Developmental programming of bone deficits in growth-restricted offspring
Tania Romano A B E , John D. Wark C D and Mary E. Wlodek BA Department of Human Biosciences, La Trobe University, Bundoora, Vic. 3086, Australia.
B Department of Physiology, The University of Melbourne, Parkville, Vic. 3010, Australia.
C Department of Medicine, The University of Melbourne, Parkville, Vic. 3010, Australia.
D Bone and Mineral Medicine, Royal Melbourne Hospital, Parkville, Vic. 3050, Australia.
E Corresponding author. Email: t.romano@latrobe.edu.au
Reproduction, Fertility and Development 27(5) 823-833 https://doi.org/10.1071/RD13388
Submitted: 15 November 2013 Accepted: 28 January 2014 Published: 11 March 2014
Abstract
Recent evidence links low birthweight and poor adult bone health. We characterised bone size, mineral content, density and strength (stress strain index of bone bending strength (SSI)) in rats from weaning to 12 months. Bilateral uterine vessel ligation (Restricted) or sham surgery (Control) was performed on gestational Day 18 in rats inducing uteroplacental insufficiency. Postmortem of male and female offspring was performed at postnatal Day 35 and at 2, 4, 6 and 12 months. Femur mineral content, density and strength were measured using quantitative computed tomography (pQCT). Restricted pups were born 10%–15% lighter and remained smaller with shorter femurs than Controls (P < 0.05). Male and female Restricted rats had lower trabecular bone content compared with Controls (P < 0.05), without trabecular density changes. Cortical content was reduced in Restricted males (Day 35 and 6 and 12 months) and at all ages in Restricted females (P < 0.05). Cortical density was lower at Day 35 in Restricted males (P < 0.05). SSI was lower at Day 35 and at 6 and 12 months in Restricted males, and at all ages in Restricted females (P < 0.05). Skeletal deficits were detected in Restricted offspring with gender-specific differences during juvenile and adolescent periods. Bone deficits observed at 6 months in males were greater than at 12 months, indicating that aging can exacerbate programmed bone phenotypes.
Additional keywords: bone densitometry, fetal programming, nutrition, pregnancy, skeleton, uteroplacental insufficiency.
References
Anderson, C. M., Lopez, F., Zimmer, A., and Benoit, J. N. (2006). Placental insufficiency leads to developmental hypertension and mesenteric artery dysfunction in two generations of Sprague-Dawley rat offspring. Biol. Reprod. 74, 538–544.| Placental insufficiency leads to developmental hypertension and mesenteric artery dysfunction in two generations of Sprague-Dawley rat offspring.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhslejsL4%3D&md5=5406ac92150d8433b8011b820f36191eCAS | 16306423PubMed |
Baird, J., Kurshid, M. A., Kim, M., Harvey, N., Dennison, E., and Cooper, C. (2011). Does birthweight predict bone mass in adulthood? A systematic review and meta-analysis. Osteoporos. Int. 22, 1323–1334.
| Does birthweight predict bone mass in adulthood? A systematic review and meta-analysis.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BC3MvitVSlsQ%3D%3D&md5=88282d9cadf2ac484b53c24f7e9430adCAS | 20683711PubMed |
Barker, D. J. P. (1994). Outcome of low birthweight. Horm. Res. 42, 223–230.
| Outcome of low birthweight.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXitlOqsL8%3D&md5=70220ee583a5becb811defd17ebd4e36CAS |
Barker, D. J. P., Osmond, C., Golding, J., Kuh, D., and Wadsworth, M. E. J. (1989). Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 298, 564–567.
| Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaL1M7psVGhuw%3D%3D&md5=1635d68ba21ede37aa6aede115dfd1eeCAS |
Cooper, C., Cawley, M., Bhalla, A., Egger, P., Ring, F., Morton, L., and Barker, D. (1995). Childhood growth, physical activity, and peak bone mass in women. J. Bone Miner. Res. 10, 940–947.
| Childhood growth, physical activity, and peak bone mass in women.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK28%2Fht1anuw%3D%3D&md5=e5779ccff45e75d2f38cb0fcb176003eCAS | 7572318PubMed |
Cooper, C., Fall, C., Egger, P., Hobbs, R., Eastell, R., and Barker, D. (1997). Growth in infancy and bone mass in later life. Ann. Rheum. Dis. 56, 17–21.
| Growth in infancy and bone mass in later life.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK2s3ht1akuw%3D%3D&md5=9bb1add95c615e0afdcdd80d35207779CAS | 9059135PubMed |
Danielsen, C. C., Mosekilde, L., and Andreassen, T. T. (1992). Long-term effect of orchidectomy on cortical bone from rat femur: bone mass and mechanical properties. Calcif. Tissue Int. 50, 169–174.
