mice and to explore the underlying mechanism. The mouse mammary epithelial cell line HC11, along with C57BL/6J mice, were treated with different concentrations of sodium hydrosulfide (NaHS), which is a donor of H2S. The HC11 cell viability, pubescent mammary gland development, and the involvement of proliferative proteins and pathways were assessed by CCK‑8 assay, EdU assay, whole mount staining, H&E staining, western blotting and reverse transcription‑quantitative PCR. Both in vitro and in vivo, a low concentration of NaHS (100 µM in vitro; 9 mg/kg in vivo) significantly promoted the viability of HC11 cells and the development of mammary glands by increasing the expression of the proliferative markers cyclin D1/3 and proliferating cell nuclear antigen. However, a high concentration of NaHS (1,000 µM in vitro; 18 mg/kg in vivo) inhibited HC11 cell viability, mammary gland development and the expression levels of proteins involved in proliferation. Subsequent experiments revealed that NaHS regulated the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (Akt)‑mammalian target of rapamycin (mTOR) signaling pathway during this process. In vivo, intraperitoneal injection of low concentration NaHS (9 mg/kg) activated the PI3K/Akt‑mTOR pathway in mammary glands of pubescent mice, increased the secretion of insulin‑like growth factor 1 (IGF‑1) and estradiol (E2), and then stimulated mammary gland ductal development. Whereas a high concentration of NaHS (18 mg/kg) elicited the opposite effects to those of low‑dose NaHS. In conclusion, the present study demonstrated that exogenous H2S supplied by NaHS may exert bidirectional effects on mammary gland ductal development; promoting ductal development at a low concentration and inhibiting it at a high concentration. The effects of H2S may occur via the intracellular PI3K/Akt‑mTOR signaling pathway, or by regulation of the secretion of IGF‑1 and E2.

View Figures

View References

1	Rezaei R, Wu Z, Hou Y, Bazer FW and Wu G: Amino acids and mammary gland development: Nutritional implications for milk production and neonatal growth. J Anim Sci Biotechnol. 7:202016. View Article : Google Scholar : PubMed/NCBI
2	Hennighausen L and Robinson GW: Signaling pathways in mammary gland development. Dev Cell. 1:467–475. 2001. View Article : Google Scholar : PubMed/NCBI
3	Mcnally S and Stein T: Overview of mammary gland development: A comparison of mouse and human. Methods Mol Biol. 1501:1–17. 2017. View Article : Google Scholar : PubMed/NCBI
4	Visvader JE and Smith GH: Murine mammary epithelial stem cells: Discovery, function, and current status. Cold Spring Harb Perspect Biol. 3:a0048792011. View Article : Google Scholar : PubMed/NCBI
5	Macias H and Hinck L: Mammary gland development. Wiley Interdiscip Rev Dev Biol. 1:533–557. 2012. View Article : Google Scholar : PubMed/NCBI
6	Brisken C and Ataca D: Endocrine hormones and local signals during the development of the mouse mammary gland. Wiley Interdiscip Rev Dev Biol. 4:181–195. 2015. View Article : Google Scholar : PubMed/NCBI
