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Hypergravity exposure during gestation modifies the TCR? repertoire of newborn mice.

ABSTRACT: During spaceflight, organisms are subjected to mechanical force changes (gravity (G) changes) that affect the immune system. However, gravitational effects on lymphopoiesis have rarely been studied. Consequently, we investigated whether the TCR? repertoire, created by V(D)J recombination during T lymphopoiesis, is affected by hypergravity exposure during murine development. To address this question, C57BL/6j mice were mated in a centrifuge so that embryonic development, birth and TCR? rearrangements occurred at 2G. Pups were sacrificed at birth, and their thymus used to quantify transcripts coding for factors required for V(D)J recombination and T lymphopoiesis. We also created cDNA mini-libraries of TCR? transcripts to study the impact of hypergravity on TCR? diversity. Our data show that hypergravity exposure increases the transcription of TCR? chains, and of genes whose products are involved in TCR signaling, and affects the V(D)J recombination process. We also observed that ~85% of the TCR? repertoire is different between hypergravity and control pups. These data indicate that changing a mechanical force (the gravity) during ontogeny will likely affect host immunity because properties of loops constituting TCR antigen-binding sites are modified in hypergravity newborns. The spectrum of peptides recognized by TCR will therefore likely be different.

SUBMITTER: Ghislin S

PROVIDER: S-EPMC5380131 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Hypergravity exposure during gestation modifies the TCRβ repertoire of newborn mice.

Ghislin Stéphanie S Ouzren-Zarhloul Nassima N Kaminski Sandra S Frippiat Jean-Pol JP

Scientific reports 20150320

During spaceflight, organisms are subjected to mechanical force changes (gravity (G) changes) that affect the immune system. However, gravitational effects on lymphopoiesis have rarely been studied. Consequently, we investigated whether the TCRβ repertoire, created by V(D)J recombination during T lymphopoiesis, is affected by hypergravity exposure during murine development. To address this question, C57BL/6j mice were mated in a centrifuge so that embryonic development, birth and TCRβ rearrangem ...[more]

PMID: 25792033

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Project description:BackgroundHigh blood pressure (BP) in childhood is frequently renal in origin and a risk factor for adult hypertension and cardiovascular disease. Shorter gestations are a known risk factor for increased BP in adults and children, due in part to a nephron deficit in children born preterm. As nephrogenesis is incomplete until 36 weeks gestation, prenatal lead exposure occurring during a susceptible period of renal development may contribute to programming for later life renal disease. The relationship between shorter gestation and children's BP has not yet been explored to identify i) critical windows using nonlinear piecewise models or ii) combined with other early life risk factors such as prenatal lead exposure.Objectives(1) To evaluate the nonlinear relationship between lower gestational age and childhood BP measured at 4-6 years of age, and (2) to investigate modification by prenatal lead exposure.MethodsIn a prospective longitudinal birth cohort, we assessed 565 children between 4 and 6 years of age (mean: 4.8 years) in the PROGRESS cohort in Mexico City, Mexico. Gestational age at delivery was calculated using maternal report of last menstrual period (LMP) and confirmed with Capurro physical examination at birth. We measured pregnant women's blood lead levels (BLLs) in the second trimester via inductively coupled plasma-mass spectrometry and children's BP using an automated device. We performed both linear and nonlinear piecewise regression analyses to examine associations of gestational age with children's BP adjusting for children's age, sex, height, prenatal exposure to smoke, and maternal socioeconomic status. We stratified to assess modification by prenatal lead exposure, and used a data-adaptive approach to identify a lead cutpoint.ResultsMaternal second trimester BLLs ranged from 0.7 to 17.8 μg/dL with 112 (20%) women above the CDC guideline level of 5 μg/dL. In adjusted linear regression models, a one week reduction in gestational age was associated with a 0.5 mm Hg (95%CI: 0.2, 0.8) increase in SBP and a 0.4 mm Hg (95%CI 0.1, 0.6) increase in DBP. Our nonlinear models suggested evidence for different magnitude estimates on either side of an estimated join-point at 35.9 weeks' gestation, but did not reach statistical significance. However, when stratified by prenatal lead exposure, we identified a cutpoint lead level of concern of 2.5 μg/dL that suggested an interaction between gestational age and blood lead. Specifically, for BLLs ≥ 2.5 μg/dL, SBP was 1.6 (95%CI: 0.3, 2.9) mm Hg higher per each week reduction in gestational age among children born before 37.0 weeks; and among children born after 37.0 weeks, this relationship was attenuated yet remained significant [β: 0.9, 95%CI (0.2, 1.6)]. At BLLs below 2.5 μg/dL, there was no appreciable association between lower gestational age and SBP.ConclusionsOur findings suggest that shorter gestation combined with higher prenatal lead exposure contributes to a higher risk of increased SBP at 4-6 years of age, particularly among infants born <37 weeks gestation. Our results underscore the importance of preventing prenatal lead exposure - even levels as low as 2.5 μg/dL - especially among pregnant women at risk for preterm birth. Given that high BP in childhood is a risk factor for adult hypertension and cardiovascular disease later in life, these results may have implications that extend across the life span.

Dataset Information

Hypergravity exposure during gestation modifies the TCR? repertoire of newborn mice.

Publications

Hypergravity exposure during gestation modifies the TCRβ repertoire of newborn mice.

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