Prenatal exposure to lps leads to long‐lasting physiological consequences in male offspring

Asiaei, Masoud; Solati, Jalal; Salari, Ali-Akbar

doi:10.1002/dev.20568

Cited by 28 publications

(13 citation statements)

References 77 publications

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“…As expected (Asiaei et al, 2011;Kirsten et al, 2013), maternal plasma corticosterone and IL-1β were elevated 3 h after LPS challenge on gestational day 15. We did not measure maternal IL-6 levels as this proinflammatory cytokine is not consistently induced by LPS during the early-tomid gestational period, even in the presence of MIA-associated behavioral and neurophysiological disruptions in offspring (Asiaei et al, 2011;Elovitz et al, 2011). Evidence for MIA-associated glucocortocoid programming (Seckl & Meaney, 2004;Heussner et al, 2016) was demonstrated by a simultaneous decrease of both Hsd11b2 and Hsd11b2/Hsd11b1 in our male and female placentas.…”

Section: Discussionsupporting

confidence: 77%

Environmental influences on placental programming and offspring outcomes following maternal immune activation

Estevez

Rondón-Ortiz

Nguyen

et al. 2019

Preprint

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Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of 'positive' maternal experiences on the placenta and fetus remain unclear. In animal models of early life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic writers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1β were elevated 3 h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic writers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.

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Section: Discussionsupporting

confidence: 77%

Environmental influences on placental programming and offspring outcomes following maternal immune activation

Estevez

Rondón-Ortiz

Nguyen

et al. 2019

Preprint

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“…As the glucose requirement of the growing fetus increases through pregnancy, alterations in the gradient and placental transport capacity ensure that the glucose supply meets this demand (Molina et al 1991;Sakata et al 1995;Yamaguchi et al 1996;Ehrhardt & Bell, 1997). Glucocorticoids are well placed to influence materno-fetal glucose supply because their bioavailability changes throughout pregnancy with increasing maternal and fetal adrenal secretion and tissue-specific changes in activity of the 11β hydroxysteroid dehydrogenases, which increase (type I) or decrease (type II) the local availability of active glucocorticoids (Barlow et al 1974;Condon et al 1997) Moreover, maternal glucorticoid availability rises in response to environmental stressors that alter growth in utero, including excess light and/or heat, physical restraint, infection, and dietary restriction of calories and protein (Ward & Weisz, 1984;Montano et al 1991;Lesage et al 2001;Asiaei et al 2011;Belkacemi et al 2011;Sferruzzi-Perri et al 2011;Cottrell et al 2012). However, whether alterations in materno-fetal glucose partitioning underlie the reduction in birth weight when maternal glucocorticoids are elevated during pregnancy (Seckl, 2004) also remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Corticosterone alters materno‐fetal glucose partitioning and insulin signalling in pregnant mice

