Fetal Undernutrition Modifies Vascular RAS Balance Enhancing Oxidative Damage and Contributing to Remodeling.

Fetal stress is known to increase susceptibility to cardiometabolic diseases and hypertension in adult age in a process known as fetal programming. This study investigated the relationship between vascular RAS, oxidative damage and remodeling in fetal programming. Six-month old Sprague-Dawley offspring from mothers that were fed ad libitum (CONTROL) or with 50% intake during the second half of gestation (maternal undernutrition, MUN) were used. qPCR or immunohistochemistry were used to obtain the expression of receptors and enzymes. Plasma levels of carbonyls were measured by spectrophotometry. In mesenteric arteries from MUN rats we detected an upregulation of ACE, ACE2, AT1 receptors and NADPH oxidase, and lower expression of AT2, Mas and MrgD receptors compared to CONTROL. Systolic and diastolic blood pressure and plasma levels of carbonyls were higher in MUN than in CONTROL. Vascular morphology evidenced an increased media/lumen ratio and adventitia/lumen ratio, and more connective tissue in MUN compared to CONTROL. In conclusion, fetal undernutrition indices RAS alterations and oxidative damage which may contribute to the remodeling of mesenteric arteries, and increase the risk of adverse cardiovascular events and hypertension.

Kidney and epigenetic mechanisms of salt-sensitive hypertension.

Dietary salt intake increases blood pressure (BP) but the salt sensitivity of BP differs between individuals. The interplay of ageing, genetics and environmental factors, including malnutrition and stress, contributes to BP salt sensitivity. In adults, obesity is often associated with salt-sensitive hypertension. The children of women who experience malnutrition during pregnancy are at increased risk of developing obesity, diabetes and salt-sensitive hypertension as adults. Similarly, the offspring of mice that are fed a low-protein diet during pregnancy develop salt-sensitive hypertension in association with aberrant DNA methylation of the gene encoding type 1A angiotensin II receptor (AT1AR) in the hypothalamus, leading to upregulation of hypothalamic AT1AR and renal sympathetic overactivity. Ageing is also associated with salt-sensitive hypertension. In aged mice, promoter methylation leads to reduced kidney production of the anti-ageing factor Klotho and a decrease in circulating soluble Klotho. In the setting of Klotho deficiency, salt-induced activation of the vascular Wnt5a-RhoA pathway leads to ageing-associated salt-sensitive hypertension, potentially as a result of reduced renal blood flow and increased peripheral resistance. Thus, kidney mechanisms and aberrant DNA methylation of certain genes are involved in the development of salt-sensitive hypertension during fetal development and old age. Three distinct paradigms of epigenetic memory operate on different timescales in prenatal malnutrition, obesity and ageing.

Fetal Head Growth during Early to Mid-Gestation Associated with Weight Gain in Mothers with Hyperemesis Gravidarum: A Retrospective Cohort Study.

The epigenetic impact of malnutrition in mothers with hyperemesis gravidarum (HG) on their offspring has not been fully elucidated. Recently, several reports have demonstrated that children born to mothers with HG were small for gestational age and had low birth weight, reduced insulin sensitivity, and neurodevelopmental delays during childhood. Therefore, we examined the relationship between fetal growth and changes in the maternal body weight in HG cases. A total of 34 patients with HG were hospitalized and delivered at term between 2009 and 2012. The records of 69 cases of pregnant women without a history of HG were extracted after matching their maternal age, parity, pregestational body mass index (BMI), gestational age, and fetal sex ratio with those of the HG group for comparison. The maternal weight gain at term was less in the HG than in the control group. There was no statistical difference in birth weight, placental weight, and ultrasonic fetometric parameters expressed in standard deviation (SD) scores, including biparietal diameter, abdominal circumference, and femur length, between the HG and the control group. Whereas fetal head growth in the HG group was positively associated with maternal weight gain at 20 weeks of gestation only, this association was not observed in the control group. We herein demonstrate that maternal weight gain from the nadir is associated with fetal head growth at mid-gestation. Thus, maternal undernutrition in the first trimester of pregnancy could affect fetal brain growth and development, leading to an increased risk of neurodevelopmental delays in later life.

Female ponderal index at birth and idiopathic infertility.

