Prenatal Exposure to Benzophenone-3 Associated with Hirschsprung’s Disease

by | Sep 3, 2019 | 2016, Environmental Health, Infant and Children's Health, Pregnancy and Lactation, Women's Health

Written by Angeline A. De Leon, Staff Writer. Maternal exposure to benzophenone-3 (even at low levels not typically associated with cytotoxic effects) during a critical time period of embryo neural development increases the probability of Hirschsprung’s disease in offspring.

Hirschsprung’s Disease (HSCR), a rare congenital condition involving the absence of nerve cells in the muscles of the large intestine, is characterized by serious bowel distention [toxic mega colon], bowel obstruction, chronic constipation as well as bowel perforation. constipation 1. While studies indicate that HSCR is commonly associated with the genetic mutation of receptor tyrosine kinase (RET, involved in signal transduction pathways in cell-to-cell communication) 2,3, the environmental risk factors for HSCR are still under study. Benzophenone-3 (BP-3), an organic compound used in the formulation of cosmetic products and enamels, is commonly used as an ultraviolet filter in sunscreen products 4 and has received attention for its association with abnormal embryo development and adverse birth outcomes 5-7. Exposure to BP-3 is alarmingly high, with one study reporting the presence of BP-3 in over 95% of urine samples collected across the general U.S. 8. Given that HSCR involves the abnormal migration of ganglion cells to the distal colon during early gestation 9, it is possible that maternal exposure to compounds like BP-3, which possess endocrine disrupting effects 10, may influence risk of HSCR in infants. In a 2016 study published in Chemosphere, investigators looked at the relationship between maternal concentrations of BP-3 and incidence of HSCR in offspring.

A total of 101 mothers of HSCR patients (mean age = 28.88 years) and 322 control mothers (mean age = 27.48 years) were enrolled in a population-based case-control study. Spot urine samples of participants were collected and analyzed for total urinary concentrations of phenols using ultra-high performance liquid chromatography. An additional in vitro study was also conducted using human 293T and SH-SYS5Y cells, which were treated with BP-3 (0.1 µM, 1 µM, 10 µM, 100 µM, and 1000 µM) and compared to control cells (exposed to 0.1% DMSO). Flow cytometric analyses was employed to quantify cell cycle and cell apoptosis, and a cell transwell assay was conducted to determine cell migration.

Testing showed that BP-3 was present in over 50% of the urinary samples taken from the 423 participants. Compared to women with the lowest BP-3 exposure (50th percentile with BP-3 concentration of 0.08 mL-1), women with median and high levels of BP-3 exposure (95th percentile with BP-3 concentration of 400.72 mL-1) had a higher probability of having HSCR offspring (adjusted Odds Ratios = 2.39 and 2.61, respectively; 95% Confidence Intervals: 1.10 to 5.21 and 1.15 to 5.92, respectively; p-value for trend < 0.05). In vitro findings indicated a significant decrease in cell viability after exposure to 1000 µM of BP-3 and significantly lower number of migrated cells in the 100 µM group (p < 0.001), indicative of the abnormal migration pattern associated with HSCR. Additional analysis of mRNA expression revealed that BP-3-treated  293T and SH-SYS5Y cells had significant decreases in RET mRNA expressions starting at the 100 µM dose (p < 0.05 for both cell lines).

In line with researchers’ hypothesis regarding the link between BP-3 exposure in mothers and HSCR in offspring, findings confirm that maternal exposure to BP-3 (even at low levels not typically associated with cytotoxic effects) during a critical time period of embryo neural development increases the probability of HSCR incidence. BP-3 may, therefore, be considered an environmental risk factor for HSCR. Data from the study further suggests that the potential mechanism involved in the pathogenesis of HSCR may relate to suppressed cell migration and alteration of RET expression, critical observations which deserve further investigation. A potential limitation to consider in the present study relates to its use of a case-control design which precludes causal conclusions. It would also be important in future investigations to account for other environmental factors (e.g., other forms of chemical exposure) that might contribute to the potential development of HSCR.

Source: Huo W, Cai P, Chen M, et al. The relationship between prenatal exposure to BP-3 and Hirschsprung’s disease. Chemosphere. 2016; 144: 1091-1097. DOI: 10.1016/j.chemosphere.2015.09.109

© 2015 Elsevier Ltd. All rights reserved.

 Posted September 3, 2019.

Angeline A. De Leon, MA, graduated from the University of Illinois at Urbana-Champaign in 2010, completing a bachelor’s degree in psychology, with a concentration in neuroscience. She received her master’s degree from The Ohio State University in 2013, where she studied clinical neuroscience within an integrative health program. Her specialized area of research involves the complementary use of neuroimaging and neuropsychology-based methodologies to examine how lifestyle factors, such as physical activity and meditation, can influence brain plasticity and enhance overall connectivity.

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