1 Introduction

Maternal stress exposure is a nonspecific risk factor causing neurodevelopmental outcomes in subsequent offspring [1]. It will also cause psychopathologies such as autism, schizophrenia, and anxiety problem in human [2,3,4], and lead to an increased anxiety, a decreased sociability, and deficits in cognitive and motor function in animal models [5, 6]. Increasing evidence suggests that maternal stress exposure will affect offspring development. The psychological maternal condition, intrauterine factors, hormone and immune responses are vital to the healthy development of the embryo. Maternal stress is suggested to play an essential role in the adaptation of maternal dynamic hormones and immune response, and to be capable of negatively affecting the development of the fetus with a long-term influence [7].

Although studies of model animals and epidemiological survey show that maternal stress exposure negatively affects the neurodevelopment of the offspring, few studies find that the relationship between stress exposure and female immune functions is altered. Stress has the capability of altering the maternal inflammatory responses of spleen and lymphocytes, promoting the secretion of inflammatory cytokines [8]. Another theory suggests that interplay(s) between the maternal immune reaction and the fetus brain is a latent mechanism by which maternal stress could affect the neurodevelopment [4]. However, whether maternal stress exposure could also change the fetus immune response and whether have a negative influence on the offspring remain largely unknown.

Current studies suggest that the maldevelopment of fetus caused by maternal stress exposure might be a result of interaction between maternal immune activation and embryo or fetus development adaptation. Evidence shows that obvious activation of specific lymphocytes [9], cytokines [10], and immune reactive pathway is observed in both human and animal models that are under stress. Hence, we will briefly summarize the maternal stress that women might be exposed to before and during pregnancy. And we will also have a look into the clinical outcomes and molecular alterations induced by maternal stress or the signal pathways. These signal pathways mean a consequence of stress-induced immune responses when maternal stress stimulates the downstream signals and influences the mother and her fetus.

2 Stress Exposure

During pregnancy, pregnant woman and her fetus might be confronted with various stresses which might result in significant changes of the mother’s physiological conditions and a maldevelopment of the fetus’s nerve and immune system. Such stresses can be divided into several groups according to the time they may occur.

2.1 Pregestational Stress

Pregestational stress refers to chronic stress which is suffered by a woman prior to gestation. It has been shown that pregestational stress can negatively affect offspring’s immune, cardiovascular system and neurobehavioral development [11, 12]. Pregestational chronic maternal stress can also lead to a significant decrease in fertility rate as indicated in the study of dams [13]. However, to date, no study has directly examined the relationship between pregestational maternal stress and immune alterations, and the link of pregestational maternal stress and changes of offspring immune functions.

2.2 Prenatal Stress

Prenatal stress is also known as prenatal maternal stress that occurs during pregnancy, which is closely related to developmental plasticity and it is considered a risk and dangerous factor for the development of the offspring [14]. However, a long-term observation suggests that stress from pregnancy seriously affects offspring’s development. Previous studies indicate that antenatal stress is associated with greater behavior and physiological reaction in early stage of life, increasing offspring’ reaction to both sustaining and non-sustaining rearing experiences [15, 16]. Animal study also shows that prenatal stress affects developmental plasticity by inducing greater environmental sensitivity, becoming a risk factor while facing adversity and a factor while in a supportive environment [17]. Yet, it remains unclear how such environmental sensitivity is induced. Many animal models researches suggest that stress from maternal part before pregnancy may change the environment in utero and take effects on placental construction or function during the period of organ growth and development, causing physiological adaptations in the developing fetus that have ongoing effects on persistent postnatal development [1]. In short, more and more researches indicate that prenatal stress has a negative influence on both mother and offspring.

Prenatal maternal stress exposure in both animal models and humans has related to a wide array of psychiatric and neurodevelopmental disorders and problems in resultant offspring [1]. The clinical manifestations of prenatal stress include higher levels of sadness, aggression, anxiety, and physical disorders [18]. Prenatal maternal stress might negatively influence the development of fetal brain by constricting the placental arteries, resulting in a reduction of fetal blood flow as well as the essential nutrients and oxygen supply [19, 20]. Prenatal stress might also result female embryo become to masculinization [21]. Recent evidence suggests that prenatal maternal stress may increase autism (autism spectrum disorder, ASD) risk or increase the variability in autism-like traits in the large population.

