Guinea pig preterm birth is affected by the lysine deacetylase inhibitor tichostatin A

37th Congress of IUPS (Birmingham, UK) (2013) Proc 37th IUPS, PCC352

Poster Communications: Guinea pig preterm birth is affected by the lysine deacetylase inhibitor tichostatin A

W. Tong1, M. Karolczak-Bayatti1, B. F. Mitchell2, G. N. Europe-Finner1, M. J. Taggart1

1. Institute of Cellular Medicine, Newcastle University, Necastle upon Tyne, United Kingdom. 2. Department of Obstetrics & Gynecology, University of Alberta, Edmonton, Alberta, Canada.

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There is increasing interest in investigating the roles of protein lysine acetylation in mediating cell function. Recently, evidence was presented for a role of lysine deacetylase inhibitors (KDACi) in regulating human uterine function by epigenetic and non-epigenetic actions that highlighted a possibility of utilising such substances to target pathways involved in preterm labour [1]. The pregnant guinea pig, unlike rat or mouse, has a similar endocrine physiology to that of human and is therefore a useful model of human parturition [2]. We therefore sought to determine whether trichostatin A (TSA), a broad KDACi, could affect the timing, or duration, of parturition in a guinea pig model of experimentally-induced preterm labour [3,4]. All animal experimentation was performed under Home Office License. Preterm birth was induced in time-mated pregnant guinea pigs with RU486 (3 mg/kg body weight) on gestation day d55 and d56 (analogous to ~32 weeks human gestation) and oxytocin (2 U/kg) on d57. Animals in the treatment group received additional daily doses of TSA (1.03 mg/kg) from d54 to d57. All pregnancies were monitored to determine the exact timing of birth. Effects of TSA were quantified by the following assessments: LS, time between last injection to 1st pup’s appearance; LE – time between last injection to last pup’s appearance; LD – labour duration between 1st and last pups appearance; and litter survival rate (SR). Mean ± SEM data in preterm (PTL) and TSA- treatment groups were compared using two-tailed unpaired t-test with Welsh’s correction. Term delivery occurred at d67.9 ± 0.1 (n=11). LD was 0.37 ± 0.02 hr. Of 37 pups, 30 appeared healthy and 7 were either stillborn or died shortly after birth (SR = 80.5 ± 5.0 %). In PTL group (n=4), delivery occurred in all animals on d57. LS was 2.83 ± 0.18 hr, LE was 5.53 ± 0.63 hr and LD was 2.53 ± 0.63 hr. No pups survived. In the TSA-treated group (n=7), 4 animals progressed to term (completed delivery > d67) and 3 delivered on d57-d58. Remarkably, one animal that had begun delivery on d57 (with one stillborn pup) also delivered two more pups on d69 that appeared normal and healthy. Overall, delivery was completed on d64.7 ± 0.4 (n=6, p<0.05), LS was 114.63 ± 1.65 hr, LE was 176.43 ± 1.93 hr (n=6, p<0.05) and LD was 45.43 ± 1.73 hr (n=6). Of the 19 pups, 10 appeared healthy but 9 did not survive (SR = 52.4 ± 10.1 %, n=6, p<0.05). In conclusion, TSA inhibits the onset of parturition, and/or increases the length of gestation in ~50% of cases of a guinea pig model of preterm birth with improved neonatal survival. KDACi are thus promising tools for elucidating the basis of preterm and term parturition. Further work to establish the mechanism(s) of action and optimise the efficacy of KDACi may also result in the development of new tocolytic agents.



Where applicable, experiments conform with Society ethical requirements.

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