Epidemiological studies have demonstrated an increased risk of developing non-transmittable diseases in adults subjected to adverse early developmental conditions. Metabolic and cardiovascular diseases have been the focus of most studies. Nevertheless, data from animal models also suggest early programming of fertility. In humans, it is difficult to assess the impact of the in utero environment retrospectively. Birthweight is commonly used as an indirect indicator of intrauterine development. This research is part of the ALIFERT study. We investigated a potential link between ponderal index at birth and female fertility in adulthood. Data from 51 infertile and 74 fertile women were analysed. BW was on average higher in infertile women, whereas birth length did not differ between the two groups; thus, resulting in a significantly higher ponderal index at birth in infertile women. Ponderal index at birth has been identified as a risk factor for infertility. These results suggest the importance of the intra-uterine environment, not only for long-term metabolic health but also for fertility.

Bariatric surgery and birth defects: A systematic literature review.

BACKGROUND: Bariatric procedures are on the rise. The risk of birth defects in pregnancies following such procedures may be increased (eg, due to nutrient deficiencies) or decreased (eg, due to decreased maternal body mass index, BMI). METHODS: We conducted a systematic literature review of the association between bariatric surgery and birth defects using Ovid MEDLINE and PubMed (1946-2017). Information was abstracted on study design, exposures, outcomes, covariates and estimates of association. RESULTS: Fifteen studies met our inclusion criteria: 14 evaluated the outcome of any birth defect, and one evaluated neural tube defects. Estimates of association between bariatric surgery and birth defects were available for nine studies and ranged from 0.6 to 1.9 (all 95% confidence intervals included 1.0). When studies were stratified by surgery type, there was no obvious pattern of association. When stratified by the approach used to account for BMI, positive associations were observed in studies that did not account for maternal prepregnancy BMI or used women with normal BMI as the reference group (range: 1.3-1.9). Estimates from studies that either matched or adjusted for prepregnancy BMI were closer to the null (range: 1.1-1.2) and studies that compared to morbidly obese women reported protective associations (range: 0.6-0.7). CONCLUSIONS: Studies of the association between bariatric surgery and birth defects vary with respect to the surgical procedures included, birth defects ascertainment methods and approaches used to account for maternal BMI. Consequently, it is not possible to draw a conclusion regarding the association between bariatric surgery and birth defects. Additional studies are warranted.

Critical Windows for the Programming Effects of Early-Life Nutrition on Skeletal Muscle Mass.

Skeletal myogenesis begins in the embryo with proliferation and differentiation of muscle progenitor cells that ultimately fuse to form multinucleated myofibers. After midgestation, muscle growth occurs through hypertrophy of these myofibers. The most rapid growth phase occurs in the perinatal period, resulting in the expansion of muscle mass from 25% of lean mass at birth to 40-45% at maturity. These 2 phases of muscle growth are regulated by distinct molecular mechanisms engaged by extracellular cues and intracellular signaling pathways and regulatory networks they activate. Nutrients influence muscle growth by both providing the necessary substrates and eliciting extracellular cues which regulate the signal transduction pathways that control the anabolic processes of the fibers. The uniquely large capacity of immature myofibers for hypertrophy is enabled by a heightened capacity and sensitivity of protein synthesis to feeding-induced changes in plasma insulin and amino acids, and the ability to expand their myonuclear population through proliferation of muscle precursor cells (satellite cells). With maturation, satellite cells become quiescent, limiting myonuclear accretion, and the capacity of the muscles for protein anabolism progressively diminishes. Therefore, the early developmental phases represent critical windows for muscle growth which, if disrupted, result in muscle mass deficits that are unlikely to be entirely recoverable.

Fetal growth-retardation and brain-sparing by malnutrition are associated to changes in neurotransmitters profile.

