Previous studies showed that chondrodysplasia has intrauterine origin. Although prenatal acetaminophen exposure (PAcE) can cause nervous and reproductive abnormalities in offspring, its effect on cartilage is uninvestigated. Herein, mice were treated with different doses and courses of acetaminophen at various gestational stages (100 or 400 mg/kg∙d on gestational days 10-12 (GD10-12), 400 mg/kg∙d on GD12 or GD15-17) based on clinical administration and conversion between humans and mice. Fetal knee joints were harvested on GD18 to analyze cartilage morphology, chondrocyte proliferation and apoptosis, and matrix content, synthesis and degradation. Results showed that 400 mg/kg∙d acetaminophen exposure during GD10-12 decreased chondrocyte numbers, safranin O staining, proliferation and matrix synthesis, without elevating matrix degradation and apoptosis. Low-dose, single-course, or late-pregnancy exposure had no effect on above indexes. Moreover, Tgfβ pathway was inhibited, showing a positive correlation with the expression of Col2a1, Acan, Ki67, and Pcna. Overall, clinical doses of PAcE can inhibit chondrocyte proliferation and matrix synthesis, causing fetal mice chondrodysplasia, especially after multi-course exposure of 400 mg/kg∙d acetaminophen during GD10-12, the mechanism of which might involve Tgfβ pathway inhibition. This study provides an experimental basis for assessing fetal developmental toxicity and standardizing the clinical use of acetaminophen during pregnancy.
Keywords: Development of articular cartilage; Developmental toxicity; Prenatal acetaminophen exposure; Transforming growth factor beta.
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