产前应激对子代的影响及潜在作用机制

Inappropriate diet and stress in maternal pregnancy may affect the development of the offspring. Brain dysfunction and some chronic diseases such as obesity and diabetes in offspring are associated with the factors during maternal pregnancy. Many researches focused on how prenatal stress affected cognitive function and behavior of the offspring and how nutritional modulation might prevent the pathogenesis of such diseases. Here we summarize the effects of prenatal stress on the offspring and the potential mechanism, like hypothalamus-pituitary-adrenal axis(HPA), oxidative stress, apoptosis and inflammation, and the prevention of nutrient to offspring dysfunction by prenatal stress, based on our previous work and some existing references.     

中晚期孕期束缚应激对子代下丘脑多巴胺能神经元发育的影响

目的　研究中晚期孕期束缚应激对子代下丘脑多巴胺能神经元发育的影响。 方法　使用怀孕SD大鼠,实验组在孕期第15~21 d进行束缚应激,对照组则不受任何干扰。子代大鼠出生的当天为出生后的第0 天。在子代大鼠出生后的第1天（P1）,第7天（P7）和第30天（P30）,分别测子代大鼠的体重,通过免疫组织化学染色和Western Blotting,观察和比较下丘脑内合成多巴胺的关键酶酪氨酸羟化酶（TH）染色像素密度及TH蛋白水平变化。 结果　与正常对照组相比,中晚期孕期束缚应激子代大鼠在P1体重较低,下丘脑TH染色像素密度和TH蛋白水平上调, 这种异常在P7和P30消失。 结论　孕期应激使子代下丘脑多巴胺神经元早期发育异常, 可能是造成子代神经系统行为学异常的原因之一。     

Untreated prenatal maternal depression and the potential risks to offspring: a review

Research exploring the effects of prenatal maternal depression on a developing fetus and child is underrepresented in the literature. Empirical papers have typically focused on the effects of postpartum depression (after birth) instead of prepartum depression (before birth). Disparate empirical findings have produced ongoing debate regarding the effects of prenatal depression on a developing fetus and later in infancy and early childhood. Even more controversial is determining the role of antidepressant medication on offspring outcomes and whether research that does not include the proper control population (e.g., unmedicated depressed participants) can adequately address questions about risks and benefits of treatment during pregnancy. The current review systematically summarizes the literature focusing on unmedicated prenatal depression and offspring outcome and concludes that prepartum depression is highly prevalent, is associated with negative outcomes in offspring, and remains understudied.     

Effects of prenatal hydroxyurea-treatment on mouse offspring

Hydroxyurea (HU), a ribonucleotide reductase inhibitor, induces morphological anomalies in the central nervous system, craniofacial tissues and limb buds in animals, and neonatal respiratory distress in humans. The neonates and offspring of pregnant mice treated with 400 or 800 mg/kg of HU on day 13 of gestation were examined at 0 day and 10 weeks after birth to find a clue for clarifying the relationship between HU-induced apoptosis in the fetal tissues and teratogenicity. The offspring from dams treated with HU were retarded in growth compared with controls. But there was no significant difference in the body weight gain between the 400 and 800mg/kg groups. In the teratologic changes, microencephaly, hydrocephalus and curved coccygeal vertebrae were observed in the offspring, and the incidence of these teratologic changes was similar but their degree was more severe in the 800 mg/kg group than in the 400 mg/kg group. Based on the above-mentioned previous and present studies of ours, we suggest that HU-induced apoptosis in fetal tissues may play an important role in the development of anomalies in the corresponding tissues of offspring.     