Prenatal stress may also negatively affect the activation of mother’s immune system and further influence the development of offspring. Besides, maternal immune system activation caused by prenatal stress might also contribute to mental disease risk and abnormal offspring behavior [4]. Previous studies have shown that specific cytokines, including interleukin-2 (IL-2), interleukin-6(IL-6), and IL-17A during pregnancy are linked to offspring neuropsychiatric disorders [22,23,24]. It is notable that IL-6 is likely to be of importance in the etiology of prenatal stress effects [25]. Besides, IL-6 is suggested to be a potential mediator of prenatal maternal immune activation which will affect offspring neurodevelopment [26, 27]. Animal models also show that under prenatal stress, maternal cytokine levels also alter, with a significant increase of circulating IL-6 [28]. IL-6 is essential for increased embryonic multivacuolated microglia and for persistent microglia changes [4]. Stress exposure can also activate the transcription factor NF-κB in mononuclear cells derived peripheral blood, increasing its circulating numbers of pro-inflammatory cytokines [29].

In addition to the alteration of cytokine levels, prenatal stress also affects the lymphocyte population and immune cell functions. Prenatal stress can significantly decrease the serum immunoglobulin G (IgG) concentrations in suckling pigs and has an immune suppressive effect on lymphocyte proliferation because of the T-cell mitogen concanavalin A (ConA) [30]. In addition, prenatal stress can also inhibit the response to B-cell mitogens lipopolysaccharide (LPS) in suckling pigs [30]. Compared to healthy, non-pregnant women, women under diabetes stress during pregnancy are reported to show obvious changes in lymphocyte sub-populations, such as the population of naïve T cells are decreased, while the population of memory T-cells and activated T cells (CD4 + HLA-DR+, CD4 + CD29+) are higher [31].

2.3 Perinatal Stress

Perinatal stress is reported to have a gender-dependent effect on offspring [32]. It can also intensify the risk of the development of psychoneurological, immunological, and psychological disorders and decrease the reproduction of the offspring [33]. Animal study also shows that perinatal stress can lead to learning impairment, increased anxiety and depressive behaviors, and enhanced sensitivity to drugs of abuse via fetal programming [32, 34]. Study of adult rats suggests that perinatal stress might cause an elevation of ACTH level in cell type of lymphocytes, monocytes and granulocytes, and mast cells, provoking a life-long hormonal imprinting [35]. It is notable that the inflammasome might be an important immune molecular between stress, neuroendocrine and inflammatory process [36]. In the brain, microglia are seen as the primary immune cells. Microglia and toll-like receptor 4 play a vital role in triggering various stress responses caused by the activation of the inflammasome, which increases the level of inflammatory cytokines, elevated serotonin metabolism, or decreased neurotransmitter availability as well as hypothalamic–pituitary–adrenal (HPA) axis hyperactivity [37]. During pregnancy, intricate neuroimmune communication network would dysregulate always, and it would change the maternal milieu, enhancing the emergence of depressive symptoms, even negative obstetric as well as neuropsychiatric outcomes [37].

2.4 Neonatal Stress

Neonatal stress refers to stress offspring confronted by during neonatal period. Neonatal stress can also have long-term influences on neurotransmitter system and brain, which could increase the risk of vulnerability in later life [38]. A close relationship between neonatal stress and immune function disorder is observed in animal studies. Known study reveals that neonatal stress can augment inflammatory cytokine level and viral replication when adult mice were infected by influenza virus [39, 40]. Animal model study further displays that neonatal stress damages the regulation of innate resistance resulting in immunological and behavioral responses abnormally increased when immune activated, which might even have a long-lasting effect on the susceptibility to diseases [41]. Neonatal stress as premature weaning leads to lymphocyte proliferation suppression and a higher risk of premature deaths in rat and reduced proliferation of lymphocyte in response to B or T cell mitogens in monkeys [40, 42]. Stress on separation of rat pups from their dams could result in significant aggravation in the severity of experimental autoimmune encephalomyelitis (EAE), it would aggravate the severity of airway inflammation in an asthma rat experiment and decrease in serum immunoglobulin levels in mice treated with injection of sheep red blood cells [43,44,45]. The possible mechanism(s) underlying neonatal stress-mediated negative regulation on immunity is still unclear. Studies using the maternal separation (MSP) experimental model find that the response of the HPA axis to stress is augmented and, at the same time, glucocorticoid feedback control is altered [41, 46, 47]. Hence, it is supposed that the activation of HPA axis might regulate the inflammatory response, activating the immune system accompanied by various behavioral changes [41].

