Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies

Anteneh Assefa Desalegn; Wietske van der Ent; Virissa Lenters; Nina Iszatt; Hein Stigum; Jan Ludvig Lyche; Vidar Berg; Karolina J Kirstein-Smardzewska; Camila Vicencio Esguerra; Merete Eggesbø

doi:10.1016/j.envint.2023.108271

Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies

Anteneh Assefa Desalegn
, Wietske van der Ent
, Virissa Lenters
, Nina Iszatt
, Hein Stigum
, Jan Ludvig Lyche
, Vidar Berg
, Karolina J Kirstein-Smardzewska
, Camila Vicencio Esguerra
, Merete Eggesbø

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

BACKGROUND: The etiology of autism spectrum disorder (ASD) is multifactorial, involving genetic and environmental contributors such as endocrine-disrupting chemicals (EDCs).

OBJECTIVE: To evaluate the association between perinatal exposure to 27 potential EDCs and ASD among Norwegian children, and to further examine the neurodevelopmental toxicity of associated chemicals using zebrafish embryos and larvae.

METHOD: 1,199 mothers enrolled in the prospective birth-cohort (HUMIS, 2002-2009) study. Breastmilk levels of 27 chemicals were measured: polychlorinated biphenyls, organochlorine pesticides, polybrominated diphenyl ethers, and perfluoroalkyl substances as a proxy for perinatal exposure. We employed multivariable logistic regression to determine association, utilized elastic net logistic regression as variable selection method, and conducted an in vivo study with zebrafish larvae to confirm the neurodevelopmental effect.

RESULTS: A total of 20 children had specialist confirmed diagnosis of autism among 1,199 mother-child pairs in this study. β-Hexachlorocyclohexane (β-HCH) was the only chemical associated with ASD, after adjusting for 26 other chemicals. Mothers with the highest levels of β-HCH in their milk had a significant increased risk of having a child with ASD (OR = 1.82, 95 % CI: 1.20, 2.77 for an interquartile range increase in ln-transformed β-HCH concentration). The median concentration of β-HCH in breast milk was 4.37 ng/g lipid (interquartile range: 2.92-6.47), and the estimated daily intake (EDI) for Norwegian children through breastfeeding was 0.03 µg/kg of body weight. The neurodevelopmental and social behavioral effects of β-HCH were established in zebrafish embryos and larvae across various concentrations, with further analysis suggesting that perturbation of dopaminergic neuron development may underlie the neurotoxicity associated with β-HCH.

CONCLUSIONS: Prenatal exposure to β-HCH was associated with an increased risk of specialist-confirmed diagnoses of ASD among Norwegian children, and the EDI surpasses the established threshold. Zebrafish experiments confirm β-HCH neurotoxicity, suggesting dopaminergic neuron disruption as a potential underlying mechanism.

Original language	English
Article number	108271
Pages (from-to)	108271
Journal	Environment International
Volume	181
DOIs	https://doi.org/10.1016/j.envint.2023.108271
Publication status	Published - Nov 2023

Bibliographical note

Funding

This work was funded in part by the Research Council of Norway, NEVRINOR, Norway [grant agreement no. 226402 ]; the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie [grant agreement No. 722634 ]; the Czech Ministry of Education, Youth, and Sports, Czech [ LM2011028 ]; ERA-NET cofund scheme [Project No.: 284365 ]; and the MSCA − COFUND-FP scheme [ EU 801133 - Scientia Fellows II ] . We are grateful to all HUMIS cohort participants. Funding, This work was funded in part by the Research Council of Norway, NEVRINOR, Norway [grant agreement no. 226402]; the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie [grant agreement No. 722634]; the Czech Ministry of Education, Youth, and Sports, Czech [LM2011028]; ERA-NET cofund scheme [Project No.: 284365]; and the MSCA − COFUND-FP scheme [EU 801133 - Scientia Fellows II]. Role of the Funder/Sponsor, The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Access to Data, Dr. Merete Eggesbø had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data Sharing Statement, The consent given by the participants does not allow for storage of data on an individual level in repositories or journals. Researchers who want access to datasets for replication should submit an application to ([email protected]). Access to datasets requires approval from the Regional Committee for Medical and Health Research Ethics in Norway.