Effects of prenatal stress on development in mice: maturation and learning

Female CD-1 mice were stressed during the final week of gestation. Beginning 3 days after birth, until weaning, their pups were examined for eye opening, startle response, tooth eruption, surface righting, ability to cling to and climb an incline, tail pull reflex, rotation, linear movement and exploration. At 3 months of age, they were tested in a Morris Water Maze.Stressed animals were significantly lighter and shorter than non-stressed animals the first week after birth. By 3 days after birth, significantly fewer stressed animals could rotate or right themselves. By 6 days after birth, significantly fewer stressed animals could cling to or climb an inclined screen, or show the tail pull reflex. By 9 days of age, significantly fewer stressed animals had teeth. In contrast, by day 12 of age, significantly more stressed animals demonstrated exploratory behavior than did non-stressed animals. There were no sex differences in the ability of animals to perform these tasks at the same age.Stressed animals were significantly slower than non-stressed animals to reach the hidden platform in the water maze on all trials, and this difference was due to stressed females being slower to find the platform than non-stressed females, with no main effect of stress on males.This study supports and expands previous findings in rodents that prenatal stress can cause deficiencies in some early indices of physical maturation and also that these deficiencies can be continued into adulthood.     

Effects of maternal immunization on the survival and postnatal development of the offspring.

Immunization of females prior to mating altered the size of their litters and the incidence of postnatal death and runting, and the effect varied with the antigen used. Litter size was decreased after immunization with an aggregated synthetic polypeptide or with DNP-BGG, but not with aggregated insulin. Postnatal mortality was increased after immunization with an aggregated polypeptide, aggregated insulin or DNP-BGG. Postnatal runting was increased after immunization with the aggregated polypeptide or with aggregated insulin.     

Experimental maternal hyperphenylalaninemia: biochemical effects and offspring development

Subcutaneous injections of para-chloro-D, L-phenylalanine (pCl-Phe) and phenylalanine (Phe) over the last third of pregnancy were found to produce hyperphenylalaninemic states in maternal and fetal rats. The pCl-Phe, when administered to maternal animals alone or in conjunction with Phe, was associated with maternal muricide. The muricide was counteracted by the administration of 5-hydroxy-D, L-tryptophan prior to delivery. Prolonged treatment of maternal animals with pCl-Phe and Phe suppressed normal weight gain and resulted in smaller offspring. The elevated levels of maternal plasma Phe decreased with time, reflecting a lessening of pCl-Phe inhibition of maternal phenylalanine hydroxylase and normal Phe clearance. Fetal plasma Phe levels mirrored those of treated maternal animals. Similarly, fetal brain Phe reflected the increase in fetal plasma Phe.     

Effects of prenatal and postnatal maternal ethanol on offspring response to alcohol and psychostimulants in long evans rats

An important factor that may influence addiction liability is exposure during the early life period. Exposure to ethanol, early in life, can have long-lasting implications on brain function and drugs of abuse response later in life. In the present study we investigated the behavioral responses to ethanol and to psychostimulants in Long Evans rats that have been exposed to pre- and postnatal ethanol. Since a relationship between heightened drug intake and susceptibility to drug-induced locomotor activity/sensitization has been demonstrated, we tested these behavioral responses, in control and early life ethanol-exposed animals. The young adult male and female progeny were tested for locomotor response to alcohol, cocaine and d-amphetamine. Sedative, rewarding effects of alcohol and alcohol consumption were measured. Our results show that early life ethanol exposure behaviorally sensitized animals to subsequent ethanol and psychostimulants exposure. Ethanol-exposed animals were also more sensitive to the hyperlocomotor effects of all drugs of abuse tested and to those of the dopamine receptor agonist apomorphine. Locomotor sensitization to repeated injections of cocaine was facilitated in ethanol-exposed animals. Ethanol-induced conditioned place preference was also facilitated in ethanol-exposed animals. Ethanol consumption and preference were increased after early life ethanol exposure and this was associated with decreased sensitivity to the sedative effects of ethanol. The altered behavioral responses to drugs of abuse were associated with decreased striatal dopamine transporter and hippocampal NMDAR binding. Our results outline an increased vulnerability to rewarding and stimulant effects of ethanol and psychostimulants and support the epidemiological and clinical data that suggested that early chronic exposure to ethanol may increase the propensity for later self-administration of ethanol or other substances.     