| Long-term effect of orchidectomy on cortical bone from rat femur: bone mass and mechanical properties.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK383ktVCltg%3D%3D&md5=345f44315803dfd0df050061f888c198CAS | 1571835PubMed |
Danielsen, C. C., Mosekilde, L., and Svenstrup, B. (1993). Cortical bone mass, composition, and mechanical properties in female rats in relation to age, long-term ovariectomy, and estrogen substitution. Calcif. Tissue Int. 52, 26–33.
| Cortical bone mass, composition, and mechanical properties in female rats in relation to age, long-term ovariectomy, and estrogen substitution.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3sXisVOqs7g%3D&md5=031872ae169c3ca3bdf56f62c19d8596CAS | 8453502PubMed |
Davison, K. S., Siminoski, K., Adachi, J. D., Hanley, D. A., Goltzman, D., Hodsman, A. B., Josse, R., Kaiser, S., Olszynski, W. P., Papaioannou, A., Ste-Marie, L. G., Kendler, D. L., Tenehouse, A., and Brown, J. P. (2006). Bone strength: the whole is greater than the sum of its parts. Semin. Arthritis Rheum. 36, 22–31.
| 16887465PubMed |
Dennison, E. M., Syddall, H. E., Sayer, A. A., Gilbody, H. J., and Cooper, C. (2005). Birth weight and weight at 1 year are independent determinants of bone mass in the seventh decade: the Hertfordshire cohort study. Pediatr. Res. 57, 582–586.
| Birth weight and weight at 1 year are independent determinants of bone mass in the seventh decade: the Hertfordshire cohort study.Crossref | GoogleScholarGoogle Scholar | 15695596PubMed |
Engelbregt, M. J., Houdijk, M. E., Popp-Snijders, C., and Delemarre-van de Waal, H. A. (2000). The effects of intra-uterine growth retardation and postnatal undernutrition on onset of puberty in male and female rats. Pediatr. Res. 48, 803–807.
| The effects of intra-uterine growth retardation and postnatal undernutrition on onset of puberty in male and female rats.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3M7hsVGrtA%3D%3D&md5=120799df390eb7c102e6a5eddc511078CAS | 11102550PubMed |
Engelbregt, M. J. T., Van Weissenbruch, M. M., Popp-Snijders, C., and Delemarre-van de Waal, H. A. (2002). Delayed first cycle in intrauterine growth-retarded and postnatally undernourished female rats: follicular growth and ovulation after stimulation with pregnant mare serum gonadotrophin at first cycle. J. Endocrinol. 173, 297–304.
| Delayed first cycle in intrauterine growth-retarded and postnatally undernourished female rats: follicular growth and ovulation after stimulation with pregnant mare serum gonadotrophin at first cycle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xkt1SlsLc%3D&md5=0f1b212a4020f50401abc4889fbc1073CAS |
Engelbregt, M. J., Weissenbruch, M. M., Lips, P., Lingen, A., Roos, J. C., and Delemarre-van de Waal, H. A. (2004). Body composition and bone measurements in intra-uterine growth retarded and early postnatally undernourished male and female rats at the age of 6 months: comparison with puberty. Bone 34, 180–186.
| Body composition and bone measurements in intra-uterine growth retarded and early postnatally undernourished male and female rats at the age of 6 months: comparison with puberty.Crossref | GoogleScholarGoogle Scholar | 14751576PubMed |
Eriksson, J. G., Kajantie, E., Osmond, C., Thornburg, K., and Barker, D. J. (2010). Boys live dangerously in the womb. Am. J. Hum. Biol. 22, 330–335.
| Boys live dangerously in the womb.Crossref | GoogleScholarGoogle Scholar | 19844898PubMed |
Ferretti, J. L., Capozza, R. F., and Zanchetta, J. R. (1996). Mechanical validation of a tomographic (pQCT) index for nonivasive estimation of rat femur bending strength. Bone 18, 97–102.
| Mechanical validation of a tomographic (pQCT) index for nonivasive estimation of rat femur bending strength.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK28vjtVSmsA%3D%3D&md5=322c436fa1df1b9ca4dbcf2dc1e885f6CAS | 8833202PubMed |
Fritz, H., and Hess, R. (1970). Ossification of the rat and mouse skeleton in the perinatal period. Teratology 3, 331–337.
