Abstract
Benzophenones are widely supplemented in personal care products, but little is known about its neurodevelopmental toxicity. The previous epidemiological study discovered a negative correlation between maternal exposure to a benzophenone metabolite 4‐hydroxybenzophenone (4HBP) and child's neurodevelopment, yet the causal relationship and detailed mechanism remain to be defined. Here, it is reported that prenatal, but not postnatal, exposure to environmentally relevant level of 4HBP impairs hippocampus development and causes cognitive dysfunction in offspring mice. Transcriptomic analyses reveal that 4HBP induces the endoplasmic reticulum stress‐induced apoptotic signaling and inflammatory response in hippocampal neural stem cells. Mechanistically, 4HBP exposure activates protein kinase R‐like ER kinase (PERK) signaling, which induces CHOP, inhibits IκB translation, and transactivates p65, thereby promoting inflammation and apoptosis on multiple levels. Importantly, genetic or pharmacological inhibition of PERK pathway significantly attenuates 4HBP‐induced NFκB signaling and neurodevelopmental abnormalities in mice and in a human brain organoid model. The study uncovers the neurodevelopmental toxicity of BP and cautions its exposure during pregnancy.
Highlights
Neural development is a complex process and exquisitelysensitive to environmental insults.[1]
The level of 4HBP in serum, placenta, fetal brain was measured by Mass spectrometry, and compared to the concentrations reported in human studies by us and others.[10b,11b,13] We found that the dose of 1 mg kg–1 day–1 4HBP exposure fell close to environmentally relevant parameters (Figure S1a, Supporting Information), hereafter chose the dosage of 0.1 and 1 mg kg–1 day–1 4HBP for the in vivo experiments in this study
4HBP exposure of the same dosage and duration did not significantly alter the behavioral performance of adult mice (Figure S2a–c, Supporting Information), indicating a selective early-life sensitivity to 4HBP exposure. These results indicate that maternal exposure to 4HBP impairs cognitive development in offspring mice
Summary
Neural development is a complex process and exquisitelysensitive to environmental insults.[1]. Exposure to environmental insults during this period of time may cause inflammatory response in NSCs, resulting in profound and long-lasting adverse effects on neurodevelopment.[3]. We showed that maternal 4HBP exposure inhibited NSCs proliferation, which resulted in neuronal loss, impaired hippocampal development, and cognitive dysfunction in offspring mice. This phenotypic abnormality was not observed in adult mice exposed to the same dosage of 4HBP. De Vos μNEURO Research Excellence Consortium University of Antwerp Wilrijk, Antwerp 2610, Belgium new insight into the mechanistic implications of neurodevelopmental toxicity induced by BPs exposure, and caution the use of BPs-supplemented personal care products during pregnancy
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