As described above, both the mother and her fetus are influenced by psychosocial and biological stress. Maternal stress exposure in humans has been related to the psychiatric and neurodevelopmental disorders in offspring [1]. While stress was found to be associated with lower immunoglobulin G (Ig) production, reduced immune function, and elevated IL-6 and IL-1𝛽 in the first and third trimester, the mechanism through which immune modulation is conducted during pregnancy is still unclear [10, 48]. Generally, maternal immune system remains in multifaceted and dynamic state, being immune-tolerant to fetal cells and protecting maternal cells from pathogen attack at the same time. Besides, it is well acknowledged that the interaction between HPA axis and immune system plays a pivotal role in adaptation when mother is pregnant. Additionally, under stress, HPA axis activation during pregnancy is observed in both human and animal studies. Thus, it is supposed that after stress exposure, alterations in maternal HPA axis result in modulation of immune response. Namely, HPA axis might be an important mediator between prenatal stress and immune functioning [32, 49]. It is also supposed that stress-relevant neurocircuitry and immunity form an integrated system which is involved in innate and adaptive immune systems interacting with neurotransmitters and neurocircuits to influence the risk for stress [36]. Psychosocial stress causes inflammasome activation and then the stress-induced inflammatory signals are transmitted to the brain, resulting in behavioral responses.

3 Stress-Induced Activation of Hormone and Immune System

Stress will break the balance of endocrine and immune system of the body and cause the disorder of the whole internal environment, which is mainly expressed as abnormal hormone secretion level and the activation of the immune system. Under the circumstances of acute or strong stress, the cell activates a series of signaling pathways and then responds to stress state through the expression of related genes. The following is a brief introduction from four aspects, cytokine, hormone secretion and signaling, immune cell activation, and immune regulatory gene expression and modification.

3.1 Cytokine

The current study focused on two groups of female who are pregnant or infertile. There is evidence shown that secretion of inflammatory cytokines is increased due to excessive exposure to emergency conditions during pregnancy [10]. In individuals, cytokine levels are not stable during pregnancy, and IL-6 and TNF-α are significantly increased [50]. When pregnant women experience trauma, the levels of TNF-α could be significantly higher than normal pregnant women. For women who repeatedly miscarry or remain infertile, their physiological emotion stages, such as stress, anxiety, and depression, cause abnormal cytokine levels and directly relate to the IVF poor outcomes. Researchers conduct stress scale investigation for patients with infertility and detect cytokines from blood, cervicovaginal fluid, and follicular fluid. The cytokines such as TGF-β in serum are lower, while IL-6 and IL-1β in cervicovaginal fluid are higher than normal pregnant woman [51].

3.2 Hormone Secretion and Signaling

It is currently believed that stress causes changes in a variety of female hormones that affect the function of the reproductive system, such as abnormal ovulation, premature ovarian failure (POF), infertility, and so on. The stress-regulated hormones can be classified into two types, nitrogen hormone and steroid hormone. Nitrogenous hormones include insulin and corticotropin-releasing hormones (CRH). Researches have shown that pregnancy women who have experienced more stress assessed by maternal STAI trait stress score have decreased insulin sensitivity but increased corticotropin-releasing hormones [52]. Abnormal insulin levels can lead to stress hyperglycemia, even increase the risk of diabetes. High levels of CRH through the placenta cause preterm birth and intrauterine developmental retardation (IDR), even cause neonatal neural development disorders and adverse effects on psychological health potentially [53]. Steroid hormone includes cortisol, estrogen, progesterone, and androgens. The ovulation cycle of healthy women without reproductive disease will be changes when exposed to pressure source [54]. The specific mechanism is closely related to the cortisol changes. According to Karen C. Schliep, with increased stress levels, estrogen (E2), progesterone, and luteinizing hormone (LH) are decreased, and women with high stressors are more likely to be anovulatory [54]. Based on a prospective study which explored correlation between the biomarkers of the stress evaluation and pregnancy loss, researchers didn’t find clear association between cortisol and adverse pregnancy outcomes [55]. In addition, the increase of psychological stress results in decreased serum levels of anti-Müllerian hormone in infertile women, implying that stress induction continuously may lead to amenorrhea, early menopause, and premature ovarian failure [56].