Vaughan

Fisher

Dionelis

et al. 2015

The Journal of Physiology

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Key pointsr Glucocorticoids regulate fetal and adult glucose metabolism, in part by influencing the actions of insulin. However, their effects on materno-fetal glucose partitioning remain largely unknown.r In the present study, when pregnant mice were given the natural glucocorticoid, corticosterone, plasma insulin concentrations and liver insulin-signalling increased but the blood glucose concentration remained normal.r However, in the placenta, glucose transport was reduced in association with the lower activity of some insulin signalling proteins, depending on the day of pregnancy and maternal food intake.r In both liver and placenta, there was increased expression of the Redd1 (Ddit4) gene when the plasma corticosterone concentration was raised.r The results show that maternal glucocorticoids interact with signalling pathways in the placenta to limit materno-fetal glucose partitioning.Abstract Glucocorticoids affect glucose metabolism in adults and fetuses, although their effects on materno-fetal glucose partitioning remain unknown. The present study measured maternal hepatic glucose handling and placental glucose transport together with insulin signalling in these tissues in mice drinking corticosterone either from day (D) 11 to D16 or D14 to D19 of pregnancy (term = D21). On the final day of administration, corticosterone-treated mice were hyperinsulinaemic (P < 0.05) but normoglycaemic compared to untreated controls. In maternal liver, there was no change in glycogen content or glucose 6-phosphatase activity but increased Slc2a2 glucose transporter expression in corticosterone-treated mice, on D16 only (P < 0.05). On D19, but not D16, transplacental 3 H-methyl-D-glucose clearance was reduced by 33% in corticosterone-treated dams (P < 0.05). However, when corticosterone-treated animals were pair-fed to control intake, aiming to prevent the corticosterone-induced increase in food consumption, 3 H-methyl-D-glucose clearance was similar to the controls. Depending upon gestational age, corticosterone treatment increased phosphorylation of the insulin-signalling proteins, protein kinase B (Akt) and glycogen synthase-kinase 3β, in maternal liver (P < 0.05) but not placenta (P > 0.05). Insulin receptor and insulin-like growth factor type I receptor abundance did not differ with treatment in either tissue. Corticosterone upregulated the stress-inducible mechanistic target of rapamycin (mTOR) suppressor, Redd1, in liver (D16 and D19) and placenta (D19), in ad libitum fed animals (P < 0.05). Concomitantly, hepatic protein content and placental weight were reduced on D19 (P < 0.05), in association with altered abundance and/or phosphorylation of signalling proteins downstream of mTOR. Taken together, the data indicate that maternal glucocorticoid excess reduces fetal growth partially by altering placental glucose transport and mTOR signalling.

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“…These data are consistent with emerging evidence for the protective effects of early adversity on some behavioral measures. Indeed, young adult male mice that were prenatally exposed to LPS have demonstrated reduced anxiety-type behavior in the elevated plus maze (Asiaei et al 2011). Notably, the open field does not provide a definitive measure of anxiety-type behaviour in rodents and future additional measures of anxiety (as well as measures of grooming, rearing and defecation in activity tasks) are warranted.…”

Section: Discussionmentioning

confidence: 99%

Immune stress in late pregnant rats decreases length of gestation and fecundity, and alters later cognitive and affective behaviour of surviving pre-adolescent offspring

Paris¹,

Brunton²,

Russell³

et al. 2011

Stress

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Immune challenge during pregnancy is associated with preterm birth and poor perinatal development. The mechanisms of these effects are not known. 5α-Pregnan-3α-ol-20-one (3α,5α-THP), the neuroactive metabolite of progesterone, is critical for neurodevelopment and stress responses, and can influence cognition and affective behaviours. To develop an immune challenge model of preterm birth, pregnant Long–Evans rat dams were administered lipopolysaccharide [LPS; 30 μg/kg/ml, intraperitoneal (IP)], interleukin-1β (IL-1β; 1 μg/rat, IP) or vehicle (0.9% saline, IP) daily on gestational days 17–21. Compared to control treatment, prenatal LPS or IL-1β reduced gestational length and the number of viable pups born. At 28–30 days of age, male and female offspring of mothers exposed to prenatal IL-1β had reduced cognitive performance in the object recognition task compared to controls. In females, but not males, prenatal IL-1β reduced anxiety-like behaviour, indicated by entries to the centre of an open field. In the hippocampus, progesterone turnover to its 5α-reduced metabolites was lower in prenatally exposed IL-1β female, but not in male offspring. IL-1β-exposed males and females had reduced oestradiol content in hippocampus, medial prefrontal cortex and diencephalon compared to controls. Thus, immune stress during late pregnancy reduced gestational length and negatively impacted birth outcomes, hippocampal function and central neurosteroid formation in the offspring.

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Prenatal exposure to lps leads to long‐lasting physiological consequences in male offspring

Cited by 28 publications

References 77 publications

Environmental influences on placental programming and offspring outcomes following maternal immune activation

Environmental influences on placental programming and offspring outcomes following maternal immune activation

Corticosterone alters materno‐fetal glucose partitioning and insulin signalling in pregnant mice

Immune stress in late pregnant rats decreases length of gestation and fecundity, and alters later cognitive and affective behaviour of surviving pre-adolescent offspring

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