Distinct genotype-dependent differences in transcriptome responses in humans exposed to environmental carcinogens

Espín-Pérez, Almudena; Kok, Theo M. C. M. de; Jennen, Danyel; Hendrickx, Diana M.; Coster, Sam De; Schoeters, Greet; Baeyens, Willy; Larebeke, N. Van; Kleinjans, Jos

doi:10.1093/carcin/bgv111

Cited by 13 publications

(16 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Per subject we calculated a Z-Score (POPs) as a representative of the internal exposure to the mixture of POPs. The Z-Score (POPs ) was defined as the sum of the Z-Scores for each compound: Z-Score (compound) = (X − μ)/σ (where X represents the value of the subject, μ the mean and σ the standard deviation of the population) 42 . Therefore, Z-Score (POPs) = Z-Score (PCB118) + Z-Score (PCB153) + Z-Score (PCB138) + Z-Score (PCB156) + Z-Score (PCB170) + Z-Score (PCB180) + Z-Score (HCB) + Z-Score (DDE) .…”

Section: Methodsmentioning

confidence: 99%

MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery

Krauskopf

Kok

Hebels

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Persistent organic pollutants (POPs) are synthetic chemical substances that accumulate in our environment. POPs such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane (DDT) have been classified as carcinogenic to humans and animals. Due to their resistance to biodegradation humans are still exposed to these compounds worldwide. We aim to evaluate the miRNA and transcriptomic response of a human population exposed to POPs. The miRNA and transcriptomic response was measured in blood of healthy subjects by microarray technology and associated with the serum concentrations of six PCB congeners, DDE (a common DDT metabolite), and HCB. A total of 93 miRNA levels appeared significantly associated with the POP-exposure (FDR < 0.05). The miRNA profile includes four tumor suppressor miRNAs, namely miR-193a-3p, miR-152, miR-31-5p and miR-34a-5p. Integration of the miRNA profile with the transcriptome profile suggests an interaction with oncogenes such as MYC, CCND1, BCL2 and VEGFA. We have shown that exposure to POPs is associated with human miRNA and transcriptomic responses. The identified miRNAs and target genes are related to various types of cancer and involved in relevant signaling pathways like wnt and p53. Therefore, these miRNAs may have great potential to contribute to biomarker-based environmental health risk assessment.

show abstract

Section: Methodsmentioning

confidence: 99%

MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery

Krauskopf

Kok

Hebels

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…15, 57 A recent clinical study testing the impact of environmental carcinogens on gene expression differences in humans found ADI1 as a gene having a direct link to cancer development. 58 An N-terminal truncated variant of HsARD called SipL was shown to be implicated in the replication of hepatitis C virus in non-permissive cell lines. At the time of publication of that work, the enzymatic function of the protein was unclear, and so it was identified as SipL (submergence-induced protein like) due to sequence homology with what was later identified as OsARD.…”

Section: Mammalian Ard Homologs and “Moonlighting” Functions Of Armentioning

confidence: 99%

The Metal Drives the Chemistry: Dual Functions of Acireductone Dioxygenase

2017

View full text Add to dashboard Cite

Acireductone dioxygenase (ARD) from the methionine salvage pathway (MSP) is a unique enzyme that exhibits dual chemistry determined solely by the identity of the divalent transition metal ion (Fe2+ or Ni2+) in the active site. The Fe2+ containing isozyme catalyzes the on-pathway reaction using substrates 1,2 dihydroxy-3-keto-5-methylthiopent-1-ene (acireductone) and dioxygen to generate formate and the ketoacid precursor of methionine, 2-keto-4-methylthiobutyrate, whereas the Ni2+ containing isozyme catalyzes an off-pathway shunt with the same substrates, generating methylthiopropionate, carbon monoxide and formate. The dual chemistry of ARD was originally discovered in the bacterium Klebsiella oxytoca, but it has recently been shown that mammalian ARD enzymes (mouse and human) are also capable of catalyzing metal-dependent dual chemistry in vitro. This is particularly interesting since carbon monoxide, one of the products of off-pathway reaction, has been identified as an anti-apoptotic molecule in mammals. In addition, several biochemical and genetic studies have indicated an inhibitory role of human ARD in cancer. This comprehensive review describes the biochemical and structural characterization of the ARD family, the proposed experimental and theoretical approaches to establishing mechanisms for the dual chemistry, insights into the mechanism based on comparison with structurally and functionally similar enzymes and the applications of this research to the field of artificial metalloenzymes and synthetic biology.

show abstract

“…17, 19 A recent study has also shown that the gene ADI1 has a direct link with cancer development. 20 ARD thus has been shown to perform an inhibitory role in tumor progression and cancer.…”

mentioning

confidence: 99%

Metal-Dependent Function of a Mammalian Acireductone Dioxygenase

Deshpande¹,

Wagenpfeil²,

Pochapsky³

et al. 2016

Biochemistry

View full text Add to dashboard Cite

The two acireductone dioxygenase (ARD) isozymes from the methionine salvage pathway of Klebsiella oxytoca are the only known pair of naturally occurring metalloenzymes with distinct chemical and physical properties determined solely by the identity of the divalent transition metal ion (Fe2+ or Ni2+) in the active site. We now show that this dual chemistry can also occur in mammals. ARD from Mus musculus (MmARD) was studied to relate metal ion identity and three-dimensional structure to enzyme function. The iron-containing isozyme catalyzes the cleavage of 1,2-dihydroxy-3-keto-5-(thiomethyl)pent-1-ene (acireductone) by O2 to formate and the ketoacid precursor of methionine, the penultimate step in methionine salvage. The nickel bound form of ARD catalyzes an off-pathway reaction resulting in formate, carbon monoxide (CO) and 5-(thiomethyl) propionate. Recombinant MmARD was expressed and purified to obtain a homogeneous enzyme with a single transition metal ion bound. The Fe2+ bound protein, which shows about ten-fold higher activity than others, catalyzes on-pathway chemistry, whereas the Ni2+, Co2+ or Mn2+ forms exhibit off-pathway chemistry, as has been seen with ARD from Klebsiella. Thermal stability of the isozymes is strongly affected by metal ion identity, with Ni2+ bound MmARD being the most stable followed by Co2+ and Fe2+, and Mn2+-bound ARD being the least stable. Ni2+ and Co2+ bound MmARD were crystallized and the structures of the two proteins found to be similar. Enzyme-ligand complexes provide insight into substrate binding, metal coordination and catalytic mechanism.

show abstract

Distinct genotype-dependent differences in transcriptome responses in humans exposed to environmental carcinogens

Cited by 13 publications

References 48 publications

MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery

MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery

The Metal Drives the Chemistry: Dual Functions of Acireductone Dioxygenase

Metal-Dependent Function of a Mammalian Acireductone Dioxygenase

Contact Info

Product

Resources

About