Biology subjects

Larcombe, A. N.

Publications and source records attributed to Larcombe, A. N..

3 recordsLinked to original sources

bioRxiv2023

The influence of prenatal alcohol exposure and maternal diet on offspring DNA methylation: a cross-species study

Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in new-born pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.

genetics↗

bioRxiv2021

Early-life respiratory viral infection results in impairment of adult lung function

Respiratory viral infections in early-life are linked to the development of chronic lung diseases that persist into adulthood. The aim of this study was to develop a mouse model of early-life respiratory viral infection that would lead to impaired lung function in adulthood. BALB/c pups were infected at seven days of life with one of the following respiratory viruses: influenza A/Mem/1/71 "M71", influenza A/Puerto Rico/8/34 "PR8" or attenuated mengovirus "Mengo". Lung function and airways responsiveness (AHR) to methacholine were assessed seven weeks later, using the forced oscillation technique, and data were compared between male and female mice. PR8 infection was associated with significantly increased responsiveness to methacholine (for airway resistance, tissue damping, tissue elastance and hystersivity) for both sexes. M71 infection resulted in less severe responses especially in adult males. Early-life Mengo infection led to significantly higher responsiveness to MCh for males only (for airway resistance and tissue damping), suggesting sex dependant effects in lung function parameters measured. In summary, we have established a murine model where respiratory viral infection on day seven of life leads to AHR in adulthood. Importantly, the model recapitulates key variations in susceptibility related to sex and nature of viral pathogen that have previously been observed in human epidemiological studies. Our findings reveal new insights into the early origins of AHR and provide a tractable model system for future studies to unlock the mechanisms that determine pathogenesis.

immunology↗

bioRxiv2017

Transplacental protection against asthma by maternal treatment with a bacterial-derived immunomodulatory agent

Studies in European and US farming populations have documented major reductions in asthma prevalence in offspring of mothers exposed to microbial breakdown products present in farm dusts and unprocessed foods. This was associated with enhancement of innate immune competence in the offspring. We sought to (i) identify a safe therapeutic that would reproduce these immunomodulatory effects in a murine model, (ii) elucidate underlying mechanism(s)-of-action, and (iii) develop a scientific rationale for progressing this approach to human trials. We demonstrate in mice that maternal treatment during pregnancy with the microbial-derived immunomodulator OM85, which has been used clinically in adults and children in Europe for >30 years for bolstering resistance to infection-associated airways inflammation, markedly reduces the susceptibility of the offspring of treated mothers to development of experimental atopic asthma. We identify bone marrow precursors of the dendritic cell populations responsible for airway mucosal immune surveillance as the primary targets for the asthma-protective effects of maternal OM85 treatment in the offspring.

immunology↗