Advanced maternal age causes adverse programming of mouse blastocysts leading to altered growth and impaired cardiometabolic health in post-natal life.

STUDY QUESTION: Does advanced maternal age (AMA) in mice affect cardiometabolic health during post-natal life in offspring derived from an assisted reproduction technology (ART) procedure? SUMMARY ANSWER: Offspring derived from blastocysts collected from aged female mice displayed impaired body weight gain, blood pressure, glucose metabolism and organ allometry during post-natal life compared with offspring derived from blastocysts from young females; since all blastocysts were transferred to normalized young mothers, this effect is independent of maternal pregnancy conditions. WHAT IS KNOWN ALREADY: Although studies in mice have shown that AMA can affect body weight and behaviour of offspring derived from natural reproduction, data on the effects of AMA on offspring cardiometabolic health during post-natal development are not available. Given the increasing use of ART to alleviate infertility in women of AMA, it is pivotal to develop ART-AMA models addressing the effects of maternal aging on offspring health. STUDY DESIGN, SIZE, DURATION: Blastocysts from old (34-39 weeks) or young (8-9 weeks) C57BL/6 females mated with young CBA males (13-15 weeks) were either subjected to differential cell staining (inner cell mass and trophectoderm) or underwent embryo transfer (ET) into young MF1 surrogates (8-9 weeks) to produce young (Young-ET, 9 litters) and old (Old-ET, 10 litters) embryo-derived offspring. Offspring health monitoring was carried out for 30 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: All animals were fed with standard chow. Blood pressure was measured at post-natal Weeks 9, 15 and 21, and at post-natal Week 30 a glucose tolerance test (GTT) was performed. Two days after the GTT mice were killed for organ allometry. Blastocyst cell allocation variables were evaluated by T-test and developmental data were analysed with a multilevel random effects regression model. MAIN RESULTS AND THE ROLE OF CHANCE: The total number of cells in blastocysts from aged mice was decreased (P < 0.05) relative to young mice due to a lower number of cells in the trophectoderm (mean ± SEM: 34.5 ± 2.1 versus 29.6 ± 1.0). Weekly body weight did not differ in male offspring, but an increase in body weight from Week 13 onwards was observed in Old-ET females (final body weight at post-natal Week 30: 38.5 ± 0.8 versus 33.4 ± 0.8 g, P < 0.05). Blood pressure was increased in Old-ET offspring at Weeks 9-15 in males (Week 9: 108.5 ± 3.13 versus 100.8 ± 1.5 mmHg, Week 15: 112.9 ± 3.2 versus 103.4 ± 2.1 mmHg) and Week 15 in females (115.9 ± 3.7 versus 102.8 ± 0.7 mmHg; all P < 0.05 versus Young-ET). The GTT results and organ allometry were not affected in male offspring. In contrast, Old-ET females displayed a greater (P < 0.05) peak glucose concentration at 30 min during the GTT (21.1 ± 0.4 versus 17.8 ± 1.16 mmol/l) and their spleen weight (88.2 ± 2.6 ± 105.1 ± 4.6 mg) and several organ:body weight ratios (g/g × 10(3)) were decreased (P < 0.05 versus Young-ET), including the heart (3.7 ± 0.06 versus 4.4 ± 0.08), lungs (4.4 ± 0.1 versus 5.0 ± 0.1), spleen (2.4 ± 0.06 versus 3.2 ± 0.1) and liver (36.4 ± 0.6 versus 39.1 ± 0.9). LIMITATIONS, REASONS FOR CAUTION: Results from experimental animal models cannot be extrapolated to humans. Nevertheless, they are valuable to develop conceptual models that can produce hypotheses for eventual testing in the target species (i.e. humans). WIDER IMPLICATIONS OF THE FINDINGS: Our data show that offspring from mouse embryos from aged mothers can develop altered phenotypes during post-natal development compared with embryos from young mothers. Because all embryos were transferred into young mothers for the duration of pregnancy to normalize the maternal in vivo environment, our findings indicate that adverse programming via AMA is already established at the blastocyst stage. Whilst human embryos display increased aneuploidy compared with mouse, we believe our data have implications for women of AMA undergoing assisted reproduction, including surrogacy programmes. STUDY FUNDING/COMPETING INTERESTS: This work was supported through the European Union FP7-CP-FP Epihealth programme (278418) to T.P.F. and the BBSRC (BB/F007450/1) to T.P.F. The authors have no conflicts of interest to declare.