| Ossification of the rat and mouse skeleton in the perinatal period.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaE2M7nvVGqsQ%3D%3D&md5=cfea93a4314e2429589e8dc684eb5276CAS | 5538530PubMed |
Horton, J. A., Murray, G. M., Spadaro, J. A., Margulies, B. S., Allen, M. J., and Damron, T. A. (2003). Precision and accuracy of DXA and pQCT for densitometry of the rat femur. J. Clin. Densitom. 6, 381–390.
| Precision and accuracy of DXA and pQCT for densitometry of the rat femur.Crossref | GoogleScholarGoogle Scholar | 14716052PubMed |
Hunziker, E. B., and Schenk, R. K. (1989). Physiological mechanisms adopted by chondrocytes in regulating longitudinal bone growth in rats. J. Physiol. 414, 55–71.
| 1:STN:280:DyaK3c7ht1Sltw%3D%3D&md5=89fd65815212bb32b92ea711254169aaCAS | 2607442PubMed |
Javaid, M. K., Crozier, S. R., Harvey, N. C., Gale, C. R., Dennison, E. M., Boucher, B. J., Arden, N. K., Godfrey, K. M., and Cooper, C. (2006). Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 367, 36–43.
| Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhsFalsg%3D%3D&md5=488d7d9136a132ddb9c029d46629618eCAS | 16399151PubMed |
Kember, N. F. (1973). Aspects of the maturation process in growth cartilage in the rat tibia. Clin. Orthop. Relat. Res. 95, 288–294.
| 4754213PubMed |
Kensara, O. A., Wootton, S. A., Phillips, D. I., Patel, M., Jackson, A. A., Elia, M., and Hertfordshire Study Group (2005). Fetal programming of body composition: relation between birth weight and body composition measured with dual-energy X-ray absorptiometry and anthropometric methods in older Englishmen. Am. J. Clin. Nutr. 82, 980–987.
| 1:CAS:528:DC%2BD2MXht1ektLnL&md5=36c029561016eeda141619b1e8c51fe8CAS | 16280428PubMed |
McMillen, I. C., and Robinson, J. S. (2005). Developmental origins of the metabolic syndrome: prediction, plasticity and programming. Physiol. Rev. 85, 571–633.
| Developmental origins of the metabolic syndrome: prediction, plasticity and programming.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXjt12lsLw%3D&md5=e60f1e5087cede1852b656d288b1cc2dCAS | 15788706PubMed |
Nagy, T. R., Prince, C. W., and Li, J. (2001). Validation of peripheral dual-energy X-ray absorptiometry for the measurement of bone mineral in intact and excised long bones of rats. J. Bone Miner. Res. 16, 1682–1687.
| Validation of peripheral dual-energy X-ray absorptiometry for the measurement of bone mineral in intact and excised long bones of rats.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3Mvpslelsw%3D%3D&md5=6d6f2c13425c2873f36fc7ef92776622CAS | 11547838PubMed |
O’Dowd, R., Kent, J. C., Moseley, J. M., and Wlodek, M. E. (2008). Effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R539–R548.
| 1:CAS:528:DC%2BD1cXit1ylu78%3D&md5=17f96fd3e0683f70167f02dd94fc9f9cCAS | 18077510PubMed |
Oliver, H., Jameson, K. A., Sayer, A. A., Cooper, C., and Dennison, E. M. (2007). Growth in early life predicts bone strength in late adulthood: the Hertfordshire cohort study. Bone 41, 400–405.
| Growth in early life predicts bone strength in late adulthood: the Hertfordshire cohort study.Crossref | GoogleScholarGoogle Scholar | 17599849PubMed |
Pandolfi, C., Zugaro, A., Lattanzio, F., Necozione, S., Barbonetti, A., Colangeli, M. S., Francavilla, S., and Francavilla, F. (2008). Low birth weight and later development of insulin resistance and biochemical/clinical features of polycystic ovary syndrome. Metabolism 57, 999–1004.
| Low birth weight and later development of insulin resistance and biochemical/clinical features of polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXnt1egsrw%3D&md5=f10658aad07cb9fdfe600ba775028829CAS | 18555843PubMed |
Pedersen, J. F. (1980). Ultrasound evidence of sexual difference in fetal size in first trimester. BMJ 281, 1253.
| Ultrasound evidence of sexual difference in fetal size in first trimester.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaL3M%2FktFGisA%3D%3D&md5=59ff5c401f6f8247d7ede6037154d9ceCAS | 7427655PubMed |
Roach, H. I., Mehta, G., Oreffo, R. O. C., Clarke, N. M. P., and Cooper, C. (2003). Temporal analysis of rat growth plates: cessation of growth with age despite presence of a physis. J. Histochem. Cytochem. 51, 373–383.