Prenatal stress reduces maternal aggression by mice offspring

Pregnant mice were subjected to the simultaneous stress of heat, restraint and bright lights during the last trimester of gestation whereas control mothers remained unhandled in the home cage. As adults, prenatally-stressed and nonstressed mice were mated and tested for maternal aggression. Compared with nonstressed controls, prenatally-stressed females bit intruder males on significantly fewer occasions. Prenatal stress therefore reduced maternal aggression by mice offspring. Prenatal stress also significantly reduced maternal and neonatal body weight. Because the appearance of maternal aggression characteristically has been associated with the postpartum period, prenatal stress may reduce maternal aggression in mice by disrupting gonadotropin secretions (possibly prolactin) associated with the lactational phase.     

Effects on offspring of chronic maternal methamphetamine exposure.

Twenty-five Sprague-Dawley derived rats were administered 1.0, 3.0 or 5.0 mg/kg of methamphetamine HC1 or saline twice daily throughout gestation beginning on Day 1 of pregnancy. Rats were allowed to deliver normally; offspring were culled to 8 and sexed on Day 7, and weaned on Day 21. All females had viable litters except at the 5.0 mg/kg dose where 4 of 7 failed to deliver. The rats given methamphetamine delivered earlier than did controls. Weight gain over gestation decreased as a function of increasing drug dose. No gross anomalies were visible in the offspring. Litter size decreased as a function of increased dose and eye opening was delayed in the drug groups; the 5.0 mg/kg offspring made more conditioned avoidance responses than did the 3.0 mg/kg and saline offspring.     

Influence of prenatal maternal stress on umbilical cord blood cytokine levels

Purpose

Prenatal maternal stress (PNMS) is known to influence fetal programming and development. Thus far, the effects of PNMS on the developing immune system have mainly been documented in animal studies. This study aimed to examine the association between PNMS and immune cytokine profiles in the umbilical cord blood of newborn human infants.

Methods

PNMS, including perceived stress, numbers of stressful life events experiences (both partner and health related), and state and trait anxiety, was assessed with five questionnaires and interviews from 43 pregnant women during the second trimester. Seven key cytokines important for immune function, i.e., IL-12, IL-1β, IL-4, IL-5, IL-6, IL-8, and TNF-α, were analyzed in cord blood by bead-based ELISA method (Luminex 200). Logistic regression was used to estimate the associations of PNMS scores and cytokine levels.

Results

Increased levels of IL-1β, IL-4, IL-5, IL-6, and IL-8 were significantly associated with at least one of the maternal stress assessments, while the levels of IL-12 and TNF-α were not significantly associated with any of the PNMS measurements examined.

Conclusion

These preliminary findings suggest that PNMS may influence cytokine levels in newborn infants, in particular Th2-related cytokines. This report supports previous findings in animal studies and could suggest that newborns born to mothers with elevated PNMS have a predisposition to immune-related disorders.

     

Effects of malnutrition,maternal stress,or ACTH injections during pregnancy on sexual behavior of male offspring

Pregnant rats were subjected to nutritional stress, environmental stress (immobilization-illumination-heat), or injections of adrenocorticotropic hormone (ACTH) during the third trimester of gestation. Masculine and feminine behavior potentials of the male offspring were determined in adulthood. Compared to control males, male copulatory behavior was severely impaired in all three experimental groups. The prenatally stressed animals showed a significant reduction in the cumulative percent ejaculating and an increase in the number of intromissions prior to the first ejaculation compared to control animals. When tested for female behavior, all three treatment groups displayed a significantly greater lordosis quotient than the control males. Gestation length was increased in the mothers exposed to environmental stress and ACTH injections but not in the nutritional stress animals. At birth, offspring from all experimental groups showed a significant reduction in body weight when compared with control offspring. These results confirm and extend earlier data which indicate that exposure of the mother to stress during the period of fetal sexual differentiation may impair masculine and feminine sexual behavior of the male offspring.     

