Abstract
BackgroundDevelopmental exposure to low doses of the endocrine disruptor bisphenol A (BPA) is known to alter bone tissue in young rodents, although how bone tissue is affected in aged animals is not well known. We have recently shown that low-dose developmental exposure to BPA increases procollagen type I N-terminal propeptide (P1NP) levels, a peptide formed during type 1 collagen synthesis, in plasma of 5-week-old female rat offspring while male offspring showed reduced bone size. ObjectiveTo analyze offspring bone phenotype at 52 weeks of age and clarify whether the BPA-induced increase in P1NP levels at 5 weeks is an early sign of bone marrow fibrosis development. MethodsAs in our 5-week study, pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5 μg/kg BW/day (BPA0.5), which is in the range of human daily exposure, or 50 μg/kg BW/day (BPA50) from gestational day 3.5 until postnatal day 22. Controls were given only vehicle. The offspring were sacrificed at 52 weeks of age. Bone effects were analyzed using peripheral quantitative and micro-computed tomography (microCT), 3-point bending test, plasma markers and histological examination. ResultsCompared to a smaller bone size at 5 weeks, at the age of 52 weeks, femur size in male offspring had been normalized in developmentally BPA-exposed rats. The 52-week-old female offspring showed, like the 5-week-old siblings, higher plasma P1NP levels compared to controls but no general increasing bone growth or strength. However, 2 out of 14 BPA-exposed female offspring bones developed extremely thick cortices later in life, discovered by systematic in vivo microCT scanning during the study. This was not observed in male offspring or in female controls. Biomechanical testing revealed that both doses of developmental BPA exposure reduced femur stiffness only in female offspring. In addition, histological analysis showed an increased number of fibrotic lesions only in the bone marrow of female rat offspring developmentally exposed to BPA. In line with this, plasma markers of inflammation, Tnf (in BPA0.5) and Timp1 (in BPA50) were increased exclusively in female offspring. ConclusionsDevelopmental BPA exposure at an environmentally relevant concentration resulted in female-specific effects on bone as well as on plasma biomarkers of collagen synthesis and inflammation. Even a dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4 μg/kg BW/day, appeared to induce bone stiffness reduction, bone marrow fibrosis and chronic inflammation in female rat offspring later in life.
Highlights
The number of studies describing associations between human disease and exposure to synthetic compounds with endocrine-disrupting properties is mounting (Vandenberg et al, 2009; Rubin, 2011; Gore et al, 2015; Seachrist et al, 2016)
We reported that developmental exposure to bisphenol A (BPA) at doses between 25 and 50,000 μg/kg BW/day had a sexually dimorphic effect on offspring bone tissue on all doses tested except the highest (Lejonklou et al, 2016)
Of the total of 58 femurs examined, extreme values were observed in two of the BPA-exposed female offspring (#605 and #606). These animals had reduced endocortical circumference (ENDO_C, smaller bone marrow volume), and the reduction was more pronounced after BPA50 exposure than after BPA0.5 exposure (Fig. 1A)
Summary
The number of studies describing associations between human disease and exposure to synthetic compounds with endocrine-disrupting properties is mounting (Vandenberg et al, 2009; Rubin, 2011; Gore et al, 2015; Seachrist et al, 2016). We have recently shown that low-dose developmental exposure to BPA increases procollagen type I N-terminal propeptide (P1NP) levels, a peptide formed during type 1 collagen synthesis, in plasma of 5-week-old female rat offspring while male offspring showed reduced bone size. 2 out of 14 BPA-exposed female offspring bones developed extremely thick cortices later in life, discovered by systematic in vivo microCT scanning during the study This was not observed in male offspring or in female controls. Even a dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4 μg/kg BW/ day, appeared to induce bone stiffness reduction, bone marrow fibrosis and chronic inflammation in female rat offspring later in life
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