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.

A successful pregnancy requires multiple adaptations in the mother's brain that serve to optimise foetal growth and development, protect the foetus from adverse prenatal programming and prevent premature delivery of the young. Pregnancy hormones induce, organise and maintain many of these adaptations. Steroid hormones play a critical role and of particular importance is the progesterone metabolite and neurosteroid, allopregnanolone. Allopregnanolone is produced in increasing amounts during pregnancy both in the periphery and in the maternal and foetal brain. This review critically examines a role for allopregnanolone in both the maternal and foetal brain during pregnancy and development in protecting pregnancy and birth outcomes, with particular emphasis on its role in relation to stress exposure at this time. Late pregnancy is associated with suppressed stress responses. Thus, we begin by considering what is known about the central mechanisms in the maternal brain, induced by allopregnanolone, that protect the foetus(es) from exposure to harmful levels of maternal glucocorticoids as a result of stress during pregnancy. Next we discuss the central mechanisms that prevent premature secretion of oxytocin and consider a role for allopregnanolone in minimising the risk of preterm birth. Allopregnanolone also plays a key role in the foetal brain, where it promotes development and is neuroprotective. Hence we review the evidence about disruption to neurosteroid production in pregnancy, through prenatal stress or other insults, and the immediate and long-term adverse consequences for the offspring. Finally we address whether progesterone or allopregnanolone treatment can rescue some of these deficits in the offspring.

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Background: Preterm birth is a major cause of neurodevelopmental disorders. Allopregnanolone, a key metabolite of progesterone, has neuroprotective and developmental effects in the brain. The objectives of this study were to measure the neuroactive steroid concentrations following preterm delivery in a neonatal guinea pig model and assess the potential for postnatal progesterone replacement therapy to affect neuroactive steroid brain and plasma concentrations in preterm neonates. Methods: Preterm (62-63 days) and term (69 days) guinea pig pups were delivered by cesarean section and tissue was collected at 24 hours. Plasma progesterone, cortisol, allopregnanolone, and brain allopregnanolone concentrations were measured by immunoassay. Brain 5a-reductase (5aR) expression was determined by Western blot. Neurodevelopmental maturity of preterm neonates was assessed by immunohistochemistry staining for myelination, glial cells, and neurons. Results: Brain allopregnanolone concentrations were significantly reduced after birth in both preterm and term neonates. Postnatal progesterone treatment in preterm neonates increased brain and plasma allopregnanolone concentrations. Preterm neonates had reduced myelination, low birth weight, and high mortality compared to term neonates. Brain 5aR expression was also significantly reduced in neonates compared to fetal expression. Conclusions: Delivery results in a loss of neuroactive steroid concentrations resulting in a premature reduction in brain allopregnanolone in preterm neonates. Postnatal progesterone therapy reestablished neuroactive steroid levels in preterm brains, a finding that has implications for postnatal growth following preterm birth that occurs at a time of neurodevelopmental immaturity.

Pregnane steroids have sedative and neuroprotective effects on the brain, due to interactions with the steroid-binding site of the GABA A receptor. In the adult brain, synthesis of the pregnane steroids is increased in response to stress. Therefore, we have used umbilicoplacental embolization to mimic chronic placental insufficiency during late gestation in sheep, to investigate the expression of the steroidogenic enzymes P450scc, 5␣-reductase type I (5␣RI), 5␣-reductase type II (5␣RII), and allopregnanolone (AP) content in the fetal brain. Umbilicoplacental embolization was induced from 114 d gestation (term~147 d) by daily injection of inert microspheres into the umbilical artery and continued for 17-23 d. Fetal arterial oxygen saturation was reduced to~60% of the preembolization value in each fetus, with a significant reduction in blood arterial PO 2 , pH, and plasma glucose concentrations (p Ͻ 0.05) and a significant increase in blood arterial PCO 2 and plasma lactate concentrations (p Ͻ 0.05). At postmortem at 131-137 d gestation, embolized fetuses were growth-restricted (2.10 Ϯ 0.14 kg, n ϭ 5) compared with agematched controls (4.43 Ϯ 0.56 kg, n ϭ 7, p Ͻ 0.05). Umbilicoplacental embolized fetuses showed increased P450scc expression in the primary motor cortex; 5␣RI expression was not changed in any of the regions examined, whereas 5␣RII expression was markedly increased in all brain regions. Brain AP content did not significantly change, whereas plasma concentrations were increased. These findings suggest that the increased expression of P450scc and 5␣RII may be a response that maintains AP concentration in the fetal brain after compromised placental function and/or intrauterine stress. Chronic hypoxemia and placental insufficiency are associated with fetal growth retardation (1). Generally, the brains of these growth-retarded fetuses are either not smaller, or are reduced to a lesser degree compared with the overall size of the fetus, suggesting that the brain is able to adapt to the intrauterine conditions that compromise fetal growth. On the other hand, growth-retarded and premature infants are at a greater risk of perinatal brain damage (2), indicating that some of these adaptive changes leave the brain more vulnerable to cytotoxic damage arising from a range of insults, such as acute hypoxia, asphyxia, or infection-induced inflammation.Pregnane steroids, including AP, modify the excitability of the CNS by interaction with the GABA A receptor at the steroid binding site. In the adult, AP has been shown to have potent anxiolytic (3, 4), anticonvulsant (5, 6), sedative/hypnotic, and anesthetic effects (7) on behavior. A constitutive role for neuroactive steroids in the developing brain was proposed after the observation that progesterone metabolites such as AP appear to maintain the low level of arousal-like behavior that typifies fetal life (8,9). In the rat, stressful stimuli of handling or swim stress have been shown to increase plasma AP content (10, 11), suggesting that modulation of the GABA A rece...

