Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

• Published in: Biology of sex differences Vol. 15; no. 1; pp. 51 - 19
• Main Authors: Bourne, Lucie E, Jayash, Soher N, Michels, Lysanne V, Hopkinson, Mark, Guppy, Fergus M, Clarkin, Claire E, Gard, Paul, Brissett, Nigel, Staines, Katherine A
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18-06-2024; BioMed Central; BMC
• Subjects: Analysis; Animal cognition; Animal models; Animals; Body weight; Bone; Bone and Bones - drug effects; Bone growth; Cancellous bone; Children; Computed tomography; Cortical bone; CT imaging; Drinking behavior; Drinking water; Effect of alcohol on; Ethanol; Ethanol - pharmacology; Ethanol - toxicity; Ethylenediaminetetraacetic acid; Female; Females; Fetal alcohol syndrome; Fetus; Fractures; Gender differences; Gene expression; Growth plate; Male; Males; Mechanical properties; Mice; Mice, Inbred C57BL; Murine model; Neonates; Offspring; Osteoblasts; Osteoblasts - drug effects; Osteogenesis; Osteogenesis - drug effects; Phenotypes; Phenotyping; Porosity; Pregnancy; Pregnant women; Prenatal alcohol exposure (PAE); Prenatal experience; Prenatal Exposure Delayed Effects; Sex Characteristics; Sex differences; Sexes; Sexual dimorphism; Skeleton; Teenagers; Vascular endothelial growth factor; X-Ray Microtomography; United Kingdom > UK; Prenatal alcohol exposure (PAE); Bone; Sexual dimorphism; Murine model
• ISSN: 2042-6410; 2042-6410
• DOI: 10.1186/s13293-024-00626-y

Prenatal alcohol exposure (PAE) can result in lifelong disabilities known as foetal alcohol spectrum disorder (FASD) and is associated with childhood growth deficiencies and increased bone fracture risk. However, the effects of PAE on the adult skeleton remain unclear and any potential sexual dimorphism is undetermined. Therefore, we utilised a murine model to examine sex differences with PAE on in vitro bone formation, and in the juvenile and adult skeleton.
Pregnant C57BL/6J female mice received 5% ethanol in their drinking water during gestation. Primary calvarial osteoblasts were isolated from neonatal offspring and mineralised bone nodule formation and gene expression assessed. Skeletal phenotyping of 4- and 12-week-old male and female offspring was conducted by micro-computed tomography (µCT), 3-point bending, growth plate analyses, and histology.
Osteoblasts from male and female PAE mice displayed reduced bone formation, compared to control (≤ 30%). Vegfa, Vegfb, Bmp6, Tgfbr1, Flt1 and Ahsg were downregulated in PAE male osteoblasts only, whilst Ahsg was upregulated in PAE females. In 12-week-old mice, µCT analysis revealed a sex and exposure interaction across several trabecular bone parameters. PAE was detrimental to the trabecular compartment in male mice compared to control, yet PAE females were unaffected. Both male and female mice had significant reductions in cortical parameters with PAE. Whilst male mice were negatively affected along the tibial length, females were only distally affected. Posterior cortical porosity was increased in PAE females only. Mechanical testing revealed PAE males had significantly reduced bone stiffness compared to controls; maximum load and yield were reduced in both sexes. PAE had no effect on total body weight or tibial bone length in either sex. However, total growth plate width in male PAE mice compared to control was reduced, whilst female PAE mice were unaffected. 4-week-old mice did not display the altered skeletal phenotype with PAE observed in 12-week-old animals.
Evidence herein suggests, for the first time, that PAE exerts divergent sex effects on the skeleton, possibly influenced by underlying sex-specific transcriptional mechanisms of osteoblasts. Establishing these sex differences will support future policies and clinical management of FASD.