3.3 Immune Cell Activation

It is known that psychological pressure and stress promote pregnancy inflammation, including changes in the number of immune cells and increased secretion of inflammatory cytokines from these cells [9]. In general, the proportion of immune cells in uterine microenvironment is subtly changed after successful pregnancy, and inflammatory factors secreted by immune cells are slightly increased. But early pregnancy stress occurring on the first trimester can activate lymphocytes and promote high expression of cytokines, such as IL-1β and IL-6. A series of reactions can lead to an excessive inflammatory response and increase adverse pregnancy outcomes [57]. In addition, persistent stress in early pregnancy affects the proportion of Treg cells which cause Th1/Th2 cells unbalance. The current evidence shows that Th1 cells environment is harmful to embryo implantation and increases placental vascular resistance, which might cause preeclampsia, even lead to premature birth [58]. According to a large retrospective study, investigators detected the blood from specific kids whose mothers had experienced serious natural disasters (The 1998 Quebec ice storm) when they were pregnant. This survey found that the number of lymphocytes and CD4+ T cells was reduced while their cytokines significantly increased, such as TNF-α, IL-1β, and IL-6 levels. Stress can potentially alter the nervous and immune systems of offspring [59]. Neonatal immune system growth was regulated by the interaction between the nerve and endocrine system. Stress experienced by women in their early pregnancy permanently alters the fetal respond ability of the nervous system. It affects the hypothalamic–pituitary–adrenal cortex (HPA) axis and alters the neural regulation of the immune system after birth subsequently [60].

3.4 Immune Regulatory Gene Expression and Modification

At present, there are few studies on the abnormal gene expression and modification induced by stress, and the specific mechanism is still unclear. Some scholars believe that the key mediator of stress is glucocorticoid (GC), which may affect the expression of related genes by binding to GC receptors, and possibly increase allergy susceptibility [61]. In the first trimester, neural stem cells have a rapid speed of self-renewal and proliferation. Then, they established synaptic connections in cerebrum. If this process is affected by stress, neural cells’ proliferation and migration will be disordered, increasing the risk of neurological dysfunction. Then, these stress responses will be retained until birth through epigenetics, such as DNA methylation and histone modification. Finally, it’s linked directly to schizophrenia and developmental disorders [62].

Oxidative stress (OS) is a physiological process of unbalance between oxidation and anti-oxidation. The main manifestation is neutrophil inflammatory infiltration and accumulation of oxidation intermediate products. OS is closely related to diseases of the female reproductive system, such as endometriosis, polycystic ovary syndrome (PCOS), and unexplained infertility, which directly leads to female reproductive failure [63]. Meanwhile, oxidative diseases are related to poor pregnancy outcomes, even spontaneous abortion and preeclampsia [64]. OS activates nuclear gene transcription through a variety of ROS (reactive oxygen species) sensitive components to regulate fetal development, including Nrf-2, NF-κB, and HIF-1 [63].

4 Outcomes of Stress-Induced Immune Response in Reproductive System

Various reports demonstrate that stress-induced immune response in pregnant female could lead to an abnormal increase of specific cytokines, resulting in fetal maldevelopment. Therefore, the alterations of immune response and the main clinical outcomes are briefly summarized here.

4.1 Alterations in Maternal Immune Function

Stress exposure has been shown to be capable of regulating both the maternal and offspring’s immune function. We will briefly summarize these changes in recent studies from the aspects of immune cells, cytokines, and the immune-HPA axis.

Th1/Th2 and Th17/Treg immune balances are critical to maintain a successful pregnancy [37]. Literature reported that women with both severe depression (SD) and severe anxiety (SA) during the late pregnancy had the highest levels of Th1- (IL-6, TNF-α, IL-2, IFN-γ), Th17- (IL-17A, IL-22), and Th2- (IL-9, IL-10, and IL-13) related cytokines, and the SA group showed higher levels of Th1- (IL-6, TNF-α, IL-2, IFN-γ) and Th2- (IL-4, and IL-10) related cytokines than that of control group in serum [65].

Elevated stress can result in alterations of serum cytokine levels during pregnancy, leading to an alteration of maternal immune function. During early pregnancy, elevated stress is related to higher serum IL-6 and lower IL-10; during the second trimester of pregnancy, it is related to higher serum levels of C-reactive protein (CRP); elevated stress levels across pregnancy is related to an increased level of pro-inflammatory cytokines IL-1B and IL-6 [10, 66]. It is further confirmed by Giese S. et al that elevated stress is positively correlated with higher levels of the pro-inflammatory cytokines IL-6 and TNF-alpha, but is negetively correlated with lower levels of the anti-inflammatory cytokine IL-10 [67].