7	Hue-Beauvais C, Laubier J, Brun N, Houtia I, Jaffrezic F, Bevilacqua C, Provost FL and Charlier M: Puberty is a critical window for the impact of diet on mammary gland development in the rabbit. Dev Dyn. 248:948–960. 2019. View Article : Google Scholar : PubMed/NCBI
8	Farmer C: Review: Mammary development in swine: Effects of hormonal status, nutrition and management. Canadian J Anim Sci. 93:1–7. 2013. View Article : Google Scholar
9	Silva AL, Detmann E, Dijkstra J, Pedroso AM, Silva LHP, Machado AF, Sousa FC, Santos GBD and Marcondes MI: Effects of rumen-undegradable protein on intake, performance, and mammary gland development in prepubertal and pubertal dairy heifers. J Dairy Sci. 101:5991–6001. 2018. View Article : Google Scholar : PubMed/NCBI
10	Meng Y, Zhang J, Zhang F, Ai W, Zhu X, Shu G, Wang L, Gao P, Xi Q, Zhang Y, et al: Lauric acid stimulates mammary gland development of pubertal mice through activation of GPR84 and PI3K/Akt signaling pathway. J Agric Food Chem. 65:95–103. 2017. View Article : Google Scholar : PubMed/NCBI
11	Farmer C, Palin MF and Martel-Kennes Y: Impact of diet deprivation and subsequent over-allowance during prepuberty. Part 2. Effects on mammary gland development and lactation performance of sows. J Anim Sci. 90:872–880. 2012. View Article : Google Scholar : PubMed/NCBI
12	Kapila N, Sharma A, Kishore A, Sodhi M, Tripathi PK, Mohanty AK and Mukesh M: Impact of heat stress on cellular and transcriptional adaptation of mammary epithelial cells in riverine buffalo (Bubalus Bubalis). PLoS One. 11:e01572372016. View Article : Google Scholar : PubMed/NCBI
13	Zhang J, Ye J, Yuan C, Fu Q, Zhang F, Zhu X, Wang L, Gao P, Shu G, Jiang Q and Wang S: Exogenous H₂S exerts biphasic effects on porcine mammary epithelial cells proliferation through PI3K/Akt-mTOR signaling pathway. J Cell Physiol. 233:7071–7081. 2018. View Article : Google Scholar : PubMed/NCBI
14	Sciascia Q, Sales F, van der Linden D, Wards N, Oliver M, Blair H and McCoard S: Nutritional plane of twin-bearing ewes alters fetal mammary gland biochemical composition and mTOR/MAPK pathway signaling. J Anim Sci. 93:699–708. 2015. View Article : Google Scholar : PubMed/NCBI
15	Gao HN, Hu H, Zheng N and Wang JQ: Leucine and histidine independently regulate milk protein synthesis in bovine mammary epithelial cells via mTOR signaling pathway. J Zhejiang Univ Sci B. 16:560–572. 2015. View Article : Google Scholar : PubMed/NCBI
16	Li L, Liu L, Qu B, Li X, Gao X and Zhang M: Twinfilin 1 enhances milk bio-synthesis and proliferation of bovine mammary epithelial cells via the mTOR signaling pathway. Biochem Biophys Res Commun. 492:289–294. 2017. View Article : Google Scholar : PubMed/NCBI
17	Lim S and Kaldis P: Cdks, cyclins and CKIs: Roles beyond cell cycle regulation. Development. 140:3079–3093. 2013. View Article : Google Scholar : PubMed/NCBI
18	Park SY, Jeong MS, Han CW, Yu HS and Jang SB: Structural and functional insight into proliferating cell nuclear antigen. J Microbiol Biotechnol. 26:637–647. 2016. View Article : Google Scholar : PubMed/NCBI
19	Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R and Beach D: p21 is a universal inhibitor of cyclin kinases. Nature. 366:701–704. 1993. View Article : Google Scholar : PubMed/NCBI
