Toxicogenetics: in search of host susceptibility to environmental toxicants

Alam, Gelareh; Jones, Byron C.

doi:10.3389/fgene.2014.00327

Cited by 10 publications

(9 citation statements)

References 39 publications

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“…A key conclusion that can be reached from the multitude of investigations into the relations between PD and its causes is that the research is made more complex by the multiplicative environmental and genetic factors that are involved. 109,110 Combination of exposure to multiple environmental pollutants also needs to be factored into the multifactorial experimental process.…”

Section: Pq In Animal Tissuesmentioning

confidence: 99%

Multifactorial theory applied to the neurotoxicity of paraquat and paraquat-induced mechanisms of developing Parkinson's disease

Zhang

Thompson

2016

Laboratory Investigation

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Laboratory studies involving repeated exposure to paraquat (PQ) in different animal models can induce many of the pathological features of Parkinson's disease (PD), such as the loss of dopaminergic neurons in the nigrostriatal dopamine system. Epidemiological studies identify an increased risk of developing PD in human populations living in areas where PQ exposure is likely to occur and among workers lacking appropriate protective equipment. The mechanisms involved in developing PD may not be due to any single cause, but rather a multifactorial situation may exist where PQ exposure may cause PD in some circumstances. Multifactorial theory is adopted into this review that includes a number of sub-cellular mechanisms to explain the pathogenesis of PD. The theory is placed into an environmental context of chronic low-dose exposure to PQ that consequently acts as an oxidative stress inducer. Oxidative stress and the metabolic processes of PQ-inducing excitotoxicity, α-synuclein aggregate formation, autophagy, alteration of dopamine catabolism, and inactivation of tyrosine hydroxylase are positioned as causes for the loss of dopaminergic cells. The environmental context and biochemistry of PQ in soils, water, and organisms is also reviewed to identify potential routes that can lead to chronic rates of low-dose exposure that would replicate the type of response that is observed in animal models, epidemiological studies, and other types of laboratory investigations involving PQ exposure. The purpose of this review is to synthesize key relations and summarize hypotheses linking PD to PQ exposure by using the multifactorial approach. Recommendations are given to integrate laboratory methods to the environmental context as a means to improve on experimental design. The multifactorial approach is necessary for conducting valid tests of causal relations, for understanding of potential relations between PD and PQ exposure, and may prevent further delay in solving what has proven to be an evasive etiological problem.

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Section: Pq In Animal Tissuesmentioning

confidence: 99%

Multifactorial theory applied to the neurotoxicity of paraquat and paraquat-induced mechanisms of developing Parkinson's disease

Zhang

Thompson

2016

Laboratory Investigation

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“…that segregate in the family [13]. The strains are appropriate for systems genetics/systems biology analysis [14], genetic mapping and genetic correlations of parameter means, and thus constitute an ideal platform for toxicogenomic research [15]. All data are available at www.genenetwork.org.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness

Jones

Miller

et al. 2020

Brain Sciences

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Between 25% and 30% of the nearly one million military personnel who participated in the 1991 Persian Gulf War became ill with chronic symptoms ranging from gastrointestinal to nervous system dysfunction. This disorder is now referred to as Gulf War Illness (GWI) and the underlying pathophysiology has been linked to exposure-based neuroinflammation caused by organophosphorous (OP) compounds coupled with high circulating glucocorticoids. In a mouse model of GWI we developed, corticosterone was shown to act synergistically with an OP (diisopropylflurophosphate) to dramatically increase proinflammatory cytokine gene expression in the brain. Because not all Gulf War participants became sick, the question arises as to whether differential genetic constitution might underlie individual differences in susceptibility. To address this question of genetic liability, we tested the impact of OP and glucocorticoid exposure in a genetic reference population of 30 inbred mouse strains. We also studied both sexes. The results showed wide differences among strains and overall that females were less sensitive to the combined treatment than males. Furthermore, we identified one OP-glucocorticoid locus and nominated a candidate gene—Spon1—that may underlie the marked differences in response.

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“…that segregate in the family [10]. The strains are appropriate for systems genetics/systems biology analysis [11], genetic mapping and genetic correlations of parameter means, and thus constitute an ideal platform for toxicogenomic research [12]. All data are available at no cost from www.genenetwork.org.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness

Jones

Miller

et al. 2020

Preprint

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Between 25 and 30% of the nearly one million military personnel who participated in the 1991 Persian Gulf War became ill with chronic symptoms ranging from gastrointestinal to nervous system dysfunction. This disorder is now referred to as Gulf War Illness (GWI) and the underlying pathophysiology has been linked to exposure-based neuroinflammation caused by organophosphorous (OP) compounds coupled with high circulating glucocorticoids. In a mouse model of GWI we developed, corticosterone was shown to act synergistically with an OP (diisopropylflurophosphate) to dramatically increase proinflammatory cytokine gene expression in the brain. Because not all Gulf War participants became sick, the question arises as to whether differential genetic constitution might underlie individual differences in susceptibility. To address this question of genetic liability, we tested the impact of OP and glucocorticoid exposure in a genetic reference population of 30 inbred mouse strains. We also studied both sexes. The results showed wide differences among strains and overall that females were less sensitive to the combined treatment than males. Furthermore, we identified one OP-glucocorticoid locus and nominated a candidate gene—Spon1—that may underlie the marked differences in response.

show abstract

Toxicogenetics: in search of host susceptibility to environmental toxicants

Cited by 10 publications

References 39 publications

Multifactorial theory applied to the neurotoxicity of paraquat and paraquat-induced mechanisms of developing Parkinson's disease

Multifactorial theory applied to the neurotoxicity of paraquat and paraquat-induced mechanisms of developing Parkinson's disease

Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness

Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness

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