Sustained TL1A expression modulates effector and regulatory T-cell responses and drives intestinal goblet cell hyperplasia.

The tumor necrosis factor (TNF) superfamily protein TNF-like 1A (TL1A) is the ligand for death receptor 3 (DR3). TL1A is induced on activated dendritic cells (DCs) and its expression has been linked to human inflammatory bowel disease. To address how TL1A might influence intestinal inflammation, we generated transgenic mice that constitutively express TL1A on DCs. TL1A transgenic mice developed striking goblet cell hyperplasia in the ileum that was associated with elevated interleukin (IL)-13 levels in the small intestine. IL-13- and IL-17-producing small intestinal lamina propria T cells were increased in TL1A transgenic mice. TL1A also enhanced regulatory T (Treg) cell turnover in vivo and directly stimulated Treg cell proliferation in vitro. The presence of TL1A attenuated the ability of Treg cells to suppress conventional T cells, an effect that required DR3 signaling in either conventional T cells or Treg cells. Our findings identify mechanisms by which chronic DR3 signaling could promote pathogenesis in inflammatory bowel disease.

Susceptibility in cell culture of feline immunodeficiency virus to eighteen antiviral agents.

The in-vitro susceptibilities of two strains of feline immunodeficiency virus to 18 antiviral agents were determined in two cell lines. In terms of inhibiting p24 antigen production, the nucleoside-analogue reverse transcriptase inhibitors were the most effective compounds. Inhibition was also observed with aurintricarboxylic acid, phosphonoformate and butyldeoxynorjirimycin, but not with the other agents tested.

Effect of 3'azido-2',3'-deoxythymidine (AZT) on experimental feline immunodeficiency virus infection in domestic cats.

The compound 3'azido-2',3'-deoxythymidine (AZT) inhibits the replication of feline immunodeficiency virus (FIV) in cell culture, and treatment with the compound has been reported to induce some clinical improvement in some cases of feline FIV infection. In order to determine the effect of prophylactic treatment with AZT on experimental FIV infection, cats were treated with the compound at 0.2, 1.0, 5, 25 or 50 mg kg-1 day-1 for 29 days. One day after the treatment was started, they were inoculated with 150 cat infectious doses of FIV. All the cats became viraemic, seroconverted and developed lymphadenopathy, although the onset of each was delayed in the cats given higher doses of AZT. Anaemia developed in the cats given high doses of AZT. Virus re-isolated from the cats given 50 mg kg-1 day-1 was as susceptible to AZT in cell culture as the inoculated virus. Thus AZT is much less effective in cats than might have been expected from the results of in vitro studies.

Feline immunodeficiency virus: a brief review.

Feline immunodeficiency virus (FIV), previously known as feline T-lymphotropic lentivirus (FTLV), was first described by Pedersen et al. (1987) who isolated the virus from cats with a variety of clinical signs suggestive of immunodeficiency. Since then FIV has become one of the most studied feline viruses, not least because of its similarity to human immunodeficiency viruses (HIV) which cause acquired immunodeficiency syndrome (AIDS) in man.

Effect of primary-stage feline immunodeficiency virus infection on subsequent feline calicivirus vaccination and challenge in cats.

The effect of experimental primary-stage feline immunodeficiency virus (FIV) infection on feline calicivirus (FCV) vaccination and challenge in cats was studied. Clinical signs of acute FCV disease were more widespread in the cats which were infected with FIV than in those which were not. FIV infection also prolonged shedding of FCV, with more of the FIV-infected cats becoming chronic carriers. Although vaccination induced protection against acute FCV disease, this was to a lesser degree in FIV-infected cats. Vaccination by itself also appeared to enhance long-term virus shedding. There was evidence of an impaired anamnestic FCV-neutralizing antibody response in FIV-infected cats following FCV challenge.