20	Meng Y, Yuan C, Zhang J, Zhang F, Fu Q, Zhu X, Shu G, Wang L, Gao P, Xi Q, et al: Stearic acid suppresses mammary gland development by inhibiting PI3K/Akt signaling pathway through GPR120 in pubertal mice. Biochem Biophys Res Commun. 491:192–197. 2017. View Article : Google Scholar : PubMed/NCBI
21	Meng Y, Zhang J, Yuan C, Zhang F, Fu Q, Su H, Zhu X, Wang L, Gao P, Shu G, et al: Oleic acid stimulates HC11 mammary epithelial cells proliferation and mammary gland development in peripubertal mice through activation of CD36-Ca2⁺ and PI3K/Akt signaling pathway. Oncotarget. 9:12982–12994. 2018. View Article : Google Scholar : PubMed/NCBI
22	Zhang S, Bian H, Li X, Wu H, Bi Q, Yan Y and Wang Y: Hydrogen sulfide promotes cell proliferation of oral cancer through activation of the COX2/AKT/ERK1/2 axis. Oncol Rep. 35:2825–2832. 2016. View Article : Google Scholar : PubMed/NCBI
23	Liu D, Wang Z, Zhan J, Zhang Q, Wang J, Zhang Q, Xian X, Luan Q and Hao A: Hydrogen sulfide promotes proliferation and neuronal differentiation of neural stem cells and protects hypoxia-induced decrease in hippocampal neurogenesis. Pharmacol Biochem Behav. 116:55–63. 2014. View Article : Google Scholar : PubMed/NCBI
24	King AL, Polhemus DJ, Bhushan S, Otsuka H, Kondo K, Nicholson CK, Bradley JM, Islam KN, Calvert JW, Tao YX, et al: Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc Natl Acad Sci USA. 111:3182–3187. 2014. View Article : Google Scholar : PubMed/NCBI
25	Olas B: Hydrogen sulfide in signaling pathways. Clin Chim Acta. 439:212–218. 2015. View Article : Google Scholar : PubMed/NCBI
26	Dong XB, Yang CT, Zheng DD, Mo LQ, Wang XY, Lan AP, Hu F, Chen PX, Feng JQ, Zhang MF and Liao XX: Inhibition of ROS-activated ERK1/2 pathway contributes to the protection of H2S against chemical hypoxia-induced injury in H9c2 cells. Mol Cell Biochem. 362:149–157. 2012. View Article : Google Scholar : PubMed/NCBI
27	Liu M, Li Y, Liang B, Li Z, Jiang Z, Chu C and Yang J: Hydrogen sulfide attenuates myocardial fibrosis in diabetic rats through the JAK/STAT signaling pathway. Int J Mol Med. 41:1867–1876. 2018.PubMed/NCBI
28	Yang B, Bai Y, Yin C, Qian H, Xing G, Wang S, Li F, Bian J, Aschner M and Lu R: Activation of autophagic flux and the Nrf2/ARE signaling pathway by hydrogen sulfide protects against acrylonitrile-induced neurotoxicity in primary rat astrocytes. Arch Toxicol. 92:2093–2108. 2018. View Article : Google Scholar : PubMed/NCBI
29	Yang F, Zhang L, Gao Z, Sun X, Yu M, Dong S, Wu J, Zhao Y, Xu C, Zhang W and Lu F: Exogenous H2S protects against diabetic cardiomyopathy by activating autophagy via the AMPK/mTOR pathway. Cell Physiol Biochem. 43:1168–1187. 2017. View Article : Google Scholar : PubMed/NCBI
30	Liu M, Li Z, Liang B, Li L, Liu S, Tan W, Long J, Tang F, Chu C and Yang J: Hydrogen sulfide ameliorates rat myocardial fibrosis induced by thyroxine through PI3K/AKT signaling pathway. Endocr J. 65:769–781. 2018. View Article : Google Scholar : PubMed/NCBI
31	Gao P, Zhang AL and Zhong YY: Separation, culture and identification of sow ovarian granulose cells. Guangdong Agric Sci. 131–135. 2014.(In Chinese).