The present study assesses possible changes in the levels of different neurotransmitters (catecholamines and indoleamines) in fetuses affected by nutrient shortage. Hence, we determined the concentration of catecholamines and indoleamines at the hypothalamus of 56 swine fetuses obtained at both 70 and 90days of pregnancy (n=33 and 23 fetuses, respectively). The degree of fetal development and the fetal sex affected the neurotransmitters profile at both stages. At Day 70, there were found higher mean concentrations of l-DOPA in both female and male fetuses with severe IUGR; male fetuses with severe IUGR also showed higher concentrations of TRP than normal male littermates. At Day 90 of pregnancy, the differences between sexes were more evident. There were no significant effects from either severe IUGR on the neurotransmitter profile in male fetuses. However, in the females, a lower body-weight was related to lower concentrations of l-DOPA and TRP and those female fetuses affected by severe IUGR evidenced lower HVA concentration. In conclusion, the fetal synthesis and use of neurotransmitters increase with time of pregnancy but, in case of IUGR, both catecholamines and indoleamines pathways are affected by sex-related effects.

Undernutrition in the parental and first generation provokes an organ-specific response to oxidative stress on neonates of second filial generation of Wistar rats.

Undernutrition induces an increase of the oxidative stress that can predispose offspring to various diseases in adulthood through epigenetic reprogramming. The aim of this study was to evaluate the effects of intergenerational undernutrition on protein oxidation and antioxidant defence response on liver, heart and brain of the second-generation neonates (F2 ) of undernourished rats. For this purpose, both parents in parental (F0 ) and first generation (F1 ) were fed with a low-nutrient diet. Body mass and length decreased (p < 0.05) in F0 , F1 and F2 being the F1 males who exhibited a greater mass loss. A decrease in plasma albumin concentration was observed in F2 neonates (p < 0.05) and also a mass loss of liver, heart and brain (p < 0.05), although proportionally to body length reduction. Undernutrition increased levels of protein oxidation in liver and heart (p < 0.05) but not in brain (p > 0.05) while catalase activity increased only in brain (p < 0.05). In summary, intergenerational undernutrition modifies the antioxidant status through an organ-specific response, on F2 neonate rats, where the brain increased catalase activity to prevent a severe oxidative damage and support the vital functions of this key organ to maintain vital functions.

The Long-term Health Effects of Fetal Malnutrition: Evidence from the 1959-1961 China Great Leap Forward Famine.

We report evidence of long-term adverse health impacts of fetal malnutrition exposure of middle-aged survivors of the 1959-1961 China Famine using data from the China Health and Retirement Longitudinal Study. We find that fetal exposure to malnutrition has large and long-lasting impacts on both physical health and cognitive abilities, including the risks of suffering a stroke, physical disabilities in speech, walking and vision, and measures of mental acuity even half a century after the tragic event. Our findings imply that policies and programs that improve the nutritional status of pregnant women yield benefits on the health of a fetus that extend through the life cycle in the form of reduced physical and mental impairment.

Fetal life malnutrition was not reflected in the relative abundances of adiponectin and leptin mRNAs in adipose tissue in male mink kits at 9.5 weeks of age.

BACKGROUND: Malnutrition in fetal life and during suckling have in some animal studies resulted in adaptive changes related to the fat and glucose metabolism, which in the long term might predispose the offspring for metabolic disorders such as obesity later in life. The objective was to study the effect of fetal life malnutrition in male mink on the gene expression of leptin and adiponectin in different adipose tissue sites. RESULTS: Thirty-two male mink, strict carnivore species, exposed to low (FL) or adequate (FA) protein provision the last 16.3 ± 1.8 days of fetal life and randomly assigned to a low (LP) or adequate (AP) protein diet from 7 to 9.5 weeks of age were used. Adipose tissues (subcutaneous, perirenal and mesenteric) were analyzed using qPCR. Fetal life or post-weaning protein provision did not affect the relative abundances of leptin and adiponectin mRNAs in adipose tissue at 9.5 weeks of age. Relative abundances of leptin and adiponectin mRNAs were different between adipose tissue sites and were significantly higher in subcutaneous than in perirenal and mesenteric tissues. CONCLUSION: Fetal life protein malnutrition in male mink, did not result in adaptive changes in the gene expression of leptin and adiponectin mRNAs in adipose tissue at 9.5 weeks of age as found in rodents. However, both leptin and adiponectin mRNAs were significantly differently expressed between tissue sites.

Effects of perinatal protein malnutrition and fenfluramine action on food intake and neuronal activation in the hypothalamus and raphe nuclei of neonate rats.