| Temporal analysis of rat growth plates: cessation of growth with age despite presence of a physis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXhslCqtLY%3D&md5=193e3f0a07ab52f38ddea5d9d59ca0ccCAS | 12588965PubMed |
Romano, T., Wark, J. D., Owens, J. A., and Wlodek, M. E. (2009). Prenatal growth restriction and postnatal growth restriction followed by accelerated growth independently program reduced bone growth and strength. Bone 45, 132–141.
| Prenatal growth restriction and postnatal growth restriction followed by accelerated growth independently program reduced bone growth and strength.Crossref | GoogleScholarGoogle Scholar | 19332163PubMed |
Romano, T., Wark, J. D., and Wlodek, M. E. (2010). Calcium supplementation does not rescue the programmed adult bone deficits associated with perinatal growth restriction. Bone 47, 1054–1063.
| Calcium supplementation does not rescue the programmed adult bone deficits associated with perinatal growth restriction.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtlKlsrvL&md5=7c48603befb0cc0747c32d55b3265b19CAS | 20817129PubMed |
Sayer, A. A., and Cooper, C. (2005). Fetal programming of body composition and musculoskeletal development. Early Hum. Dev. 81, 735–744.
| Fetal programming of body composition and musculoskeletal development.Crossref | GoogleScholarGoogle Scholar | 16081228PubMed |
Schmidt, C., Priemel, M., Kohler, T., Weusten, A., Muller, R., Amling, M., and Eckstein, F. (2003). Precision and accuracy of peripheral quantitative computed tomography (pQCT) in the mouse skeleton compared with histology and mircocomputed tomography (µCT). J. Bone Miner. Res. 18, 1486–1496.
| Precision and accuracy of peripheral quantitative computed tomography (pQCT) in the mouse skeleton compared with histology and mircocomputed tomography (µCT).Crossref | GoogleScholarGoogle Scholar | 12929938PubMed |
Simmons, R. A., Templeton, L. J., and Gertz, S. J. (2001). Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes 50, 2279–2286.
| Intrauterine growth retardation leads to the development of type 2 diabetes in the rat.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXntlGhurc%3D&md5=c301cde9dc121397f935b3acb7aaf039CAS | 11574409PubMed |
Stelzer, I., Fuchs, R., Schraml, E., Quan, P., Hansalik, M., Pietschmann, P., Quehenberger, F., Skalicky, M., Viidik, A., and Schauenstein, K. (2010). Decline of bone marrow-derived hematopoietic progenitor cell quality during aging in the rat. Exp. Aging Res. 36, 359–370.
| Decline of bone marrow-derived hematopoietic progenitor cell quality during aging in the rat.Crossref | GoogleScholarGoogle Scholar | 20544453PubMed |
Trudel, G., Kilborn, S. H., and Uhthoff, H. K. (2001). Bone growth increases the knee flexion contracture angle: a study using rats. Arch. Phys. Med. Rehabil. 82, 583–588.
| Bone growth increases the knee flexion contracture angle: a study using rats.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3M3ltVKhug%3D%3D&md5=425427702963df9dfab5ac89bceef75cCAS | 11346832PubMed |
Vidulich, L., Norris, S. A., Cameron, N., and Pettifor, J. M. (2007). Infant programming of bone size and bone mass in 10-year-old black and white South African children. Paediatr. Perinat. Epidemiol. 21, 354–362.
| Infant programming of bone size and bone mass in 10-year-old black and white South African children.Crossref | GoogleScholarGoogle Scholar | 17564593PubMed |
Wlodek, M. E., Mibus, A., Tan, A., Siebel, A. L., Owens, J. A., and Moritz, K. M. (2007). Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat. J. Am. Soc. Nephrol. 18, 1688–1696.
| Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXnt1Squrg%3D&md5=e318730d892c9fb6199225cb3d4d5992CAS | 17442788PubMed |
Wlodek, M. E., Westcott, K., Siebel, A. L., Owens, J. A., and Moritz, K. M. (2008). Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats. Kidney Int. 74, 187–195.
| Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats.Crossref | GoogleScholarGoogle Scholar | 18432184PubMed |
Wollmann, H. A. (1998). Intrauterine growth restriction: definition and etiology. Horm. Res. 49, 1–6.
| Intrauterine growth restriction: definition and etiology.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXlvVejtr4%3D&md5=6f0752d688c68d26c6703148179b7a89CAS | 9730664PubMed |