Pregnane steroids have sedative and neuroprotective effects on the brain as a result of interactions with the steroid-binding site of the GABA A receptor. To determine whether the fetal brain is able to synthesize pregnane steroids de novo from cholesterol, we measured the expression of cytochrome P450 side-chain cleavage (P450scc) and 5␣-reductase type II (5␣RII) enzymes in fetal sheep from 72 to 144 d gestation (term~147 d) and in newborn lambs at 3 and 19-26 d of age. Both P450scc and 5␣RII expression was detectable by 90 d gestation in the major regions of the brain and also in the adrenal glands. Expression increased with advancing gestation and was either maintained at fetal levels or increased further after birth. In contrast, the relatively high content (200-400 pmol/g) of allopregnanolone (5␣-pregnan-3␣-ol-20-one), a major sedative 5␣-pregnane steroid, present throughout the brain from 90 d gestation to term, was reduced significantly (Ͻ50 pmol/g) immediately after birth. These results suggest that although the perinatal brain has the enzymes potentially to synthesize pregnane steroids de novo from cholesterol, either the placenta is a major source of these steroids to the brain or other factors associated with intrauterine life may be responsible for high levels of allopregnanolone production in the fetal brain until birth. Abbreviations AP, allopregnanolone, 5␣-pregnan-3␣-ol-20-one P450scc, P450 side chain cleavage enzyme 5␣RII, 5␣-reductase type II enzyme PMC, primary motor cortex GABA A ,␥-aminobutyric acid/benzodiazepine receptor 5␣-DHP, 5␣-dihydroprogesterone Neuroactive steroids such as allopregnanolone (AP) are potent neuromodulators that modify the excitability of the CNS by interaction with the ␥-aminobutyric acid/benzodiazepine receptor-chloride ionophore (GABA A receptor). In the adult AP is a positive allosteric modulator of the GABA A receptor with potent anxiolytic (1, 2), anticonvulsant (3, 4), sedative/ hypnotic, and anesthetic effects (5) on behavior. Prenatally, neuroactive steroids have been shown to suppress fetal activity in late gestation and seem to have a role in maintaining the low level of arousal-like behavior that typifies fetal life (6, 7). This interaction between AP and the GABA A receptor complex is responsible for the major pharmacologic actions of AP and is distinct from the genomic effects exerted by other steroids such as progesterone (8). In the brain, neuroactive steroids such as AP are synthesized de novo from cholesterol, but a proportion of the pool of steroids may be derived from precursors in blood that enter the brain across the blood-brain barrier (9 -11). Thus, peripheral steroidogenesis may influence neuroactive steroid content in the brain.The cytochrome P450 side-chain cleavage enzyme (P450scc) catalyzes the irreversible conversion of cholesterol to pregnenolone on the inner side of the mitochondrial membrane (12). The primary site of pregnenolone synthesis in the brain seems to be in oligodendrocytes and astrocytes, with significantly less synthesis occ...

Progesterone and its neuroactive metabolite, allopregnanolone, are present in high concentrations during pregnancy, but drop significantly following birth. Allopregnanolone influences foetal arousal and enhances cognitive and behavioural recovery following traumatic brain injury. Inhibition of allopregnanolone synthesis increases cell death in foetal animal brains with experimental hypoxia. We hypothesised that complications during pregnancy, such as early or preterm loss of placental steroids and intrauterine growth restriction (IUGR), would disrupt the foetal neurosteroid system, contributing to poor neurodevelopmental outcomes. This study aimed to investigate the effects of chronic inhibition of allopregnanolone synthesis before term and IUGR on developmental processes in the foetal brain. Guinea pig foetuses were experimentally growth restricted at midgestation and treated with finasteride, an inhibitor of allopregnanolone synthesis. Finasteride treatment reduced foetal brain allopregnanolone concentrations by up to 75% and was associated with a reduction in myelin basic protein (MBP) (PZ0 . 001) and an increase in glial fibrillary acidic protein expression in the subcortical white matter brain region (P!0 . 001). IUGR resulted in decreased MBP expression (P!0 . 01) and was associated with a reduction in the expression of steroidogenic enzyme 5a-reductase (5aR) type 2 in the foetal brain (PZ0 . 061). Brain levels of 5aR1 were higher in male foetuses (PZ0 . 008). Both IUGR and reduced foetal brain concentrations of allopregnanolone were associated with altered expression of myelination and glial cell markers within the developing foetal brain. The potential role of neurosteroids in protecting and regulating neurodevelopmental processes in the foetal brain may provide new directions for treatment of neurodevelopmental disorders in infants who are exposed to perinatal insults and pathologies.

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