The interaction of genetic sex and prenatal alcohol exposure on health across the lifespan

Bake, Shameena; Rouzer, Siara K.; Mavuri, Shruti; Miranda, Rajesh C.; Mahnke, Amanda H.

doi:10.1016/j.yfrne.2023.101103

Cited by 4 publications

(2 citation statements)

References 188 publications

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“…Further, males with FASD exhibit larger volume reductions in brain structure than females [63]. However, human studies investigating FASD often do not report sex-specific differences either due to insufficient sample sizes or limited efforts to stratify for sex [64]. This is also true of studies specifically investigating skeletal effects of FASD.…”

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Bourne,

Jayash,

Michels

et al. 2024

Preprint

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Background: 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. Methods: 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 (uCT), 3-point bending, growth plate analyses, and histology. Results: Osteoblasts from male and female PAE mice displayed reduced bone formation, compared to control (less than or equal to 30%). Bglap and Ahsg were upregulated with PAE in both sexes compared to control, whereas Vegfa, Bmp6, Tgfbr1 and Flt1 were downregulated in PAE male osteoblasts only. In 12-week-old mice, uCT 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 tibia 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 was 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. Conclusions: 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.

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Section: Discussionmentioning

confidence: 99%

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Bourne,

Jayash,

Michels

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Modulation of this maternal and foetal environment contributes to sex-specific differences throughout life, thus suggesting that ethanol-sensitive immune and epigenetic factors during development could result in sex disparities in clinical outcomes. However, human studies investigating FASD often do not report sex-specific differences either due to insufficient sample sizes or limited efforts to stratify for sex [71]. This is also true of studies specifically investigating skeletal effects of FASD.…”

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Bourne,

Jayash,

Michels

et al. 2024

Biol Sex Differ

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Background 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. Methods 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. Results 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. Conclusions 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.

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