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AIP Mutation Leads to Significant Alterations in Gene Expression, Altered Sensitivity to AHR Ligands, and Early Lethality in Zebrafish

ABSTRACT: Humans and other organisms are regularly exposed to chemical compounds that elicit toxicity through the aryl hydrocarbon receptor (AHR) signaling pathway. AHR agonists include polycyclic aromatic hydrocarbons, polychlorinated biphenyls, as well as some natural products, pharmaceuticals, and endogenous compounds. Interindividual sensitivity to AHR agonists exists. Several populations of Atlantic Killifish (Fundulus heteroclitus) have independently evolved resistance to high levels of pollution. Genome-wide association demonstrated that variation in the AHR interacting protein (AIP) was associated with resistance to AHR ligands. AIP binds to the AHR in the cytosol where it plays a role in stability and nuclear localization, however its exact function is poorly understood. Aip mutant zebrafish (Danio rerio) lines were generated using CRISPR-Cas9 technology. Deletions were generated in exon 2 (aipwh86) or exon 5 (aipwh239), both resulting in an early stop codon. Zebrafish homozygous for either mutation died at 7–10-days post-fertilization (dpf). No such effect was observed in ahr mutant lines. Larvae from the aipwh239 line were exposed to four toxic AHR ligands from diverse chemical classes. Homozygous mutant larvae exposed to PCB126, 5-nitroacenaphthene, and benzo(k)fluoranthene showed reduced sensitivity compared to both heterozygous and wildtype larvae. However, changes in sensitivity were ligand-dependent. In contrast, homozygous larvae demonstrated increased sensitivity to leflunomide. mRNA sequencing was performed at 5 dpf in unexposed larvae from both aip lines. Around one thousand DEGs and alternative splicing products were observed in homozygous mutants from both lines. Gene sets and binding motifs involved in cellular stress, apoptosis, innate immune response, proteolysis, replication, and metabolism were enriched. Our findings highlight the context-dependent nature of Aip in Ahr modulation and the critical roles that Aip plays in regulating cellular homeostasis.

ORGANISM(S): Danio rerio

PROVIDER: GSE328610 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:Humans are exposed to chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) that cause toxicity through activation of the aryl hydrocarbon receptor (AHR). There is inter-individual variation in sensitivity to effects of AHR ligands, but it is not fully explained by variation in the human AHR, suggesting that other components of the AHR pathway are involved in controlling sensitivity. A clue to the genetic mechanisms underlying differential sensitivity to AHR agonists has emerged recently from studies of Atlantic killifish (Fundulus heteroclitus) populations with multi-generational exposure to PCBs, TCDD, and PAHs. Genomic studies of these populations identified the AHR chaperone AHR-interacting protein (AIP/Ara9/XAP2) as the strongest candidate resistance gene. However, the precise role of AIP in the mechanism of resistance is unknown. To understand the role of AIP in the toxicity of dioxin-like compounds and how variation in AIP may affect chemical sensitivity, we CRISPR-Cas9 to generate AIP loss-of-function alleles in killifish and zebrafish (Danio rerio). Homozygous mutant killifish and zebrafish die during larval development, while heterozygous mutants develop normally, survive to adulthood, and reproduce normally. Prior to death, homozygous mutant zebrafish exhibit reduced sensitivity to embryotoxic effects of exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB126) and TCDD. Gene expression profiling of control and PCB126-exposed larvae at 3 days post-fertilization reveals some genes differentially expressed between mutant and wild-type larvae, but the induction of AHR-regulated genes is similar in aip-/-, aip-/+, and aip+/+ larvae. Understanding the role of AIP in controlling sensitivity to AHR agonists in fish models may shed light on the factors that determine differential susceptibility of humans to dioxin-like compounds and on the role of AIP in human disease.

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AIP Mutation Leads to Significant Alterations in Gene Expression, Altered Sensitivity to AHR Ligands, and Early Lethality in Zebrafish

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