Abstract
Bisphenol A (BPA) is a synthetic chemical used for the manufacturing of plastics, epoxy resin, and many personal care products. This ubiquitous endocrine disruptor is detectable in the urine of over 80% of North Americans. Although adverse neurodevelopmental outcomes have been observed in children with high gestational exposure to BPA, the effects of prenatal BPA on brain structure remain unclear. Here, using magnetic resonance imaging (MRI), we studied the associations of maternal BPA exposure with children's brain structure, as well as the impact of comparable BPA levels in a mouse model. Our human data showed that most maternal BPA exposure effects on brain volumes were small, with the largest effects observed in the opercular region of the inferior frontal gyrus (ρ = −0.2754), superior occipital gyrus (ρ = −0.2556), and postcentral gyrus (ρ = 0.2384). In mice, gestational exposure to an equivalent level of BPA (2.25 μg BPA/kg bw/day) induced structural alterations in brain regions including the superior olivary complex (SOC) and bed nucleus of stria terminalis (BNST) with larger effect sizes (1.07≤ Cohens d ≤ 1.53). Human (n = 87) and rodent (n = 8 each group) sample sizes, while small, are considered adequate to perform the primary endpoint analysis. Combined, these human and mouse data suggest that gestational exposure to low levels of BPA may have some impacts on the developing brain at the resolution of MRI.
| Original language | English |
|---|---|
| Article number | 114040 |
| Number of pages | 9 |
| Journal | Environmental Research |
| Volume | 214 |
| DOIs | |
| Publication status | Published - Nov 2022 |
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The effects of prenatal bisphenol A exposure on brain volume of children and young mice. / Zheng, Jing; Reynolds, Jess E.; Long, Madison et al.
In: Environmental Research, Vol. 214, 114040, 11.2022.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - The effects of prenatal bisphenol A exposure on brain volume of children and young mice
AU - Zheng, Jing
AU - Reynolds, Jess E.
AU - Long, Madison
AU - Ostertag, Curtis
AU - Pollock, Tyler
AU - Hamilton, Max
AU - Dunn, Jeff F.
AU - Liu, Jiaying
AU - Martin, Jonathan
AU - Grohs, Melody
AU - Landman, Bennett
AU - Huo, Yuankai
AU - Dewey, Deborah
AU - Kurrasch, Deborah
AU - Lebel, Catherine
N1 - Funding Information: This work was supported by grants from Canadian Institutes of Health Research CIHR (CL: IHD-134090, MOP-136797, MOP-123535) and Natural Sciences and Engineering Research Council of Canada (DK: DG386445), the U.S. National Institutes of Health (Exploration/Development Grant 1R21ES021295-01R21), and the Alberta Children's Hospital Research Institute Foundation (CL). Funding to establish the APrON cohort was provided by a grant from Alberta Innovates-Health Solutions (AIHS) (formally the Alberta Heritage Foundation for Medical Research).The superior olivary complex (SOC) is a collection of brainstem nuclei that support multiple aspects of hearing, and is thought to be the first major site of convergence of auditory information from the left and right ears (Oliver et al., 1995). Deficits in hearing function are included in the spectrum of symptoms associated with ASD (Roper et al., 2003), with significant dysmorphology of SOC nuclei reported in individuals with ASD, such as a decrease in number of neurons and alterations of cell body shape and orientation (Kulesza and Mangunay, 2008; Kulesza et al., 2011). These findings suggest that damage to the SOC contributes to the dysfunction in the auditory system in ASD individuals. Recently, an epidemiological study revealed a positive association between prenatal BPA exposure and ASD risk in children (Stein et al., 2015). Our rodent MRI results also revealed potential decreased volume of the SOC in offspring exposed to BPA in gestation. In addition to studies showing that BPA exposure disrupts otolith formation and hair cell loss in vitro (Gibert et al., 2011; Hayashi et al., 2015), by providing volumetric alterations our results may help link prenatal BPA exposure and symptoms that have been associated with ASD in children. Our animal MRI data also showed that gestational BPA exposure may decrease the volume of the bed nucleus of stria terminalis (BNST), a sexually dimorphic nucleus associated with anxiety in response to threat monitoring (Somerville et al., 2010), which is supported by the evidence that prenatal BPA exposure resulted in increased anxiety in rodents and the facts that higher levels of maternal BPA exposure was associated with more anxiety in children (Ejaredar et al., 2017). Previous studies showed that gestational BPA exposure causes loss of sex differentiation of the locus coeruleus (Kubo et al., 2001) and corticotrophin-releasing hormone neurons in BNST (Funabashi et al., 2004), with gestational BPA exposure having transgenerational effects on ERα protein levels (Goldsby et al., 2017) and gene