Academic journal article Environmental Health Perspectives

Developmental Toxicity Assessment of Piperonyl Butoxide Exposure Targeting Sonic Hedgehog Signaling and Forebrain and Face Morphogenesis in the Mouse: An in Vitro and in Vivo Study

Academic journal article Environmental Health Perspectives

Developmental Toxicity Assessment of Piperonyl Butoxide Exposure Targeting Sonic Hedgehog Signaling and Forebrain and Face Morphogenesis in the Mouse: An in Vitro and in Vivo Study

Article excerpt

Introduction

Piperonyl butoxide (PBO) is a semisynthetic pesticide synergist that inhibits insect cytochrome p450 enzyme activity (U.S. EPA 2006; Scott 1996). Most commonly used in pyrethrin- and pyrethroid-based pesticide formulas, PBO is present in hundreds of products used in agricultural, commercial, and residential settings, including indoor and outdoor foggers and topical medications like lice shampoo. These products typically contain substantially higher concentrations of PBO than the active insecticidal ingredient (U.S. EPA 2006). PBO was one of the top 10 chemical contaminants found in indoor dust sampled from 119 homes in Cape Cod, Massachusetts (Rudel et al. 2003), and was detected in 75% of personal air samples of 230 pregnant women in New York City, New York, who self-identified as either African American or Dominican (Horton et al. 2011). Use of pyrethrin- and pyrethroid-based formulations containing PBO has increased with the decline of organophosphate pesticides, as reviewed in the U.S. Environmental Protection Agency (EPA) Registration Eligibility Decision for PBO (U.S. EPA 2006). Relative to active pesticidal components, the developmental toxicity of PBO has received little research attention.

PBO was recently discovered to inhibit the Sonic hedgehog (Shh) signaling pathway in a study using high-throughput in vitro screening and Shh-responsive cell-based and zebrafish assays (Wang et al. 2012). The Shh pathway is required for multiple aspects of embryonic development, including morphogenesis of the forebrain and midface, as illustrated by major malformations observed in Shh knockout mice (Chiang et al. 1996). Shh pathway inhibition is classically associated with holoprosencephaly (HPE), a congenital condition defined by median forebrain deficiency, typically occurring with characteristic facial dysmorphology, including hypotelorism and midface hypoplasia (Weiss et al. 2018). Mice with homozygous Shh null mutations exhibit severe HPE (Chiang et al. 1996), and SHH mutations have been identified as among the most common human HPE-associated gene mutations (Nanni et al. 1999; Roessler et al. 1996, 2018; Roessler and Muenke 2010). The Shh pathway also appears to be inherently sensitive to small molecule modulation (Chen et al. 2002b; Chen 2016). Well-characterized and structurally diverse pathway antagonists include the plant alkaloid cyclopamine, which was found to cause HPE in livestock, rabbits, and rodents (Keeler 1970, 1975, 1978), and the U.S. Federal Drug Administration (FDA)-approved drug vismodegib, which was shown to cause HPE in mice (Heyne et al. 2015a, 2016).

Human HPE is an etiologically heterogeneous condition associated with significant morbidity. Although occurring in approximately 1 in 10,000 live births (Leoncini et al. 2008), HPE was estimated to have a prevalence of 1 in 250 conceptuses (Matsunaga and Shiota 1977). These observations suggest that HPE is one of the most common human developmental abnormalities, but the vast majority of affected embryos do not survive to birth. In surviving patients, HPE can cause severe intellectual disability and learning, behavior, and motor impairment (Levey et al. 2010; Weiss et al. 2018).

HPE is thought to arise from complex gene-environment interactions (Graham and Shaw 2005; Hong and Krauss 2018; Krauss and Hong 2016; Lovely et al. 2017; Petryk et al. 2015; Roessler et al. 2003, 2018). Most single-gene mutations linked to HPE pathogenesis have been found to be heterozygous and associated with highly variable phenotypic outcomes (Roessler and Muenke 2010). Only 25% of patients with nonchromosomal HPE have been found to have mutations in one of the four most common HPE genes (Roessler and Muenke 2010), and documented examples of clear gene-gene interactions have been exceedingly rare in humans (Roessler et al. 2018). Therefore, the environmental contribution to HPE etiology is likely substantial. However, relative to genetic factors, examination of environmental influences in the complex etiology of HPE has been largely neglected. …

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