Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health.

Background: Ex-preterm children and adolescents are at risk of developing late-onset neurodevelopmental and behavioral disorders. The mechanisms by which this happens are poorly understood and relevant animal models are required. Methods: Ex-preterm (delivered at 62 d gestation) and term (spontaneously delivered) juvenile guinea pigs underwent behavioral testing at 25 d corrected postnatal age, with tissues collected at 28 d. Neurodevelopmental markers (myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP)) were analyzed in the hippocampus and subcortical white matter by immunohistochemistry. Gamma-aminobutyric acid A (GABA A ) receptor subunit mRNA levels were quantified by reverse transcription polymerase chain reaction (RT-PCR), and salivary cortisol measured by enzyme-linked immunosorbent assay. results: Preterm males travelled greater distances, were mobile for longer, spent more time investigating objects, and approached or interacted with familiar animals more than controls. Myelination and reactive astrocyte coverage was lower in the hippocampus and the subcortical white matter in preterm males. Hippocampal levels of the α5 subunit were also lower in the preterm male brain. Baseline salivary cortisol was higher for preterm males compared to controls. conclusion: We conclude that juvenile ex-preterm male guinea pigs exhibit a hyperactive phenotype and feature impaired neurodevelopment, making this a suitable model for future therapeutic studies. c hildren born preterm (birth at <37 wk gestation) have an increased risk of developing a long-term neurodevelopmental disability (1,2). Importantly, this risk exists even in those thought to be "well" at the time of discharge from neonatal care and in those with no evidence of the structural brain injuries known to be associated with adverse neurodevelopmental outcomes (e.g., intraventricular hemorrhage or periventricular leukomalacia) (3,4). Thus, although intraventricular hemorrhage and, or, periventricular leukomalacia explain neurodevelopmental problems in a subset of high-risk infants, they do not account for the overall burden of neurodisability seen in the ex-preterm population.Although major neurodevelopmental problems are usually picked up early, subtle behavioral or psychiatric disorders may not become apparent until school age, at a time distant from the causative insult (5,6). Anxiety disorder and attention deficit hyperactivity disorder are the most commonly diagnosed disorders in school-aged ex-preterm children (7,8). Attention deficit hyperactivity disorder has a male preponderance and is characterized by a deficit in behavioral inhibition, inattention, impulsivity and social difficulties, whereas anxiety disorder is more commonly diagnosed in ex-preterm females (7,8). Thus, the behavioral outcomes of preterm birth occur in a sex-dependent manner. Other neuropathologies, including depression, and impaired cognitive performance are also increased in those born preterm compared to children and adolescents born at term (5,9-11). Hypo-m...

INTRODUCTION: Microvascular dysfunction, characterized by inappropriate vasodilatation and high blood flow in the peripheral microcirculation, is linked to physiologic instability and poor outcome in neonates. specifically, preterm neonates have significantly higher levels of baseline microvascular blood flow than term neonates at 24 h postnatal age. Because of similarities between human and guinea pig endocrine profiles and maturity at birth, we hypothesized that preterm guinea pig neonates would provide a suitable model for studying the mechanisms underlying transitional microvascular function. RESULTS: Guinea pigs that were delivered preterm showed immaturity and had markedly reduced viability. Baseline microvascular blood flow was significantly higher in preterm animals than in term animals. No effect of intrauterine growth restriction or birth weight on baseline microvascular blood flow was observed in either preterm or term animals. DISCUSSION: These results are consistent with recent clinical findings and support the use of the guinea pig as a suitable model for future studies of the mechanisms underlying perinatal microvascular behavior. METHODS: Guinea pigs were delivered either prematurely or at term. Laser Doppler flowmetry was used to study microvascular blood flow at 23 h postnatal age. In term infants, the circulation undergoes rapid and extensive changes in the initial hours of extrauterine life to allow the infant to effectively deal with extrauterine systemic vascular resistance and hence provide normal and adequate perfusion of tissues (1-3). The transitional circulation of preterm neonates (especially those born at ≤30 wk gestation) differs significantly from infants born at full term. In the preterm infant, several crucial physiologic responses to extrauterine life are commonly delayed, allowing for persistence of atrial and ductal shunting and inappropriate blood flow throughout the periphery during the perinatal period (4)(5)(6)(7)(8).Previous studies in preterm infants suggest that abnormal microvascular tone, characterized by inappropriate vasodilatation of the peripheral microvasculature, may contribute to the development of circulatory compromise (4,8). These studies found that the functional integrity of the microvasculature (including appropriate control of vasodilatation) in preterm neonates is significantly altered as compared with neonates born at later gestational ages (GAs). Very preterm neonates (born at 24-28 wk GA) are known to have significantly higher microvascular blood flow at 24 h postnatal age than preterm neonates born at 29-34 wk GA and neonates born at term. High baseline microvascular blood flow in premature infants is significantly correlated with clinical illness severity and poor outcome in the immediate postnatal period (4,9). Such dysfunction in the microvasculature is also a well-established observation associated with the onset of other causes of multisystem organ failure in neonates (10).In addition to disorders relating to short gestation, intrauterine growt...