expression (Henriksen et al., 2020) in BNST. In our follow-up analysis examining sex difference in our animal study, BNST volume was found to be changed by BPA maternal exposure in female but not in male mice. In our human sex difference follow-up analysis, the regions that correlated with maternal BPA levels were different for male (i.e., gyrus rectus, putamen, medial frontal cortex, opercular part of the inferior frontal gyrus) and female (superior occipital gyrus, postcentral gyrus, superior parietal lobule, planum polare, frontal operculum, medial orbital gyrus, transverse temporal gyrus, superior frontal gyrus medial segment) offspring. Thus, our results raise the possibility that the BNST might be a potential target of prenatal BPA exposure, which may contribute to anxiety and changes in sexually dimorphic behaviors.This work was supported by grants from Canadian Institutes of Health Research CIHR (CL: IHD-134090, MOP-136797, MOP-123535) and Natural Sciences and Engineering Research Council of Canada (DK: DG386445), the U.S. National Institutes of Health (Exploration/Development Grant 1R21ES021295-01R21), and the Alberta Children's Hospital Research Institute Foundation (CL). Funding to establish the APrON cohort was provided by a grant from Alberta Innovates-Health Solutions (AIHS) (formally the Alberta Heritage Foundation for Medical Research). We acknowledge salary support from the Owerko Centre (JZ), the NSERC BRAIN CREATE Postdoctoral Fellowship (JZ) and a CIHR Postdoctoral Fellowship (MFE-183073) (JZ). Additional salary support included a University of Calgary Eyes High Postdoctoral award (JER), T. Chen Fong Postdoctoral Fellowship in Medical Imaging Science (JER), and a CIHR Postdoctoral Fellowship (MFE-164703) (JER), an Owerko Fellowship (TP), an Alberta Innovates-Health Solutions scholarship and a Faculty of Medicine and Dentistry University of Alberta Medical Science Graduate Program scholarship (JL) and a University of Calgary Queen Elizabeth-II Graduate Studentship, Vi Riddell Pediatric Rehabilitation Graduate Studentship, Alberta Children's Hospital Research Institute Studentship and an Alberta Children's Hospital Department of Pediatrics Studentship (MNG). We are extremely grateful to all the families who took part in this study and the whole APrON team (http://www.apronstudy.ca/), investigators, research assistants, graduate and undergraduate students, volunteers, clerical staff and mangers. We acknowledge the significant contributions of the APrON Study Team whose individual members are: B.J. Kaplan, C.J. Field, R.C. Bell, F.P. Bernier, M. Cantell, L.M. Casey, M. Eliasziw, A. Farmer, L. Gagnon, G.F. Giesbrecht, L. Goonewardene, D. Johnston, L. Kooistra, N. Letourneau, D.P. Manca, L.J. McCargar, M. O'Beirne, V.J. Pop, A.J. We are grateful to Dr. Tadeusz Foniok and David Rushforth in the Experimental Imaging Centre at University of Calgary who performed the animal MRI experiments. Funding Information: This work was supported by grants from Canadian Institutes of Health Research CIHR (CL: IHD-134090 , MOP-136797 , MOP-123535 ) and Natural Sciences and Engineering Research Council of Canada (DK: DG386445 ), the U.S. National Institutes of Health (Exploration/Development Grant 1R21ES021295-01R21 ), and the Alberta Children's Hospital Research Institute Foundation (CL). Funding to establish the APrON cohort was provided by a grant from Alberta Innovates-Health Solutions ( AIHS ) (formally the Alberta Heritage Foundation for Medical Research ). Funding Information: This work was supported by grants from Canadian Institutes of Health Research CIHR (CL: IHD-134090 , MOP-136797 , MOP-123535 ) and Natural Sciences and Engineering Research Council of Canada (DK: DG386445 ), the U.S. National Institutes of Health (Exploration/Development Grant 1R21ES021295-01R21 ), and the Alberta Children's Hospital Research Institute Foundation (CL). Funding to establish the APrON cohort was provided by a grant from Alberta Innovates-Health Solutions (AIHS) (formally the Alberta Heritage Foundation for Medical Research ). We acknowledge salary support from the Owerko Centre (JZ), the NSERC BRAIN CREATE Postdoctoral Fellowship (JZ) and a CIHR Postdoctoral Fellowship (MFE-183073) (JZ). Additional salary support included a University of Calgary Eyes High Postdoctoral award (JER), T. Chen Fong Postdoctoral Fellowship in Medical Imaging Science (JER), and a CIHR Postdoctoral Fellowship ( MFE-164703 ) (JER), an Owerko Fellowship (TP), an Alberta Innovates-Health Solutions scholarship and a Faculty of Medicine and Dentistry University of Alberta Medical Science Graduate Program scholarship (JL) and a University of Calgary Queen Elizabeth-II Graduate Studentship , Vi Riddell Pediatric Rehabilitation Graduate Studentship , Alberta Children's Hospital Research Institute Studentship and an Alberta Children's Hospital Department of Pediatrics Studentship (MNG). Publisher Copyright: © 2022 Elsevier Inc.