Funders	Funder number
Czech Ministry of Education, Youth, and Sports, Czech	LM2011028, 284365
Funder/Sponsor
NEVRINOR	226402
Horizon 2020 Framework Programme
H2020 Marie Skłodowska-Curie Actions	EU 801133, 722634
Norges forskningsråd
Horizon 2020

Keywords

Pregnancy
Female
Animals
Humans
Zebrafish
Endocrine Disruptors/toxicity
Prospective Studies
Autism Spectrum Disorder/chemically induced
Environmental Pollutants/toxicity
Birth Cohort
Norway/epidemiology

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10.1016/j.envint.2023.108271

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Desalegn, A. A., van der Ent, W., Lenters, V., Iszatt, N., Stigum, H., Lyche, J. L., Berg, V., Kirstein-Smardzewska, K. J., Esguerra, C. V., & Eggesbø, M. (2023). Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies. Environment International, 181, 108271. Article 108271. https://doi.org/10.1016/j.envint.2023.108271

@article{fefb319949fc4fc5ab0ac9ce126cb9f5,

title = "Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies",

abstract = "BACKGROUND: The etiology of autism spectrum disorder (ASD) is multifactorial, involving genetic and environmental contributors such as endocrine-disrupting chemicals (EDCs).OBJECTIVE: To evaluate the association between perinatal exposure to 27 potential EDCs and ASD among Norwegian children, and to further examine the neurodevelopmental toxicity of associated chemicals using zebrafish embryos and larvae.METHOD: 1,199 mothers enrolled in the prospective birth-cohort (HUMIS, 2002-2009) study. Breastmilk levels of 27 chemicals were measured: polychlorinated biphenyls, organochlorine pesticides, polybrominated diphenyl ethers, and perfluoroalkyl substances as a proxy for perinatal exposure. We employed multivariable logistic regression to determine association, utilized elastic net logistic regression as variable selection method, and conducted an in vivo study with zebrafish larvae to confirm the neurodevelopmental effect.RESULTS: A total of 20 children had specialist confirmed diagnosis of autism among 1,199 mother-child pairs in this study. β-Hexachlorocyclohexane (β-HCH) was the only chemical associated with ASD, after adjusting for 26 other chemicals. Mothers with the highest levels of β-HCH in their milk had a significant increased risk of having a child with ASD (OR = 1.82, 95 \% CI: 1.20, 2.77 for an interquartile range increase in ln-transformed β-HCH concentration). The median concentration of β-HCH in breast milk was 4.37 ng/g lipid (interquartile range: 2.92-6.47), and the estimated daily intake (EDI) for Norwegian children through breastfeeding was 0.03 µg/kg of body weight. The neurodevelopmental and social behavioral effects of β-HCH were established in zebrafish embryos and larvae across various concentrations, with further analysis suggesting that perturbation of dopaminergic neuron development may underlie the neurotoxicity associated with β-HCH.CONCLUSIONS: Prenatal exposure to β-HCH was associated with an increased risk of specialist-confirmed diagnoses of ASD among Norwegian children, and the EDI surpasses the established threshold. Zebrafish experiments confirm β-HCH neurotoxicity, suggesting dopaminergic neuron disruption as a potential underlying mechanism.",

keywords = "Pregnancy, Female, Animals, Humans, Zebrafish, Endocrine Disruptors/toxicity, Prospective Studies, Autism Spectrum Disorder/chemically induced, Environmental Pollutants/toxicity, Birth Cohort, Norway/epidemiology",

author = "Desalegn, \{Anteneh Assefa\} and \{van der Ent\}, Wietske and Virissa Lenters and Nina Iszatt and Hein Stigum and Lyche, \{Jan Ludvig\} and Vidar Berg and Kirstein-Smardzewska, \{Karolina J\} and Esguerra, \{Camila Vicencio\} and Merete Eggesb{\o}",

year = "2023",

month = nov,

doi = "10.1016/j.envint.2023.108271",

language = "English",

volume = "181",

pages = "108271",

journal = "Environment International",

issn = "0160-4120",

publisher = "Elsevier Ltd",

}

Desalegn, AA, van der Ent, W, Lenters, V, Iszatt, N, Stigum, H, Lyche, JL, Berg, V, Kirstein-Smardzewska, KJ, Esguerra, CV & Eggesbø, M 2023, 'Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies', Environment International, vol. 181, 108271, pp. 108271. https://doi.org/10.1016/j.envint.2023.108271