Interplays among stress, HPA axis, and immune system also contribute to the alteration of immune system after stress exposure. Stress exposure could lead to alteration of HPA axis as observed in animal studies [68]. The HPA axis can be activated by pro-inflammatory cytokines, resulting in glucocorticoid hormones release which in turn can deliver negative feedback and suppressed the cytokines release [69]. Lymphocyte sensitivity to corticosterone and catecholamines is altered under stress conditions, indicating adrenal’s hormones are mediators of the differential reactions of stress on the immune response [48].

4.2 Reproductive Disorders: Female Infertility and Miscarriage, Preeclampsia, Recurrent Abortion

Despite maldevelopment of offspring, stress exposure might also result in reproductive disorders. Stress-related neural immune interactions may lead to various pregnancy complications and unsatisfactorily outcome [67]. Prenatal stress disorders caused maternal physiology and immune function disorder, leading to an increased risk of pregnancy complications such as preeclampsia and premature labor [10]. Although the relevance of stress exposure and pregnancy complications is not well documented, it is clear that pregnancy complications might arise more stress and stress exposure does have a negative effect on pregnancy.

4.3 Female Infertility and Miscarriage

Although it is accepted by some researchers that stress hampers reproductive function, more investigators believe that it is the infertility or other reproductive disorders that cause the psychological stress such as anxiety, depression, and irritability [70]. Previous study shows that psychological symptoms do have a negative effect on fertility [71], and oxidative stress is associated with female infertility, in that women suffered from stress get a higher miscarriage rate [72]. The relationship between placental oxidative stress and infertility still needs to be further studied. Compared to normal ones, transcriptomic analysis showed a decreased expression of genes in miscarriage placentas [73]. However, unexplained miscarriage samples are unable to be excluded, which makes it more difficult to study the relationship between stress and miscarriage.

4.4 Preeclampsia

Preeclampsia is one of the common pregnancy complications characterized by hypertension and proteinuria, which will lead to hypertension, edema, and eclampsia in mother and fetal growth restriction, prematurity, and death in baby. Oxidative and nitrosative stresses in placenta are reported to be associated with preeclampsia [74]. Oxidative stress in the placenta leads to inflammation and cellular apoptosis, and apoptotic cells will flow into maternal circulation and thus stimulate the release of more pro-inflammatory cytokines, resulting in a massive systemic endothelial dysfunction, even preeclampsia [74, 75]. Immune cells might contribute to preeclampsia by triggering stress in placenta. Immune cells found in placenta including dendritic cells, macrophages, and T cells are supposed to be involved in generating oxidative stress and might be also related to the onset of preeclampsia. Specifically, Hofbauer cells (placental macrophages) have been shown to express catalase at early pregnancy, which catalyze the detoxification of hydrogen peroxide (H2O2). Further study shows that Hofbauer cells might also induce nitrosative stress and cause other pathologies [76].

4.5 Recurrent Abortion

Women with recurrent abortion experience more psychological stress and major depression than pregnancy planners trying to conceive naturally [77]. However, stress exposure might also in turn lead to higher rate of recurrent abortion. It has been shown that oxidative stress is linked to recurrent abortion [78]. Oxidative stress-induced endothelial and placental vascularization impairment as well as immune malfunction may play an important role in the pathophysiology of recurrent abortion [79]. However, how other stress exposure lead to a consequence of recurrent abortion requires more studies.

Collectively, stress exposure during pregnancy could bring adverse effects on both mother and offspring. From the mother’s perspective, maternal stress exposure might result in mental disorders such as anxiety, aggression, and depression, even lead to preterm delivery and preeclampsia [80]. From the aspect of fetus or offspring, stress exposure is associated with premature labor and poor birth outcome. Although this conclusion is primarily based on animal studies, maternal stress exposure is undeniable to have a negative influence on both the mother and her fetus.

5 The Major Signal Pathways That Contribute to Stress-Induced Reproductive Immune Response in Females

5.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis

Basic and clinical researches have shown that hypothalamic-pituitary-adrenal (HPA) axis plays a role in effect of stress on reproductive endocrine. Physical and psychological stresses can activate HPA axis, and affect female’s reproductive endocrine function at all three aspects of the hypothalamo-pituitary-ovary (HPO) axis. Additionally, researches also reveal that the changes in progesterone and estrogen levels, and the different stages of one menstruation cycle, have impacts on the way females respond to stress.

