Prenatal exposure to pesticides and risk for holoprosencephaly: a case-control study

Abstract

Background Pesticide exposure during susceptible windows and at certain doses are linked to numerous birth defects. Early experimental evidence suggests an association between active ingredients in pesticides and holoprosencephaly (HPE), the most common malformation of the forebrain in humans (1 in 250 embryos). No human studies to date have examined the association. This study investigated pesticides during multiple windows of exposure and fetal risk for HPE. It is hypothesized that pre-conception and early pregnancy, the time of brain development in utero, are the most critical windows of exposure. Methods A questionnaire was developed for this retrospective case-control study to estimate household, occupational, and environmental pesticide exposures. Four windows of exposure were considered: preconception, early, mid and late pregnancy. Cases were identified through the National Human Genome Research Institute’s ongoing clinical studies of HPE. Similarly, controls were identified as children with Williams-Beuren syndrome, a genetic syndrome also characterized by congenital malformations, but etiologically unrelated to HPE. We assessed for differences in odds of exposures to pesticides between cases and controls. Results Findings from 91 cases and 56 controls showed an increased risk for HPE with reports of maternal exposure during pregnancy to select pesticides including personal insect repellants (adjusted odds ratio (aOR) 2.89, confidence interval (CI): 0.96–9.50) and insecticides and acaricides for pets (aOR 3.84, CI:1.04–16.32). Exposure to household pest control products during the preconception period or during pregnancy was associated with increased risk for HPE (aOR 2.60, OR: 0.84–8.68). No associations were found for occupational exposures to pesticides during pregnancy (aOR: 1.15, CI: 0.11–11.42), although exposure rates were low. Higher likelihood for HPE was also observed with residency next to an agricultural field (aOR 3.24, CI: 0.94–12.31). Conclusions Observational findings are consistent with experimental evidence and suggest that exposure to personal, household, and agricultural pesticides during pregnancy may increase risk for HPE. Further investigations of gene by environment interactions are warranted.

Identifying environmental risk factors and gene–environment interactions in holoprosencephaly

“…Like many other birth defects (Zhu, Kartiko, & Finnell, 2009), the etiology of HPE is heterogeneous with complex interactions between genetic aberrations and nongenetic exposures (Addissie et al, 2020; Bendavid et al, 2010; Grinblat & Lipinski, 2019; Hong & Krauss, 2018; Krauss & Hong, 2016). The genetic etiology of HPE includes structural chromosomal anomalies (Kruszka, Martinez, & Muenke, 2018; Solomon, Gropman, & Muenke, 2013), monogenic syndromes in which HPE is a feature (Kruszka & Muenke, 2018), and isolated (nonsyndromic, nonchromosomal) cases in which HPE is the only finding (Hughes et al, 2020; Kruszka, Berger, Casa, et al, 2019; Kruszka, Berger, Weiss, Everson, Martinez, Hong, Anyane‐Yeboa, et al, 2019; Kruszka, Martinez, & Muenke, 2018).…”

“…Environmental factors in this context are considered anything that is not genetic in origin. Previously identified risk factors in humans studies include maternal diabetes mellitus, maternal sexually transmitted infections, use of assisted reproductive technologies, twinning, female sex, thyroid hormone use, and pesticide exposures (Addissie et al, 2020; Johnson & Rasmussen, 2010; Summers, Reefhuis, Taliano, & Rasmussen, 2018). Other risk factors have been associated with HPE in animal studies, while their significance in humans has not been strongly supported due to inconsistent or lacking evidence (Everson et al, 2019; Johnson & Rasmussen, 2010; Solomon et al, 2013; Summers et al, 2018).…”

Cdon mutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly

“…The etiology of HPE is complex, involving both genetic and environmental risk factors ( Addissie et al, 2020 ; Dubourg et al, 2018 ; Hong and Krauss, 2018 ; Johnson and Rasmussen, 2010 ; Krauss, 2007 ; National Birth Defects Prevention Study et al, 2010 ; Muenke and Beachy, 2001 ; NISC Comparative Sequencing Program et al, 2018 ; Roessler et al, 2018 ; Summers et al, 2018 ). Heterozygous, loss-of-function mutations in components or regulators of the HH, Nodal, and FGF signaling pathways are associated with HPE ( NISC Comparative Sequencing Program et al, 2018 ; Roessler et al, 2018 ).…”

“…Heterozygous, loss-of-function mutations in components or regulators of the HH, Nodal, and FGF signaling pathways are associated with HPE ( NISC Comparative Sequencing Program et al, 2018 ; Roessler et al, 2018 ). Epidemiology of HPE is less advanced than genetic analyses, but among the environmental risk factors implicated is fetal alcohol exposure ( Abe et al, 2018 ; Cohen and Shiota, 2002 ; Croen et al, 2000 ), though this is not always observed ( Addissie et al, 2020 ). A full range of clinical phenotypes is seen in both sporadic and familial HPE ( Muenke and Beachy, 2001 ; Solomon et al, 2010 ).…”

Multifactorial Genetic and Environmental Hedgehog Pathway Disruption Sensitizes Embryos to Alcohol‐Induced Craniofacial Defects

“…Inhibition of the pathway can cause specific brain and face malformations, depending on the developmental stage in which signaling is perturbed (Abramyan, 2019; Chiang et al, 1996; Heyne et al, 2015; Lipinski et al, 2010; Zhang et al, 2006). These defects include holoprosencephaly (HPE), a malformation that is also associated with PAE (Addissie et al, 2020; Cohen, 2006). Studies in mice demonstrate that a gastrulation‐stage ethanol exposure can cause HPE (Hong and Krauss, 2017; Sulik, 1984).…”