In neonatal rats, hunger and satiety responses occur particularly via dehydration and gastric distention, respectively. The control of food intake in newborns is yet to be fully consolidated, particularly with respect to the participation of the hypothalamic nuclei and their relationship with the serotonergic pathway. Moreover, it is unclear how the environmental stressors in early life, like undernutrition, interfere in these events. Therefore, this study examined the serotonin-system's impact on food intake in rat neonates at postnatal day (P) 10 and P18 and the manner in which protein undernutrition during pregnancy and lactation interferes in this behavior. To accomplish this, Wistar rats were used, nutritionally manipulated by a diet having two protein levels, (8% and 17%) during pregnancy and lactation, to form the Control (n=10) and Low protein groups (n=10). At 10 and 18 postnatal days pups received an acute dose of fenfluramine (3mg/kg) or saline (0.9% NaCl) and subjected to milk consumption testing and then perfused to obtain the brains for the analysis of cell activation of the immunoreactive c-Fos in the hypothalamic and raphe nuclei. At 10days a reduction in weight gain was observed in both groups. On comparison of the neuronal activation for the paraventricular nucleus, an increased activation in response to fenfluramine was observed. At 18days, the weight gain percentage differed between the groups according to the nutritional manipulation, in which the control animals had no significant change while the undernourished presented increased weight gain with the use of fenfluramine. The marking of c-Fos in response to fenfluramine in the hypothalamic and raphe nuclei revealed, an especially lower activation of the PVN, MnR and DR compared intra-group. However when evaluating the effect of undernutrition, marking activation was observed to increase in all the nuclei analyzed, in the hypothalamus and raphe. Data from this study indicate that the action of serotonin via food intake in the neonates may have been delayed by early protein undernutrition.

Long-Term Impacts of Foetal Malnutrition Followed by Early Postnatal Obesity on Fat Distribution Pattern and Metabolic Adaptability in Adult Sheep.

We aimed to investigate whether over- versus undernutrition in late foetal life combined with obesity development in early postnatal life have differential implications for fat distribution and metabolic adaptability in adulthood. Twin-pregnant ewes were fed NORM (100% of daily energy and protein requirements), LOW (50% of NORM) or HIGH (150%/110% of energy/protein requirements) diets during the last trimester. Postnatally, twin-lambs received obesogenic (HCHF) or moderate (CONV) diets until 6 months of age, and a moderate (obesity correcting) diet thereafter. At 2½ years of age (adulthood), plasma metabolite profiles during fasting, glucose, insulin and propionate (in fed and fasted states) tolerance tests were examined. Organ weights were determined at autopsy. Early obesity development was associated with lack of expansion of perirenal, but not other adipose tissues from adolescence to adulthood, resulting in 10% unit increased proportion of mesenteric of intra-abdominal fat. Prenatal undernutrition had a similar but much less pronounced effect. Across tolerance tests, LOW-HCHF sheep had highest plasma levels of cholesterol, urea-nitrogen, creatinine, and lactate. Sex specific differences were observed, particularly with respect to fat deposition, but direction of responses to early nutrition impacts were similar. However, prenatal undernutrition induced greater metabolic alterations in adult females than males. Foetal undernutrition, but not overnutrition, predisposed for adult hypercholesterolaemia, hyperureaemia, hypercreatinaemia and hyperlactataemia, which became manifested only in combination with early obesity development. Perirenal expandability may play a special role in this context. Differential nutrition recommendations may be advisable for individuals with low versus high birth weights.

Activation of placental insulin and mTOR signaling in a mouse model of maternal obesity associated with fetal overgrowth.

