AOP: 569

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Decreased DNA methylation of FAM50B/PTCHD3 leading to IQ loss of children via PI3K-Akt pathway

Short name

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DNA methylation of FAM50B/PTCHD3 and IQ loss of children

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Handbook Version v2.7

Graphical Representation

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Authors

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Cong Wan^{a, b}, Huimin Ma^{a, b*}, Guanghui Dong^c, Xiaowen Zeng^c, Kevin C. Jones^d, Gan Zhang^{a, b}, Zhiqiang Yu^{a, b}, Pingan Peng^{a, b}

^a State Key Laboratory of Advanced Environmental Technology and Guangdong Province Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China;

^bGuangdong-Hong Kong-Macao Joint Laboratory for Environmental Pollution and Control, Guangzhou 510640, China;

^cDepartment of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China;

^dLancaster Environmental Centre, Lancaster University, LA1 4YQ Lancaster, United Kingdom

Point of Contact

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Huimin Ma (email point of contact)

Contributors

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Huimin Ma
Cong Wan

Coaches

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OECD Information Table

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OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on May 22, 2025 11:43

Revision dates for related pages

Page	Revision Date/Time
Decreased DNA methylation of FAM50B/PTCHD3	March 02, 2025 09:26
Elevated gene expression of FAM50B/PTCHD3	March 02, 2025 09:28
Inhibition of PI3K-Akt pathway	March 02, 2025 09:32
Increase, CNS Neural cell death	October 17, 2023 04:07
decreased, Intellectual Quotient	May 29, 2025 12:51
Increase, Reactive oxygen species	June 12, 2025 01:27
FAM50B/PTCHD3 methylation leads to FAM50B/PTCHD3 expression	March 02, 2025 09:37
FAM50B/PTCHD3 methylation leads to decreased, IQ	March 02, 2025 09:41
FAM50B/PTCHD3 expression leads to PI3K-Akt pathway	March 02, 2025 09:38
PI3K-Akt pathway leads to Increase, ROS	May 22, 2025 11:32
Increase, ROS leads to Increase, CNS Neural cell death	May 22, 2025 11:32
Increase, CNS Neural cell death leads to decreased, IQ	March 02, 2025 09:40

Abstract

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Intelligence quotient (IQ) test scores are important endpoints for international agencies interested in protecting the brain health from heavy metal exposure. However, IQ test has been hampered by a lack of efficient tools. At present, IQ test is mainly relied on Wechsler Intelligence Assessment Scale, this method consumes a lot of manpower and material resources, and cannot achieve high throughput assessment. The motivation for developing this adverse outcome pathway (AOP) was to provide new method for IQ assessment by DNA methylation in a high throughput way. In this AOP, the decreased DNA methylation of FAM50B and PTCHD3 induced by heavy metal exposure (such as lead, arsenic, and so on) is the molecular initiating event (MIE) of this AOP. Decreased DNA methylation of FAM50B/PTCHD3 leads to the elevated gene expression of FAM50B/PTCHD3, which is one of the key events (KE) of molecular level. This KE leads to the inhibition of PI3K-Akt pathway, which is another KE of molecular level, leading to increased celluar ROS and cell death (two KEs of cell level). These KEs finally result in the IQ loss of children (the adverse outcome of individual level).

AOP Development Strategy

Context

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Although global lead exposure has significantly declined since the phase-out of leaded gasoline, it remains a pervasive issue, particularly in low- and middle-income countries (Larsen et al., 2023; Li et al., 2014). A report by The Lancet points out that there are still 815 million (One third of global children) children worldwide with blood lead concentrations exceeding 50 μg/L (Burki et al., 2020). DNA methylation is an important bridge to link environmental pollutants and adverse outcomes. FAM50B has relatively high expression in human brain (https://tissues.jensenlab.org). We screened two genes (FAM50B and PTCHD3) that mediated lead exposure and children's IQ and neurodevelopment through multiple epidemiological studies, and FAM50B/PTCHD3 methylation had good quantitative relationships with chidren's IQ and neurodevelopment (Wan et al., 2021; 2024). The identified FAM50B/PTCHD3 DNA methylation biomarkers could aid in developing early diagnostic tools and targeted treatments for neurodevelopmental disorders, as well as in quantitative environmental health risk assessments for heavy metals.

Strategy

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In this study, the concentrations of blood heavy metals such as lead was detected by ICP-MS. Children's IQ was tested by Wechsler and Raven Intelligence Test. Blood DNA was purified to detect genome DNA methylation and screen differentially methylated regions (DMRs). The gene expression of FAM50B/PTCHD3 was determined by RT-PCR. The protein expression of PI3K-Akt pathway was assessed by western-blotting. In addition, cell ROS and apoptosis were detected by flow cytometry. The quantitative relationships between FAM50B/PTCHD3 methylation and children's IQ was constructed by machine learning.

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Type	Event ID	Title	Short name

MIE

2309

Decreased DNA methylation of FAM50B/PTCHD3

FAM50B/PTCHD3 methylation

KE	2310	Elevated gene expression of FAM50B/PTCHD3	FAM50B/PTCHD3 expression
KE	2311	Inhibition of PI3K-Akt pathway	PI3K-Akt pathway
KE	1115	Increase, Reactive oxygen species	Increase, ROS
KE	2195	Increase, CNS Neural cell death	Increase, CNS Neural cell death

2121

decreased, Intellectual Quotient

decreased, IQ

Relationships Between Two Key Events (Including MIEs and AOs)

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Title	Adjacency	Evidence	Quantitative Understanding

FAM50B/PTCHD3 methylation leads to FAM50B/PTCHD3 expression	adjacent	Moderate	Moderate
FAM50B/PTCHD3 expression leads to PI3K-Akt pathway	adjacent	Moderate	Low
PI3K-Akt pathway leads to Increase, ROS	adjacent	Moderate	Low
Increase, ROS leads to Increase, CNS Neural cell death	adjacent	High	Low
Increase, CNS Neural cell death leads to decreased, IQ	adjacent	Moderate	Low

FAM50B/PTCHD3 methylation leads to decreased, IQ

non-adjacent

High

Network View

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Prototypical Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Known Modulating Factors

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Modulating Factor (MF)	Influence or Outcome	KER(s) involved

Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

List of the literature that was cited for this AOP. More help

Larsen, B.; Sánchez-Triana, E. Global health burden and cost of lead exposure in children and adults: a health impact and economic modelling analysis. Lancet Planet Health 2023, 7 (10), e831-e840.

Li, M. M.; Cao, J.; Xu, J.; Cai, S. Z.; Shen, X. M.; Yan, C. H. The national trend of blood lead levels among Chinese children aged 0-18 years old, 1990-2012. Environ Int 2014, 71, 109-117.

Wan, C.; Ma, H.; Liu, J.; Liu, F.; Liu, J.; Dong, G.; Zeng, X.; Li, D.; Yu, Z.; Wang, X.; et al. Quantitative relationships of FAM50B and PTCHD3 methylation with reduced intelligence quotients in school aged children exposed to lead: Evidence from epidemiological and in vitro studies. Sci Total Environ 2024, 907, 167976.

Wan, C.; Pan, S.; Lin, L.; Li, J.; Dong, G.; Jones, K. C.; Liu, F.; Li, D.; Liu, J.; Yu, Z.; et al. DNA Methylation Biomarkers of IQ Reduction are Associated with Long-term Lead Exposure in School Aged Children in Southern China. Environ. Sci. Technol. 2021, 55 (1), 412-422.