Effects of melatonin administration on embryo implantation and offspring growth in mice under different schedules of photoperiodic exposure

Abstract

BackgroundEmbryo implantation is crucial for animal reproduction. Unsuccessful embryo implantation leads to pregnancy failure, especially in human-assisted conception. Environmental factors have a profound impact on embryo implantation. Because people are being exposed to more light at night, the influence of long-term light exposure on embryo implantation should be explored.MethodsThe effects of long photoperiodic exposure and melatonin on embryo implantation and offspring growth were examined. Long photoperiodic exposure (18:6 h light:dark) was selected to resemble light pollution. Melatonin (10−2, 10−3, 10−4, 10−5 M) was added to the drinking water of mice starting at Day 1 (vaginal plugs) until delivery.ResultsMelatonin treatment (10−4,10−5 M) significantly increased litter sizes compared to untreated controls (12.9 ± 0.40 and 12.2 ± 1.01 vs. 11.5 ± 0.43; P < 0.05). The most effective concentration of melatonin (10−4 M) was selected for further investigation. No remarkable differences were found between melatonin-treated mice and controls in terms of the pups’ birth weights, weaning survival rates, and weaning weights. Long photoperiodic exposure significantly reduced the number of implantation sites in treated mice compared to controls (light/dark, 12/12 h), and melatonin rescued this negative effect. Mechanistic studies revealed that melatonin enhanced the serum 17β-estradiol (E2) levels in the pregnant mice and upregulated the expression of the receptors MT1 and MT2 and p53 in uterine tissue. All of these factors may contribute to the beneficial effects of melatonin on embryo implantation in mice.ConclusionMelatonin treatment was associated with beneficial effects in pregnant mice, especially those subjected to long photoperiodic exposure. This was achieved by enhanced embryo implantation. At the molecular level, melatonin administration probably increases the E2 level during pregnancy and upregulates p53 expression by activating MT1/2 in the uterus. All of the changes may improve the microenvironment of the uterus and, thus, the outcomes of pregnancy.

Circadian Clock, Time-Restricted Feeding and Reproduction

“…Recently, Zhang et al showed the relationship between long light exposure and negative effects on embryo implantation and pregnancy success (mimicking light pollution). Female mice who underwent spontaneous estrous were placed with fertile males and then checked for plugs the next morning [128]. These plugged females were then used for the experiment.…”

“…The administration of melatonin rescued the negative effect of long light exposure. Melatonin probably increases 17β-estradiol levels during pregnancy and upregulates tumor protein p53 expression by activating melatonin receptors type 1 or 2 in the uterus [128]. This activation likely changes the uterine microenvironment for the better and increases the chance of a positive pregnancy outcome via increased successful embryo implantation.…”

From Implantation to Birth: Insight into Molecular Melatonin Functions

“…In addition to the direct antioxidant activity, melatonin-induced functions are directly mediated by binding to melatonin membrane receptors MT1 and MT2 [ 54 ]. Following stimulation, melatonin receptors activate several signaling pathways involved in embryo implantation: the MT1, MT2, p53, and LIF levels in the uterus were evaluated in order to study the direct influence of melatonin during the implantation period [ 55 ]. It has been shown that the differential expression of MT1 and MT2 receptors in pregnant and non-pregnant human uteri is able to influence the cyclic rhythm of myo-endometrial contractility [ 41 ].…”

Seasonal Reproduction in Vertebrates: Melatonin Synthesis, Binding, and Functionality Using Tinbergen’s Four Questions

“…Research related to sexual dimorphism of melatonergic effects on reproductive physiology tends to focus on the gonads, despite research showing that there is more than what meets the gonads (testes/ovaries) when it comes to sex differences in animal research [ 235 ]. Extensive reviews have been conducted on melatonin in seminal plasma [ 236 ], on oocyte competence and blastocyst development [ 237 ], on in vitro fertilization and embryo transfer success [ 238 , 239 , 240 , 241 , 242 , 243 ], on the ovary [ 113 ], and on male reproductive health overall [ 238 , 244 ]. However, parsing out the effects of melatonin acting as a hormone from other confounding factors (e.g., other products of melatonin biosynthetic pathway, melatonin synthesizing-enzymes, melatonin as an antioxidant/free-radical scavenger, etc.)…”