Mild prenatal stress enhances learning performance in the non-adopted rat offspring

The present study was designed to investigate whether mild stress during pregnancy affects offspring behaviors, including learning performance. Prenatal stress was induced by short-lasting, mild restraint stress, which had previously been shown to facilitate the morphological development of fetal brain neurons. Adult offspring whose dams had been restrained in a small cage for 30min daily from gestation day 15 to 17 showed enhanced active avoidance and radial maze learning performance. In addition, the prenatally stressed rats showed weaker emotional responses than unstressed control, as indicated by decreases both in ambulation upon initial exposure to an open field and in Fos expression in the amygdala induced by physical stress. The observed effects of prenatal stress on learning performance and emotional behavior were attenuated by foster rearing by unstressed dams. Fos expression in the hypothalamic paraventricular nucleus following physical stress and corticosterone secretion during physical and psychological stress did not differ between the prenatally stressed and unstressed control rats. From these results we suggest that mild prenatal stress facilitates learning performance in the adult offspring. The enhancement of learning performance appears to be accompanied by reduced emotionality, but not by any apparent alterations in hypothalamic-pituitary-adrenal responses. In addition, the observation of differential behaviors in the adopted and non-adopted animals supports the notion that the postnatal environment modifies the behavioral effects of prenatal stress.     

Modulating effects of prenatal stress on hyperthermia induced in adult rat offspring by restraint or LPS-induced stress

The present study was carried out to investigate the effects of prenatal stress on stress-induced hyperthermia in adult rats. Prenatal stress was administered daily for 3 days (embryonic days 15-17) by restraining pregnant rats in a small cage either for 30 or 240 min. After birth, foster mothers raised the pups. Offspring were tested at 9-10-weeks-old. Changes in body temperature and in the plasma concentrations of corticosterone, norepinephrine (NE), and epinephrine (Epi) induced by restraint or lipopolysaccharide (LPS)-induced stress were examined. By comparison with the prenatally nonstressed control group, the 240-min stress group showed a significantly lower hyperthermia in response to restraint stress but a higher fever after injection of LPS. The 30-min stress group showed similar alterations in these hyperthermic responses but did not reach significance. Both the restraint stress and the injection of LPS evoked greater increases in the plasma level of corticosterone in the 240-min stress group than in the control group. Although restraint stress induced significant increases in NE and Epi in the control and 30-min stress groups, the plasma levels of these catecholamines did not increase in the 240-min stress group. These results demonstrate for the first time that prenatal stress has opposite effects on the hyperthermic responses to restraint and LPS injection, suggesting that different mechanisms underlie the modulating effects of prenatal stress on the responses to the two types of stressors.     

Maternal food restriction: Effects on offspring behavior and development

Pregnant rats were placed on reduced food intake or remained on adequate diet during gestation and lactation. Offspring were cross-fostered to provide for independent experiences of prenatal and/or postnatal mother malnutrition. All offspring were placed on an ad lib diet at time of weaning. When evaluated in adulthood, offspring whose mother was food-deprived during the lactation period showed body weight deficits and increased errors on the Hebb-Williams maze as compared to controls. There were no observed effects of the prenatal deprivation.     

Failure of severe maternal stress or ACTH during pregnancy to affect emotionality of male rat offspring: implications of litter effects for prenatal studies.

Daily maternal neck restraint, whole body restraint, hyperthermia, and ACTH treatment during the last 3rd of gestation had no reliable effect on open-field and cage-emergence behavior in male Sprague-Dawley offspring. Many of these treatments, however, produced considerable maternal pathology and evidence for maternal adrenocorticoid release. Significant litter effects were found for almost every morphological and behavioral measure. Failure to control for the litter variable may account for many previously reported effects of prenatal stress on emotionality in rats. Female rats showed greater activity and less defecation than males on postpubertal open-field and cage emergence tests.     

Impact of maternal prenatal and parental postnatal stress on 1-year-old child development: results from the OTIS antidepressants in pregnancy study

Perinatal psychological stress has been associated with unfavorable maternal and neonatal outcomes. We aimed to assess the impact of perinatal stress on infant development at 1 year of age. We recruited pregnant women calling North American Teratogen Information Services or attending outpatient clinics at CHU Sainte Justine (Montreal) between 2008 and 2010 and their spouses. To be part of our study, women had to be (1) >18 years of age, (2) <15 weeks of gestational age at recruitment, (3) living within 250-km radius of Montreal, and (4) taking antidepressants or non-teratogenic drugs. Stress was assessed using the telephone-administered four-item perceived stress scale during pregnancy in mothers and at 2 months postpartum in both parents. Child development at 1 year of age was evaluated with the Bayley III scales. Socio-demographic and potential confounders were collected through telephone interviews. Multivariable linear regression models were built to assess the association between perinatal parental stress and child development. Overall, 71 couples and their infants were included. When adjusted for potential confounders, maternal prenatal stress was positively associated with motor development (adjusted β?=?1.85, CI 95 % (0.01, 3.70)). Postpartum maternal and paternal stresses were negatively associated with motor and socio-emotional development, respectively (adjusted β?=??1.54, CI 95 % (?3.07, ?0.01) and adjusted β?=??1.67, CI 95 % (?3.25, ?0.10), respectively). Maternal and paternal postnatal stress seems to be harmful for the motor and socio-emotional development in 1-year-old children. No association was demonstrated between parental stress and cognitive, language, and adaptive behavioral development. However, prenatal maternal stress appears to improve motor skills.     

Effects of prenatal depressive symptoms on maternal and infant cortisol reactivity

Prenatal depression is associated with adverse offspring outcomes, and the prevailing mechanistic theory to account for mood-associated effects implicates alterations of the maternal and foetal hypothalamic-pituitary adrenal (HPA) axes. Recent research suggests that depression may be associated with a failure to attenuate cortisol reactivity during early pregnancy. The aim of the current study is to investigate whether this effect continues into mid and late gestation. A further aim is to test whether maternal prenatal cortisol reactivity directly predicts infant cortisol reactivity. One hundred three pregnant women were recruited during either the second or third trimester. Depressive symptoms were assessed by self-report, and maternal salivary cortisol responses to a stressor (infant distress film) were measured. Approximately 2 months after birth, mothers (n?=?88) reported postnatal depression and infant salivary cortisol responses to inoculation were measured. Prenatal depression was not associated with cortisol reactivity to acute stress in mid and late pregnancy. Similarly, neither prenatal depression nor maternal prenatal cortisol reactivity predicted infant cortisol reactivity to inoculation at 2 months. If the effects of prenatal depression on foetal and infant development are mediated by alterations of the maternal and foetal HPA axes, then early pregnancy may be a particularly vulnerable period. Alternatively, changes to HPA reactivity may not be as central to this association as previously thought.     

母鼠孕前营养过剩对子代小鼠生长发育影响

目的构建孕前营养过剩及超重小鼠模型,探讨孕前营养过剩对子代小鼠生长发育影响。方法 20只昆明种雌鼠随机分为对照组和实验组,分别给予标准饲料和高脂高糖饲料;两组单纯饲养4周后与雄鼠合笼,孕期继续上述饮食;产后均母乳喂养,产后3w断乳,哺乳期间母鼠仍按各自组别进食;监测单纯饲养期、孕期和哺乳期母鼠体重、血糖变化。两组子鼠断乳后一律以标准饲料喂养,监测子鼠出生至生后5w体重、身长和尾长发育。结果 1.母鼠体重和血糖变化：单纯饲养1周后开始实验组母鼠体重持续显著高于对照组（P〈0.05）;饲养1w和4w时,实验组母鼠血糖显著高于对照组（P〈0.05）。孕中、晚期实验组母鼠体重与对照组无显著差异（P〉0.05）。哺乳期两组母鼠体重、血糖均无显著差异（P〉0.05）。2.母乳喂养期子鼠发育：出生3天和7天,实验组子鼠体重显著高于对照组（P〈0.05）;整个母乳喂养期,实验组子鼠尾长显著长于对照组（P〈0.05）,两组子鼠身长无显著差异（P〉0.05）。3.自由采食期子鼠发育：整个自由采食期,实验组雌性子鼠体重显著高于对照组（P〈0.05）;出生35天,实验组雄性子鼠体重也显著高于对照组（P〈0.05）;整个自由采食期,实验组子鼠尾长均显著长于对照组（P〈0.05）,两组子鼠身长无显著差异（P〉0.05）。结论通过高脂高糖饲料可以建立孕前营养过剩及超重小鼠模型,母鼠孕前营养过剩导致子代小鼠出生体重增加以及成年早期肥胖,其对机体的深入影响及机制值得进一步研究。