Dysfunction of the transition from fetal to neonatal circulatory systems may be a major contributor to poor outcome following preterm birth. Evidence exists in the human for both a period of low flow between 5 and 11 h and a later period of increased flow, suggesting a hypoperfusion–reperfusion cycle over the first 24 h following birth. Little is known about the regulation of peripheral blood flow during this time. The aim of this study was to conduct a comparative study between the human and guinea pig to characterize peripheral microvascular behavior during circulatory transition. Very preterm (≤28 weeks GA), preterm (29–36 weeks GA), and term (≥37 weeks GA) human neonates underwent laser Doppler analysis of skin microvascular blood flow at 6 and 24 h from birth. Guinea pig neonates were delivered prematurely (62 day GA) or at term (68–71 day GA) and laser Doppler analysis of skin microvascular blood flow was assessed every 2 h from birth. In human preterm neonates, there is a period of high microvascular flow at 24 h after birth. No period of low flow was observed at 6 h. In preterm animals, microvascular flow increased after birth, reaching a peak at 10 h postnatal age. Blood flow then steadily decreased, returning to delivery levels by 24 h. Preterm birth was associated with higher baseline microvascular flow throughout the study period in both human and guinea pig neonates. The findings do not support a hypoperfusion–reperfusion cycle in the microcirculation during circulatory transition. The guinea pig model of preterm birth will allow further investigation of the mechanisms underlying microvascular function and dysfunction during the initial extrauterine period.

The present findings suggest that components of the cerebellar GABAergic system of the ex-preterm cerebellum are disrupted. The higher expression of myelin in the preterm males may be due to a deficit in axonal pruning, whereas females have a deficit in myelination at 28 corrected days of age. Together these ongoing alterations may contribute to the neurodevelopmental and behavioural disorders observed in those born preterm.

Ganaxolone improved neurobehavioural outcomes in males suggesting that neonatal treatment may be an option for reducing preterm-associated neurodevelopmental impairment. However, dosing studies are required to reduce the burden of unwanted side effects.

Excessive vasodilatation during the perinatal period is associated with cardiorespiratory instability in preterm neonates. Little evidence of the mechanisms controlling microvascular tone during circulatory transition exists. We hypothesised that hydrogen sulphide (H2S), an important regulator of microvascular reactivity and central cardiac function in adults and animal models, may contribute to the vasodilatation observed in preterm newborns. Term and preterm neonates (24–43 weeks gestational age) were studied. Peripheral microvascular blood flow was assessed by laser Doppler. Thiosulphate, a urinary metabolite of H2S, was determined by high performance liquid chromatography as a measure of 24 hr total body H2S turnover for the first 3 days of postnatal life. H2S turnover was greatest in very preterm infants and decreased with increasing gestational age (p = 0.0001). H2S turnover was stable across the first 72 hrs of life in older neonates. In very preterm neonates, H2S turnover increased significantly from day 1 to 3 (p = 0.0001); and males had higher H2S turnover than females (p = 0.04). A significant relationship between microvascular blood flow and H2S turnover was observed on day 2 of postnatal life (p = 0.0004). H2S may play a role in maintaining microvascular tone in the perinatal period. Neonates at the greatest risk of microvascular dysfunction characterised by inappropriate peripheral vasodilatation - very preterm male neonates - are also the neonates with highest levels of total body H2S turnover suggesting that overproduction of this gasotransmitter may contribute to microvascular dysfunction in preterms. Potentially, H2S is a target to selectively control microvascular tone in the circulation of newborns.

Preterm birth is common and the associated short-term morbidity well described. The adult-onset consequences of preterm birth are less clear, but cardiovascular and metabolic health may be adversely affected. Although large animal models of preterm birth addressing important short-term issues exist, long-term studies are hampered by significant logistical constraints. Current small animal models of prematurity require terminal caesarean section of the mother; both caesarean birth and early maternal care modify offspring adult cardio-metabolic function. We describe a novel method for inducing preterm labour in guinea pigs. With support comparable to that received by moderately preterm human infants, preterm pups are viable. Growth trajectories between preterm and term-born pups differ significantly; between term equivalent age and weaning ex-preterm animals demonstrate increased weight and ponderal index. We believe this novel paradigm will significantly improve our ability to investigate the cardio-metabolic sequelae of preterm birth throughout the life course and into the second generation.