PY - 2022/11
Y1 - 2022/11
N2 - Bisphenol A (BPA) is a synthetic chemical used for the manufacturing of plastics, epoxy resin, and many personal care products. This ubiquitous endocrine disruptor is detectable in the urine of over 80% of North Americans. Although adverse neurodevelopmental outcomes have been observed in children with high gestational exposure to BPA, the effects of prenatal BPA on brain structure remain unclear. Here, using magnetic resonance imaging (MRI), we studied the associations of maternal BPA exposure with children's brain structure, as well as the impact of comparable BPA levels in a mouse model. Our human data showed that most maternal BPA exposure effects on brain volumes were small, with the largest effects observed in the opercular region of the inferior frontal gyrus (ρ = −0.2754), superior occipital gyrus (ρ = −0.2556), and postcentral gyrus (ρ = 0.2384). In mice, gestational exposure to an equivalent level of BPA (2.25 μg BPA/kg bw/day) induced structural alterations in brain regions including the superior olivary complex (SOC) and bed nucleus of stria terminalis (BNST) with larger effect sizes (1.07≤ Cohens d ≤ 1.53). Human (n = 87) and rodent (n = 8 each group) sample sizes, while small, are considered adequate to perform the primary endpoint analysis. Combined, these human and mouse data suggest that gestational exposure to low levels of BPA may have some impacts on the developing brain at the resolution of MRI.
AB - Bisphenol A (BPA) is a synthetic chemical used for the manufacturing of plastics, epoxy resin, and many personal care products. This ubiquitous endocrine disruptor is detectable in the urine of over 80% of North Americans. Although adverse neurodevelopmental outcomes have been observed in children with high gestational exposure to BPA, the effects of prenatal BPA on brain structure remain unclear. Here, using magnetic resonance imaging (MRI), we studied the associations of maternal BPA exposure with children's brain structure, as well as the impact of comparable BPA levels in a mouse model. Our human data showed that most maternal BPA exposure effects on brain volumes were small, with the largest effects observed in the opercular region of the inferior frontal gyrus (ρ = −0.2754), superior occipital gyrus (ρ = −0.2556), and postcentral gyrus (ρ = 0.2384). In mice, gestational exposure to an equivalent level of BPA (2.25 μg BPA/kg bw/day) induced structural alterations in brain regions including the superior olivary complex (SOC) and bed nucleus of stria terminalis (BNST) with larger effect sizes (1.07≤ Cohens d ≤ 1.53). Human (n = 87) and rodent (n = 8 each group) sample sizes, while small, are considered adequate to perform the primary endpoint analysis. Combined, these human and mouse data suggest that gestational exposure to low levels of BPA may have some impacts on the developing brain at the resolution of MRI.
KW - APrON
KW - Bisphenol A
KW - Brain regional volumes
KW - Magnetic resonance imaging
KW - Neurodevelopment
KW - Prenatal exposure
UR - http://www.scopus.com/inward/record.url?scp=85135849731&partnerID=8YFLogxK
U2 - 10.1016/j.envres.2022.114040
DO - 10.1016/j.envres.2022.114040
M3 - Article
C2 - 35952745
AN - SCOPUS:85135849731
VL - 214
JO - Environmental Research
JF - Environmental Research
SN - 0013-9351
M1 - 114040
ER -