The hyperfunction of HPA axis induced by stress can manifest as the excessive synthesis and secretion of corticotropin-releasing hormone (CRH) in paraventricular nucleus of the hypothalamus, promoting the secretion of adrenocorticotrophic hormone (ACTH) and beta endorphin (β-EP) in anterior pituitary, and ACTH acts on adrenal cortex to release glucocorticoids (GCS). Indeed, increased GCS level in plasma is often used as an objective indicator to judge stress reaction. Similar to HPA axis, there is a HPO axis in female. Gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which trigger estradiol (E) and progesterone (P) secretion in ovaries. There is a feedback loop by which ovarian estradiol inhibits the release of GnRH and succeeding FSH and LH production. Alteration in the concentration of hormones stated above can affect the endocrine status of the HPO axis directly or indirectly. For example, hormones in HPA axis inhibit the GnRH secretion from the hypothalamus, and GCS inhibits LH secretion from the pituitary and estradiol and progesterone secretion from the ovary. In general, activation of the stress axis, especially repeating or chronic, has an inhibitory effect upon the release of gonadal hormone, and results in disorders of maternal immune function and infertility [81].

As one of the most important components of stress inhibiting reproductive endocrine, CRH is the major factor that inhibits the function of HPO axis. However, the molecular mechanisms are complex and unclear till now. Through in vitro experiments, researchers found that CRH inhibited GnRH secretion in the median eminence of the hypothalamus, and thus, we guessed there was direct synaptic connection between the terminal of axon of CRH and the dendrite of neurons secreting GnRH [82]. CRH may act directly on terminal of GnRH neuron to downregulate GnRH synthesis. Nevertheless, the inhibition of pituitary gonadotropin (Gn) release by corticotropin-releasing factor (CRF) is not mediated by ACTH, in that ACTH has no effect on the basic secretion and the release of LH from pituitary induced by LHRH. Furthermore, other studies suggest that β-endorphin bypass pathway may also involve in the effects on inhibition of CRH on GnRH [83].

Not only does CRH inhibit the secretion of Gn in pituitary, but it also inhibits ovarian estrogen synthesis directly. As FSH can promote estrogen synthesis in ovarian granulosa cells, CRH can inhibit this action by inhibiting aromatase which is essential in estrogen synthesis.

GCS are essential to the establishment and maintenance of reproductive function. Two apparent examples are two diseases with GCS disorder: Cushing’s syndrome patients often complicate with reproductive disorders such as secondary amenorrhea in female. Similarly, patients with Addison’s disease may suffer from premature ovarian failure in female or oligospermia in male. Researches reveal that increased GCS exposure, by either stress or exogenous treatment, can reduce the frequency and amplitude of LH significantly, especially near ovulation, and delay preovulatory LH and FSH surge, making E2 cannot reach the peak point, subsequently, leading to profound reproductive effects [84]. GCS modulate the HPO axis by inhibiting the release of GnRH in the hypothalamus as well as the synthesis and release of Gn in the pituitary directly. However, the exact signal pathways remain unclear yet. Some researchers argue that neuropeptides are key to study HPA function. CRH, thyrotropin-releasing hormone (TRH), oxytocin (OT), vasopressin (AVP), and some other hormones expressing neurons are among those that project to the median eminence [68]. Some of these neuropeptide neurons, such as kisspeptin (KISS1) and gonadotropin-inhibitory hormone (GnIH), are the drivers of the HPA axis. KISS1 neurons express glucocorticoid receptor (GR) in the anteroventral periventricular nucleus and periventricular nucleus continuum of the preoptic area of the hypothalamus, suggesting that GCS can directly act in neurons stated above. In the meanwhile, further studies reveal that to impair KISS1 neurons may be one of the mechanisms of GCS acting on HPO axis. Moreover, stress can increase the function of GnIH neurons, which can inhibit the neurons activity in both GnRH and KISS1 neurons, and increase contacts with GnRH neurons [85].

5.2 Epigenetic Pathway

Another signal pathways that contribute to stress-induced reproductive immune response in females is epigenetic pathway. Epigenetics describes how gene expression shows heritable changes without any change in DNA nucleotide sequence. Generally, the epigenetic signature can be passed on to the next generation and affect gene expression. The main regulation mechanisms of epigenetics include DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA, among which DNA methylation is the one that has been most researched. For instance, DNA methylation is connected with gene silencing, while demethylation is linked to increased gene expression activity. Mostly, the activation of transcription at DNA level is the demethylation of the promoter sequence, while the promoter methylation inhibits transcription.

