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The influence of stress on embryo implantation is not well understood. Prior studies have focused on later gestational stages and the long-term impact of stress on immune function. The objective of this study is to investigate the effects of restraint stress on the immune parameters and the oxidative states of the uterus during implantation. In this study, pregnant CD1 mice were subjected to restraint stress (4 h/d) on embryonic day 1 (E1) and sacrificed on E3, E5, and E7. Maternal plasma corticosterone (CORT) secretion and implantation sites in the uterus were examined. The uterine (excluding embryos) homogenate and uterine lymphocytes were collected to examine oxidative stress states and associated immune parameters. The results demonstrated that restraint stress increased maternal plasma CORT secretion and reduced the number of implantation sites by 15.3% on E5 and by 26.1% on E7. Moreover, restraint stress decreased the density of uterine natural killer (uNK) cells in the endometrium by 22.1-47.9% and increased the density of mast cells in the myometrium by 55.6-76.9%. Restraint stress remarkably decreased the CD3(+)CD4(+) T/CD3(+)CD8(+) T cell ratio (by 26.2-28.9%) and attenuated uterine lymphocyte proliferation and secretion of cytokines. In addition, restraint stress threatened the intracellular equilibrium between oxidants and antioxidants, resulting in decreased glutathione peroxidase (GSH-PX) (32.2% and 45.7%), superoxide dismutase (SOD) (15.5% and 26.1%), and total antioxidant capacity (T-AOC) (18.4% and 18.2%) activities and increased malondialdehyde (MDA) (34.4% and 43.0%) contents on E5 and E7. In conclusion, these findings demonstrate that restraint stress causes abnormal implantation and negatively impacts immune parameters in association with oxidative stress in mice.

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We showed previously in mice that restraint stress reduces the number of embryo implantation sites in the endometrium. Here we hypothesized that the uterine microenvironment is altered by restraint stress and consequently is sub-optimal for embryo implantation. On embryonic day 1 (E1), 60 of 154 pregnant CD1 mice underwent restraint stress (4h), repeated daily to E3, E5 or E7 (n = 10 mice per group). Restraint stress decreased food intake and suppressed body weight gain on E3, E5 and E7. Restraint stress decreased the actual and relative weight (percent body weight) of uterus and ovary on E5 (by 14.9%, P = 0.03; 16.1%, P = 0.004) and E7 (by 16.8%, P = 0.03; 20.0%, P = 0.01). Morphologically, restraint stress decreased relative endometrial area (by 8.94-18.8%, P = 0.003-0.021) and uterine gland area (by 30.6%, P < 0.01 on E3 and 44.5%, P < 0.01 on E5). Immunohistochemistry showed that restraint stress decreased microvessel density (by 12.9-70.5%, P < 0.01) and vascular endothelial growth factor expression (by 14.6-45.9%, P = 0.007-0.02). Restraint stress decreased by 32.4-39.8% (P = 0.002-0.01) the mean optical density ratio for proliferating cell nuclear antigen/terminal deoxynucleotidyl transferase dUTP nick end labeling. Methyl thiazolyl tetrazolium assay showed a dosedependent decrease in proliferative activity of endometrial stromal cells (from 52 of 154 pregnant E5 control mice) incubated with H 2 O 2 (100-1000 μM) in vitro. These findings supported the hypothesis that restraint stress negatively influences endometrial adaptive remodeling via an oxidative stress pathway, which resulted in fewer implantation sites. Stress Downloaded from informahealthcare.com by Nanyang Technological University on 08/26/15 For personal use only. Stress Downloaded from informahealthcare.com by Nanyang Technological University on 08/26/15 For personal use only. Stress Downloaded from informahealthcare.com by Nanyang Technological University on 08/26/15 For personal use only. Stress Downloaded from informahealthcare.com by Nanyang Technological University on 08/26/15 For personal use only. Stress Downloaded from informahealthcare.com by Nanyang Technological University on 08/26/15 For personal use only.

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