32	Ball SM: The development of the terminal end bud in the prepubertal-pubertal mouse mammary gland. Anat Rec. 250:459–464. 1998. View Article : Google Scholar : PubMed/NCBI
33	Zhang M, Xu J, Wang T, Wan X, Zhang F, Wang L, Zhu X, Gao P, Shu G, Jiang Q and Wang S: The dipeptide pro-gly promotes IGF-1 expression and secretion in HepG2 and female mice via PepT1-JAK2/STAT5 pathway. Front Endocrinol (Lausanne). 9:4242018. View Article : Google Scholar : PubMed/NCBI
34	Ye J, Ai W, Zhang F, Zhu X, Shu G, Wang L, Gao P, Xi Q, Zhang YL, Jiang Q and Wang S: Enhanced proliferation of porcine bone marrow mesenchymal stem cells induced by extracellular calcium is associated with the activation of the calcium-sensing receptor and ERK signaling pathway. Stem Cells Int. 2016:657–671. 2016. View Article : Google Scholar
35	Luo XY, Jiang XK, Li J, Bai Y, Li Z, Wei P, Sun S, Liang Y, Han S, Li X and Zhang BY: Insulin-like growth factor-1 attenuates oxidative stress-induced hepatocyte premature senescence in liver fibrogenesis via regulating nuclear p53-progerin interaction. Cell Death Dis. 10:4512019. View Article : Google Scholar : PubMed/NCBI
36	Roy JR, Chakraborty S and Chakraborty TR: Estrogen-like endocrine disrupting chemicals affecting puberty in humans-a review. Med Sci Monit. 15:RA137–RA145. 2009.PubMed/NCBI
37	Hu X, Luan L, Guan W, Zhang S, Li B, Ji W and Fan H: Hydrogen sulfide attenuates isoflurane-induced neuroapoptosis and cognitive impairment in the developing rat brain. BMC Anesthesiol. 17:1232017. View Article : Google Scholar : PubMed/NCBI
38	Mani S, Cao W, Wu L and Wang R: Hydrogen sulfide and the liver. Nitric Oxide. 41:62–71. 2014. View Article : Google Scholar : PubMed/NCBI
39	Guo Q, Feng X, Xue H, Teng X, Jin S, Duan X, Xiao L and Wu Y: Maternal renovascular hypertensive rats treatment with hydrogen sulfide increased the methylation of AT1b gene in offspring. Am J Hypertens. 30:1220–1227. 2017. View Article : Google Scholar : PubMed/NCBI
40	Pichette J, Fynn-Sackey N and Gagnon J: Hydrogen sulfide and sulfate prebiotic stimulates the secretion of GLP-1 and improves glycemia in male mice. Endocrinology. 158:3416–3425. 2017. View Article : Google Scholar : PubMed/NCBI
41	Askari H, Seifi B, Kadkhodaee M, Sanadgol N, Elshiekh M, Ranjbaran M and Ahghari P: Protective effects of hydrogen sulfide on chronic kidney disease by reducing oxidative stress, inflammation and apoptosis. EXCLI J. 17:14–23. 2018.PubMed/NCBI
42	Wang SC: PCNA: A silent housekeeper or a potential therapeutic target? Trends Pharmacol Sci. 35:178–186. 2014. View Article : Google Scholar : PubMed/NCBI
43	Zhou R, Chen H, Chen J, Chen X, Wen Y and Xu L: Extract from astragalus membranaceus inhibit breast cancer cells proliferation via PI3K/AKT/mTOR signaling pathway. BMC Complement Altern Med. 18:832018. View Article : Google Scholar : PubMed/NCBI
44	Zhou H, Jiao G, Dong M, Chi H, Wang H, Wu W, Liu H, Ren S, Kong M, Li C, et al: Orthosilicic acid accelerates bone formation in human osteoblast-like cells through the PI3K-Akt-mTOR pathway. Biol Trace Elem Res. 190:327–335. 2019. View Article : Google Scholar : PubMed/NCBI
45	Yu JS and Cui W: Proliferation, survival and metabolism: The role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. 143:3050–3060. 2016. View Article : Google Scholar : PubMed/NCBI
46	Rosen JM: On hormone action in the mammary gland. Cold Spring Harb Perspect Biol. 4:a0130862012. View Article : Google Scholar : PubMed/NCBI
47	Mallepell S, Krust A, Chambon P and Brisken C: Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci USA. 103:2196–2201. 2006. View Article : Google Scholar : PubMed/NCBI
48	Zhou Y, Li S, Li J, Wang D and Li Q: Effect of microRNA-135a on cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer. Cell Physiol Biochem. 42:1431–1446. 2017. View Article : Google Scholar : PubMed/NCBI