Neonatal estrogen exposure results in biphasic age-dependent effects on the skeletal development of male mice
Kara J Connelly1, Emily A Larson, Daniel L Marks
1Department of Pediatrics (K.J.C., D.L.M.), Division of Pediatric Endocrinology, Oregon Health and Science University Doernbecher Children's Hospital, Portland, Oregon 97239; Bone and Mineral Research Unit (E.A.L., R.F.K.), Department of Medicine, Oregon Health and Science University, Portland, Oregon 97239; Pape Pediatric Research Institute (D.L.M.), Oregon Health and Science University, Portland, Oregon 97239; and Portland Veterans Affairs Medical Center (R.F.K.), Portland, Oregon 97239.
Insights
Neonatal estrogen exposure in mice impacts adult bone health. Early estrogen exposure in males leads to reduced skeletal integrity and increased fracture risk by adulthood.
Area of Science:
- Endocrinology
- Skeletal Biology
- Developmental Biology
Background:
- Peak bone mass is crucial for preventing fractures later in life.
- Hormonal influences, including gonadal hormones and growth factors, significantly impact bone development.
- Neonatal hormonal exposure can have long-lasting effects on skeletal maturation.
Purpose of the Study:
- To investigate the effects of brief neonatal estrogen exposure on growth and skeletal development in mice.
- To determine the long-term consequences of early estrogen exposure on bone structure and strength.
Main Methods:
- C57BL/6J mice received a single neonatal injection of estradiol or vehicle.
- Growth parameters were monitored, and skeletal phenotyping was conducted at various ages (4 and 16 weeks in males, 16 weeks in females).
- Measurements included femoral length, body weight, bone mineral density, cortical volume, and bone strength.
Main Results:
- Neonatal estrogen exposure reduced adult femoral length in both sexes.
- In males, early estrogen exposure led to increased bone density and cortical thickness prepubertally, but these effects reversed by adulthood, resulting in lower bone density and reduced skeletal integrity.
- Estrogen-exposed adult males showed reduced testicular volume and lower circulating IGF-I levels.
Conclusions:
- Neonatal estrogen exposure induces age-dependent changes in male skeletal development.
- While prepubertal males show enhanced bone acquisition, adult males exhibit compromised skeletal integrity and increased fracture susceptibility.
- Early-life estrogen exposure can disrupt normal skeletal development and hormonal balance, impacting long-term bone health.
Abstract:
Peak bone mass, one of the most important predictors for fracture risk later in life, is attained during puberty and adolescence and influenced by neonatal and pubertal sex-specific gonadal hormones and GH-IGF-I secretion patterns. This study examined the effects of brief neonatal estrogen (NE) exposure on growth and skeletal development in C57BL/6J mice. A single injection of 100-μg estradiol or vehicle was administered on the first day of life. Growth parameters were monitored and skeletal phenotyping performed at 16 weeks in female mice and at 4 and 16 weeks in male mice. NE exposure negatively impacted adult femoral length in both sexes, but adult body weight, areal bone density, and bone strength in female mice were unaffected. In contrast, somatic growth was attenuated in estrogen-exposed male mice throughout the study period. At the prepubertal time point, the estrogen-exposed males exhibited higher bone mineral density, cortical volume, and cortical thickness compared with controls. However, by the time of peak bone mass acquisition, the early skeletal findings had reversed; estrogen-exposed mice had lower bone density with reduced cross-sectional area, cortical volume, and cortical thickness, resulting in cortical bones that were less resistant to fracture. NE exposure also resulted in reduced testicular volume and lower circulating IGF-I. Male mice exposed to estrogen on the first day of life experience age-dependent changes in skeletal development. Prepubertal animals experience greater endocortical bone acquisition as a result of estrogen exposure. However, by adulthood, continued developmental changes result in overall reduced skeletal integrity.