TY - JOUR

T1 - Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder

T2 - From Norwegian birth cohort to zebrafish studies

AU - Desalegn, Anteneh Assefa

AU - van der Ent, Wietske

AU - Lenters, Virissa

AU - Iszatt, Nina

AU - Stigum, Hein

AU - Lyche, Jan Ludvig

AU - Berg, Vidar

AU - Kirstein-Smardzewska, Karolina J

AU - Esguerra, Camila Vicencio

AU - Eggesbø, Merete

PY - 2023/11

Y1 - 2023/11

N2 - BACKGROUND: The etiology of autism spectrum disorder (ASD) is multifactorial, involving genetic and environmental contributors such as endocrine-disrupting chemicals (EDCs).OBJECTIVE: To evaluate the association between perinatal exposure to 27 potential EDCs and ASD among Norwegian children, and to further examine the neurodevelopmental toxicity of associated chemicals using zebrafish embryos and larvae.METHOD: 1,199 mothers enrolled in the prospective birth-cohort (HUMIS, 2002-2009) study. Breastmilk levels of 27 chemicals were measured: polychlorinated biphenyls, organochlorine pesticides, polybrominated diphenyl ethers, and perfluoroalkyl substances as a proxy for perinatal exposure. We employed multivariable logistic regression to determine association, utilized elastic net logistic regression as variable selection method, and conducted an in vivo study with zebrafish larvae to confirm the neurodevelopmental effect.RESULTS: A total of 20 children had specialist confirmed diagnosis of autism among 1,199 mother-child pairs in this study. β-Hexachlorocyclohexane (β-HCH) was the only chemical associated with ASD, after adjusting for 26 other chemicals. Mothers with the highest levels of β-HCH in their milk had a significant increased risk of having a child with ASD (OR = 1.82, 95 % CI: 1.20, 2.77 for an interquartile range increase in ln-transformed β-HCH concentration). The median concentration of β-HCH in breast milk was 4.37 ng/g lipid (interquartile range: 2.92-6.47), and the estimated daily intake (EDI) for Norwegian children through breastfeeding was 0.03 µg/kg of body weight. The neurodevelopmental and social behavioral effects of β-HCH were established in zebrafish embryos and larvae across various concentrations, with further analysis suggesting that perturbation of dopaminergic neuron development may underlie the neurotoxicity associated with β-HCH.CONCLUSIONS: Prenatal exposure to β-HCH was associated with an increased risk of specialist-confirmed diagnoses of ASD among Norwegian children, and the EDI surpasses the established threshold. Zebrafish experiments confirm β-HCH neurotoxicity, suggesting dopaminergic neuron disruption as a potential underlying mechanism.

AB - BACKGROUND: The etiology of autism spectrum disorder (ASD) is multifactorial, involving genetic and environmental contributors such as endocrine-disrupting chemicals (EDCs).OBJECTIVE: To evaluate the association between perinatal exposure to 27 potential EDCs and ASD among Norwegian children, and to further examine the neurodevelopmental toxicity of associated chemicals using zebrafish embryos and larvae.METHOD: 1,199 mothers enrolled in the prospective birth-cohort (HUMIS, 2002-2009) study. Breastmilk levels of 27 chemicals were measured: polychlorinated biphenyls, organochlorine pesticides, polybrominated diphenyl ethers, and perfluoroalkyl substances as a proxy for perinatal exposure. We employed multivariable logistic regression to determine association, utilized elastic net logistic regression as variable selection method, and conducted an in vivo study with zebrafish larvae to confirm the neurodevelopmental effect.RESULTS: A total of 20 children had specialist confirmed diagnosis of autism among 1,199 mother-child pairs in this study. β-Hexachlorocyclohexane (β-HCH) was the only chemical associated with ASD, after adjusting for 26 other chemicals. Mothers with the highest levels of β-HCH in their milk had a significant increased risk of having a child with ASD (OR = 1.82, 95 % CI: 1.20, 2.77 for an interquartile range increase in ln-transformed β-HCH concentration). The median concentration of β-HCH in breast milk was 4.37 ng/g lipid (interquartile range: 2.92-6.47), and the estimated daily intake (EDI) for Norwegian children through breastfeeding was 0.03 µg/kg of body weight. The neurodevelopmental and social behavioral effects of β-HCH were established in zebrafish embryos and larvae across various concentrations, with further analysis suggesting that perturbation of dopaminergic neuron development may underlie the neurotoxicity associated with β-HCH.CONCLUSIONS: Prenatal exposure to β-HCH was associated with an increased risk of specialist-confirmed diagnoses of ASD among Norwegian children, and the EDI surpasses the established threshold. Zebrafish experiments confirm β-HCH neurotoxicity, suggesting dopaminergic neuron disruption as a potential underlying mechanism.

KW - Pregnancy

KW - Female

KW - Animals

KW - Humans

KW - Zebrafish

KW - Endocrine Disruptors/toxicity

KW - Prospective Studies

KW - Autism Spectrum Disorder/chemically induced

KW - Environmental Pollutants/toxicity

KW - Birth Cohort

KW - Norway/epidemiology

U2 - 10.1016/j.envint.2023.108271

DO - 10.1016/j.envint.2023.108271

M3 - Article

C2 - 37879205

SN - 0160-4120

VL - 181

SP - 108271

JO - Environment International

JF - Environment International

M1 - 108271

ER -

Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Persistent URL (handle)

Fingerprint

Cite this