Dietary Supplementation with N-acetyl-L-cysteine Ameliorates Hyperactivated ERK Signaling in the Endometrium That is Linked to Poor Pregnancy Outcomes Following Ovarian Stimulation in Pigs

Overview

Journal J Anim Sci Biotechnol

Publisher Biomed Central

Date 2024 Nov 6

PMID 39501409

Authors

Linghua Cheng

Zhicheng Shi

Yuan Yue

Yue Wang

Yusheng Qin

Wei Zhao

Yupei Hu

Qin Li

Min Guo

Lei An

Shumin Wang

Jianhui Tian

Affiliations

Soon will be listed here.

Abstract

Background: Exogenous gonadotropin-controlled ovarian stimulation is the critical step in animal reproductive management, such as pig, sheep, bovine and other species. It helps synchronize ovulation or stimulate multiple ovulations. However, a number of evidence indicated an unexpected decrease in pregnancy outcomes following ovarian stimulation. This study aimed to explore the underlying mechanism of the pregnancy defect and develop a practical rescue strategy.

Results: Compared with those in the control group, gilts that underwent ovarian stimulation showed a decrease in pregnancy rate, farrowing rate, and total number of piglets born. Stimulated gilts also showed an increase in estradiol (E) levels. The supraphysiological E level was correlated with the decrease in the number of piglets born. Furthermore, we found that high levels of E impair uterine receptivity, as shown by the overproliferation of endometrial epithelial cells. In vitro mechanistic studies demonstrated that high levels of E hyperactivate FGF-FGFR-ERK signaling cascade in the uterine endometrium, and in turn induces overproliferation of endometrial epithelial cells. Of note, N-acetyl-L-cysteine (NAC) supplementation effectively inhibits ERK hyperphosphorylation and ameliorates endometrial epithelial overproliferation. Importantly, in vivo experiments indicated that dietary NAC supplementation, compared with ovarian stimulation group, improves the uterine receptivity in gilts, and significantly increases the pregnancy rate and total number of piglets born.

Conclusions: Ovarian stimulation-induced supraphysiological levels of E impairs uterine receptivity by hyperactivating FGF-FGFR-ERK signaling cascade, thereby reducing pregnancy rate and litter size. Supplementing NAC to a conventional diet for gilts ameliorates hyperactivated ERK signaling and improves uterine receptivity, thus rescuing adverse pregnancy outcomes following ovarian stimulation.

References

Angel M, Gil M, Cuello C, Sanchez-Osorio J, Gomis J, Parrilla I . The effects of superovulation of donor sows on ovarian response and embryo development after nonsurgical deep-uterine embryo transfer. Theriogenology. 2014; 81(6):832-9. DOI: 10.1016/j.theriogenology.2013.12.017. View

Papaioannou V, Behringer R . Counting Murine Corpora Lutea to Determine the Number of Oocytes Ovulated. Cold Spring Harb Protoc. 2023; . DOI: 10.1101/pdb.prot107986. View

De Marco M, Montanari G, Ruscito I, Giallonardo A, Ubaldi F, Rienzi L . Natural Cycle Results in Lower Implantation Failure than Ovarian Stimulation in Advanced-Age Poor Responders Undergoing IVF: Fertility Outcomes from 585 Patients. Reprod Sci. 2021; 28(7):1967-1973. PMC: 8190016. DOI: 10.1007/s43032-020-00455-5. View

Moradi N, Bidgoli S, Chaichian S . Ovarian cysts disappear after 14-day oral regimen of Korean red ginseng extract in letrozole-induced polycystic ovarian syndrome. Obstet Gynecol Sci. 2021; 64(3):274-283. PMC: 8138080. DOI: 10.5468/ogs.20094. View

Honda H, Barrueto F, Gogusev J, Im D, Morin P . Serial analysis of gene expression reveals differential expression between endometriosis and normal endometrium. Possible roles for AXL and SHC1 in the pathogenesis of endometriosis. Reprod Biol Endocrinol. 2008; 6:59. PMC: 2615013. DOI: 10.1186/1477-7827-6-59. View

Bouayad D, Pederzoli-Ribeil M, Mocek J, Candalh C, Arlet J, Hermine O . Nuclear-to-cytoplasmic relocalization of the proliferating cell nuclear antigen (PCNA) during differentiation involves a chromosome region maintenance 1 (CRM1)-dependent export and is a prerequisite for PCNA antiapoptotic activity in mature.... J Biol Chem. 2012; 287(40):33812-25. PMC: 3460476. DOI: 10.1074/jbc.M112.367839. View

