J Physiol Volume 586, Number 8, 2231-2244, April 15, 2008 DOI: 10.1113/jphysiol.2007.149229
Low protein diet fed exclusively during mouse oocyte maturation leads to behavioural and cardiovascular abnormalities in offspring
Adam J. Watkins1,
Adrian Wilkins1,
Colm Cunningham1,
V. Hugh Perry1,
Meei J. Seet1,
Clive Osmond2,
Judith J. Eckert1,3,
Christopher Torrens3,
Felino R. A. Cagampang3,
Jane Cleal3,
William P. Gray4,
Mark A. Hanson3 and
Tom P. Fleming1
1 School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK
2
MRC Epidemiology Resource Centre, Southampton General Hospital, Southampton SO16 6YD, UK
3
Institute of Developmental Sciences, Developmental Origins of Health and Disease (DOHaD) Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
4
Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
Early embryonic development is known to be susceptible to maternal undernutrition, leading to a disease-related postnatal phenotype. To determine whether this sensitivity extended into oocyte development, we examined the effect of maternal normal protein diet (18% casein; NPD) or isocaloric low protein diet (9% casein; LPD) restricted to one ovulatory cycle (3.5 days) prior to natural mating in female MF-1 mice. After mating, all females received NPD for the remainder of gestation and all offspring were litter size adjusted and fed standard chow. No difference in gestation length, litter size, sex ratio or postnatal growth was observed between treatments. Maternal LPD did, however, induce abnormal anxiety-related behaviour in open field activities in male and female offspring (P < 0.05). Maternal LPD offspring also exhibited elevated systolic blood pressure (SBP) in males at 9 and 15 weeks and in both sexes at 21 weeks (P < 0.05). Male LPD offspring hypertension was accompanied by attenuated arterial responsiveness in vitro to vasodilators acetylcholine and isoprenaline (P < 0.05). LPD female offspring adult kidneys were also smaller, but had increased nephron numbers (P < 0.05). Moreover, the relationship between SBP and kidney or heart size or nephron number was altered by diet treatment (P < 0.05). These data demonstrate the sensitivity of mouse maturing oocytes in vivo to maternal protein undernutrition and identify both behavioural and cardiovascular postnatal outcomes, indicative of adult disease. These outcomes probably derive from a direct effect of protein restriction, although indirect stress mechanisms may also be contributory. Similar and distinct postnatal outcomes were observed here compared with maternal LPD treatment during post-fertilization preimplantation development which may reflect the relative contribution of the paternal genome.
(Received 4 December 2007;
accepted after revision 25 February 2008;
first published online 28 February 2008)
Corresponding author A. J. Watkins: School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK. Email: ajw7{at}soton.ac.uk
Copyright © 2008 The Physiological Society.