Large amount of evidence demonstrates the association of epigenetics and reproduction. Kiss1 gene, as stated above, is discovered as a metastasis suppressor gene in malignant melanoma cell. Interestingly, it is then proved to be related to reproductive function in the aspect of the release of GnRH, onset of puberty, and also has functions on the maintenance of reproduction in adults [86]. Researches argue that the methylation of Kiss1 and kisspeptin receptor (Kiss1R) genes promotes changes throughout puberty, and during puberty, the activation of Kiss1 gene is the consequence of histone H3 modification activation [86]. Another example is the relationship between follicle maturation and chromatin remodeling. The aryl hydrocarbon receptor, Ahr, is regulated during ovarian follicle maturation, and its up-regulation relies on FSH and LH. The increase in Ahr protein is specifically related to large antral follicles in induced follicle maturation. Researches demonstrate that the activation of Ahr promoter can be regulated by chromatin remodeling, resulting in increased Ahr transcription [87]. In addition, Ahr in response to hCG is down-regulated by chromatin remodeling in preovulatory follicles in murine [87].

Recent studies reveal that DNA methylation is a possible mechanism of the effect of prenatal stress in the offspring. Prenatal stress may lead to aberrant heart structure, glucose intolerance, and brain function, etc. A study in America [88] studied whether stress and the absence of social support during pregnancy would affect maternal DNA methylation, and reached a conclusion that lack of support from family and friends, especially the baby’s father, was associated with maternal DNA hypermethylation on multiple genes. Another study in 2017 [89] examined the multigenerational epigenetic effects of stress, especially psychosocial stress, and revealed that grandmaternal exposure to stress such as interpersonal violence during pregnancy was closely related to 27 differentially methylated CpG sites in children that mapped to 22 uniquely annotated genes. We take CORIN as an example, as for neonate. CORIN has functions on circulatory system processes and congenital abnormalities and as for prenatal disorders, it is associated with regulation of blood pressure and is important for physiological changes at the maternal–fetal interface. Animal studies have suggested that this gene plays a vital role in preventing gestational hypertensive disorder. Furthermore, methylation of another gene, CFTR, may have relationship with depression symptoms and post-traumatic stress disorder (PTSD) [89].

Oxidative stress can also be a kind of stress in female reproduction. Oxidative and reductive stress can both have potentially hazardous effects. Oxidative stress has negative effects on reproductive function. Researches prove that it has been linked to female reproductive system diseases such as polycystic ovary syndrome and endometriosis [63]. As for epigenetics, reactive oxygen species (ROS) can cause DNA damage, which may affect the oocyte. Also, it may affect gametes quality and development of embryos. However, reactive oxygen species (ROS) are necessary for some physiological reproduction processes such as ovulation, capacitation, and corpus luteum formation and function. A regular example is ovulation. During an ovarian process, preovulatory LH surge emerge, ROS levels rise, and antioxidant levels fall [63].

6 Conclusions and Future Prospects

Stress exposure before and during pregnancy has capability to negatively affect both the mother and her fetus as reported by various human and animal models researches. One assumption accepted by most investigators indicate that maternal stress exposure might adversely affect the mother and her fetus via hormones and immune regulation. Therefore, it is promising to reduce maternal stress exposure to decrease the incidence of stress-induced physiological and psychological disorders. Hormones and immune regulation are also potential strategies through which we can lower the negative influence caused by stress-induced hormone or immune activation. Unfortunately, although specific cytokines and signal molecules are identified in both human and animals which suffered from pregnancy stress, the mechanisms by which maternal stress affect the mother and her fetus remain largely unknown. It is of great significance studying stress exposure during pregnancy since it has detrimental influence on maternal and child health with a high prevalence among pregnancy women worldwide. Further studies are still required to further elucidate the following issues: (1) How maternal stress triggers the activation of maternal immune system. (2) How different immune cells react to maternal stress. (3) How we can appropriately measure the maternal stress and establish a systemic stress management. (4) The mechanisms underlying the maldevelopment of the fetus and offspring. An insight into these issues will provide us more inspirations to successfully control maternal stress, providing the mother and her fetus a healthier physical and mental state.