Li M, Han J, Yang N, Li X, Wu X . Transcriptome profiling reveals superovulation with the gonadotropin-releasing hormone agonist trigger impaired embryo implantation in mice. Front Endocrinol (Lausanne). 2024; 15:1354435. PMC: 10925639. DOI: 10.3389/fendo.2024.1354435. View

Da Silva C, Laurenssen B, Knol E, Kemp B, Soede N . Validation of transrectal ultrasonography for assessment of corpora lutea characteristics in pregnant sows and its relationship with litter characteristics at birth. Transl Anim Sci. 2020; 1(4):507-517. PMC: 7204989. DOI: 10.2527/tas2017.0057. View

Yang L, Zheng J, Xu R, Zhang Y, Gu L, Dong J . Melatonin suppresses hypoxia-induced migration of HUVECs via inhibition of ERK/Rac1 activation. Int J Mol Sci. 2014; 15(8):14102-21. PMC: 4159841. DOI: 10.3390/ijms150814102. View

10.

Ezoe K, Daikoku T, Yabuuchi A, Murata N, Kawano H, Abe T . Ovarian stimulation using human chorionic gonadotrophin impairs blastocyst implantation and decidualization by altering ovarian hormone levels and downstream signaling in mice. Mol Hum Reprod. 2014; 20(11):1101-16. DOI: 10.1093/molehr/gau065. View

11.

Hansen P . Implications of Assisted Reproductive Technologies for Pregnancy Outcomes in Mammals. Annu Rev Anim Biosci. 2020; 8:395-413. DOI: 10.1146/annurev-animal-021419-084010. View

12.

Blitek A, Szymanska M, Pieczywek M, Morawska-Pucinska E . Luteal P4 synthesis in early pregnant gilts after induction of estrus with PMSG/hCG. Anim Reprod Sci. 2016; 166:28-35. DOI: 10.1016/j.anireprosci.2016.01.001. View

13.

Guthrie H, Henricks D, Handlin D . Plasma hormone levels and fertility in pigs induced to superovulate with PMSG. J Reprod Fertil. 1974; 41(2):361-70. DOI: 10.1530/jrf.0.0410361. View

14.

Kafali H, Iriadam M, Ozardali I, Demir N . Letrozole-induced polycystic ovaries in the rat: a new model for cystic ovarian disease. Arch Med Res. 2004; 35(2):103-8. DOI: 10.1016/j.arcmed.2003.10.005. View

15.

Kalra S, Ratcliffe S, Coutifaris C, Molinaro T, Barnhart K . Ovarian stimulation and low birth weight in newborns conceived through in vitro fertilization. Obstet Gynecol. 2011; 118(4):863-71. PMC: 3178887. DOI: 10.1097/AOG.0b013e31822be65f. View

16.

Avo Santos M, Kuijk E, Macklon N . The impact of ovarian stimulation for IVF on the developing embryo. Reproduction. 2009; 139(1):23-34. DOI: 10.1530/REP-09-0187. View

17.

Shi D, Zhou J, Zhao L, Rong X, Fan Y, Hamid H . Alleviation of mycotoxin biodegradation agent on zearalenone and deoxynivalenol toxicosis in immature gilts. J Anim Sci Biotechnol. 2018; 9:42. PMC: 5956560. DOI: 10.1186/s40104-018-0255-z. View

18.

Buhimschi C, Bahtiyar M, Zhao G, Abdelghany O, Schneider L, Razeq S . Antenatal N-acetylcysteine to improve outcomes of premature infants with intra-amniotic infection and inflammation (Triple I): randomized clinical trial. Pediatr Res. 2020; 89(1):175-184. PMC: 7451831. DOI: 10.1038/s41390-020-01106-w. View

19.

Bazer F, Song G, Kim J, Dunlap K, Satterfield M, Johnson G . Uterine biology in pigs and sheep. J Anim Sci Biotechnol. 2012; 3(1):23. PMC: 3436697. DOI: 10.1186/2049-1891-3-23. View

20.

Huang H, Chen P, Liang X, Wu X, Wang C, Gu X . Dietary N-Carbamylglutamate (NCG) alleviates liver metabolic disease and hepatocyte apoptosis by suppressing ERK1/2-mTOR-S6K1 signal pathway via promoting endogenous arginine synthesis in Japanese seabass (Lateolabrax japonicus). Fish Shellfish Immunol. 2019; 90:338-348. DOI: 10.1016/j.fsi.2019.04.294. View