Fetal overgrowth is common in obese women and is associated with perinatal complications and increased risk for the child to develop metabolic syndrome later in life. Placental nutrient transport capacity has been reported to be increased in obese women giving birth to large infants; however, the underlying mechanisms are not well established. Obesity in pregnancy is characterized by elevated maternal serum insulin and leptin, hormones that stimulate placental amino acid transporters in vitro. We hypothesized that maternal obesity activates placental insulin/IGF-I/mTOR and leptin signaling pathways. We tested this hypothesis in a mouse model of obesity in pregnancy that is associated with fetal overgrowth. C57BL/6J female mice were fed a control (C) or a high-fat/high-sugar (HF/HS) pelleted diet supplemented by ad libitum access to sucrose (20%) solution. Placentas were collected at embryonic day 18.5. Using Western blot analysis, placental mTOR activity was determined along with energy, inflammatory, leptin, and insulin signaling pathways (upstream modulators of mTOR). Phosphorylation of S6 ribosomal protein (S-235/236), 4E-BP1 (T-37/46), Insulin receptor substrate 1 (Y-608), Akt (T-308), and STAT-3 (Y-705) was increased in obese dams. In contrast, expression of placental caspase-1, IкBα, IL-1ß, and phosphorylated-JNK(p46/54-T183/Y185) was unaltered. Fetal amino acid availability is a key determinant of fetal growth. We propose that activation of placental insulin/IGF-I/mTOR and leptin signaling pathways in obese mice stimulates placental amino acid transport and contributes to increased fetal growth.

Respiratory modulation of sympathetic nerve activity is enhanced in male rat offspring following uteroplacental insufficiency.

Sympathetic nerve activity to the cardiovascular system displays prominent respiratory-related modulation which leads to the generation of rhythmic oscillations in blood pressure called Traube-Hering waves. An amplification of this respiratory modulation of sympathetic activity is observed in hypertension of both genetic, the spontaneously hypertensive rat, and induced, chronic intermittent hypoxia or maternal protein restriction during gestation, origin. Male offspring of mothers with uteroplacental insufficiency, induced by bilateral uterine vessel ligation at 18 days of gestation, are also hypertensive in adulthood. In this study we examined whether these male offspring display altered respiratory modulation of sympathetic activity at pre-hypertensive ages compared to controls. Respiratory, cardiovascular and sympathetic parameters were examined using the working heart-brainstem preparation in 35 day old male rats that had reduced birth weight due to uteroplacental insufficiency. Whilst all respiratory parameters were not different between groups, we observed an enhanced respiratory-related burst of thoracic sympathetic nerve activity and amplified Traube-Hering waves in the growth-restricted group. This group also showed an increased sympathetic and bradycardic response to activation of peripheral chemoreceptors. The observations add support to the view that altered respiratory modulation of sympathetic activity represents a common mechanism involved in the development of several forms of hypertension.

Optimal fetal growth: a misconception?

Alterations in fetal growth trajectory, either in terms of individual organs or the fetal body, constitute part of a suite of adaptive responses that the fetus can make to a developmental challenge such as inadequate nutrition. Nonetheless, despite substantial changes in nutrition in many countries over recent centuries, mean birthweight has changed relatively little. Low birthweight is recognized as a risk factor for later noncommunicable disease, although the developmental origins of such risk are graded across the full range of fetal growth and birthweight. Many parental and environmental factors, some biological and some cultural, can influence fetal growth, and these should not be viewed as abnormal. We argue that the suggestion of establishing a universal standard for optimal fetal growth ignores the breadth of these normal fetal responses. It may influence practice adversely, through incorrect estimation of gestational age and unnecessary elective deliveries. It raises ethical as well as practical issues.

Effect of fetal undernutrition and postnatal overfeeding on rat adipose tissue and organ growth at early stages of postnatal development.

Intrauterine and perinatal life are critical periods for programming of cardiometabolic diseases. However, their relative role remains controversial. We aimed to assess, at weaning, sex-dependent alterations induced by fetal or postnatal nutritional interventions on key organs for metabolic and cardiovascular control. Fetal undernutrition was induced by dam food restriction (50 % from mid-gestation to delivery) returning to ad libitum throughout lactation (Maternal Undernutrition, MUN, 12 pups/litter). Postnatal overfeeding (POF) was induced by litter size reduction from normally fed dams (4 pups/litter). Compared to control, female and male MUN offspring exhibited: 1) low birth weight and accelerated growth, reaching similar weight and tibial length by weaning, 2) increased glycemia, liver and white fat weights; 3) increased ventricular weight and tendency to reduced kidney weight (males only). Female and male POF offspring showed: 1) accelerated growth; 2) increased glycemia, liver and white fat weights; 3) unchanged heart and kidney weights. In conclusion, postnatal accelerated growth, with or without fetal undernutrition, induces early alterations relevant for metabolic disease programming, while fetal undernutrition is required for heart abnormalities. The progression of cardiac alterations and their role on hypertension development needs to be evaluated. The similarities between sexes in pre-pubertal rats suggest a role of sex-hormones in female protection against programming.

Early postnatal alteration of body composition in preterm and small-for-gestational-age infants: implications of catch-up fat.

The concept of the developmental origins of health and disease is based on studies by Barker et al. They proposed a hypothesis that undernutrition in utero permanently changes the body's structure, function, and metabolism in ways that lead to atherosclerosis and insulin resistance in later life. In addition, profound effects on the extent of body fatness and insulin sensitivity are demonstrated, if there is a "mismatch" between prenatal and postnatal environments. In previous studies, undernutrition in utero has been evaluated simply by birth weight itself or birth weight for gestational age, and the degree of mismatch has been estimated by postnatal rapid weight gain. Recently, we investigated subcutaneous fat accumulation in small-for-gestational-age infants and found that a rapid catch-up in skinfold thickness developed prior to the body weight catch-up. Furthermore, insulin-like growth factor-I and lipoprotein lipase mass concentrations also demonstrate rapid increase during the neonatal period with fat accumulation. Investigating the precise mechanisms of developmental origins of health and disease including mediating metabolic and hormonal factors may provide a new approach to prevent atherosclerosis and insulin resistance. Better management of undernutrition during gestation and neonatal growth during the early postnatal period is an important theme for future health.

Developmental origins of pregnancy loss in the adult female common marmoset monkey (Callithrix jacchus).

BACKGROUND: The impact of the intrauterine environment on the developmental programming of adult female reproductive success is still poorly understood and potentially underestimated. Litter size variation in a nonhuman primate, the common marmoset monkey (Callithrix jacchus), allows us to model the effects of varying intrauterine environments (e.g. nutrient restriction, exposure to male womb-mates) on the risk of losing fetuses in adulthood. Our previous work has characterized the fetuses of triplet pregnancies as experiencing intrauterine nutritional restriction. METHODOLOGY/PRINCIPAL FINDINGS: We used over a decade of demographic data from the Southwest National Primate Research Center common marmoset colony. We evaluated differences between twin and triplet females in the number of pregnancies they produce and the proportion of those pregnancies that ended in fetal loss. We found that triplet females produced the same number of total offspring as twin females, but lost offspring during pregnancy at a significantly higher rate than did twins (38% vs. 13%, p = 0.02). Regardless of their own birth weight or the sex ratio of the litter the experienced as fetuses, triplet females lost more fetuses than did twins. Females with a male littermate experienced a significant increase in the proportion of stillbirths. CONCLUSIONS/SIGNIFICANCE: These striking findings anchor pregnancy loss in the mother's own fetal environment and development, underscoring a "Womb to Womb" view of the lifecourse and the intergenerational consequences of development. This has important translational implications for understanding the large proportion of human stillbirths that are unexplained. Our findings provide strong evidence that a full understanding of mammalian life history and reproductive biology requires a developmental foundation.

Placental programming of chronic diseases, cancer and lifespan: a review.

Particular paths of fetal growth are now known to predict a range of disorders in adult life. This is thought to reflect fetal programming, the phenomenon whereby nutrition and other influences during development set the body's organs and systems for life. The thesis of this review is that normal variations in the processes of placental development lead to variations in the supply of nutrients to the fetus and programme a small number of key systems that are linked to later disease. A baby's growth and nutrition depend both on the function of the placenta, reflected in its gross morphology at birth, and on the mother's lifetime nutrition, reflected in her height and weight. In many studies, the effects of placental size and shape on later disease have been examined within different categories of mother's body size. The review shows that variations in gross placental morphology at birth predict a wide range of disorders in later life. Any particular placental phenotype seems to predict a limited number of diseases. Further research into the links between the processes of placentation and the morphology of the placenta at birth is now required. We need to know more about the relative importance of nutrient flow, nutrient balance and the timing of nutritional events in determining disorders in later life. We also need to understand why, compared to other placental mammals, the human placenta is so variable in its morphology and functional capacity.

Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex.

Iron deficiency (ID) during early life causes long-lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early-life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus-specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT-1). Our second model used a classic rat dietary-based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT-1 knockout model displayed reduced long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia.