Table 1.
Genes, enzymes, and proteins positively (↑) or negatively (↓) affected by dioxin in the anchor models, according to the Comparative Toxicogenomics Database [14].
Fig 1.
Hepatic cholesterol biosynthesis through the mevalonate pathway as one of the anchor models.
The various components of the biosynthetic mevalonate pathway system are color-coded by type, as indicated. Metabolic reactions, transport steps, and the production of mRNAs and proteins are shown as solid lines, while regulatory signals, representing feedback inhibition (red) and modulation of enzyme activity [15], are given as dotted lines; mRNAs whose transcription is affected by dioxin, are indicated by boxes outlined in red. The key transcription factor SREBP binds to sterol regulatory elements (SREs) in the promoter regions of its target genes. It controls the activity of mevalonate pathway via these target genes, among which HMG CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase is considered the rate-limiting step of the pathway, even though control of the pathway is distributed. Adapted from [13].
Fig 2.
Overview of cholesterol metabolism and transport pathways.
The diagram illustrates the processes of organism-wide cholesterol handling, and especially the involvement of the lipoproteins VLDL, IDL, LDL, and HDL, which are responsible for the transport of cholesterol between the liver and the peripheral tissues. The receptor proteins SR-BI and LDL-R, along with enzymes such as LPL and ACAT, are also depicted. The red boxes and arrows indicate the impact of dioxin on specific processes.
Fig 3.
Anchor model of female steroidogenesis, describing the estradiol synthesis pathway, its regulation, and perturbation by dioxin.
Molecules are color-coded by type, as indicated. Solid lines show reactions and transport steps, with the red solid line signifying the 20,22-desmolase reaction (k_Des), which is affected by dioxin. Dashed lines represent feedback regulation (red) from estradiol and progesterone on the synthesis and release of FSH and LH hormones from the pituitary to plasma, exerting control over the development of the antral follicles and the corpus luteum. Key genes are displayed in grey rectangular boxes.
Fig 4.
Template model of dioxin exposure affecting organism-wide cholesterol handling at a systemic level.
Processes affected by dioxin exposure are indicated by red arrows. Adapted from [13].
Fig 5.
The variables correspond to the processes in Fig 4. Specifically, Dietary intake: X0; Cholesterol biosynthesis: X1; Cholesterol storage: X2; Peripheral cholesterol utilization: X3; Plasma transport and conversion of cholesterol: X4; Steroid hormone production: X5; Excretion: X6. The hollow arrows represent the hand-over of cholesterol from one process to another. Each activation arrow (green, dashed) represents a positive effect of the source process on the target process. For example, dietary cholesterol intake leads to increased cholesterol storage. An inhibition arrow (red, dashed, blunted) indicates that the source process affects the target process. For example, dietary intake of cholesterol reduces the rate of cholesterol biosynthesis. Once it is clear that the variables represent processes, the mathematical implementation in BST follows the same guidelines as for a traditional model: The change in the rate of a process is driven by increasing and decreasing influences, and each term describing these influences is modeled as a power-law term containing a rate constant and those variables (processes) that directly affect the term in question, raised to an appropriate power.
Fig 6.
Signals in conventional models and T&A models.
A: In a conventional model, variables modulate fluxes, either through activation or inhibition. B: In a T&A model, variables represent process systems that can directly affect each other.
Fig 7.
Simulation results with the steroidogenesis anchor model.
The output captures the dynamics of gonadotropins (FSH and LH) and steroid hormones (E2 and P4) throughout one menstrual cycle.
Fig 8.
Computational results from the biosynthesis anchor model (adapted from [13]).
Left Panel: The dose-response curve of the effect of dioxin on the biosynthesis rate of hepatic cholesterol is expressed as the percent of remaining activity in comparison with the control. The trendline was matched to fit experimental data (symbols) on mice [60,61]. Right Panel: The model results were formulated as a dose-response relationship characterizing the effect of dioxin on the steady-state amount of hepatic cholesterol.
Fig 9.
Dose-response curves quantifying the effects of increasing dosage of dioxin on hepatic, and plasma LDL, HDL, and total cholesterol concentrations.
Fig 10.
Effect of increased dietary cholesterol intake on LDL, HDL, IDL, VLDL, as well as on hepatic and plasma cholesterol concentrations, according to the model.
Fig 11.
Dose response curves accounting for the effects of dioxin and increased diet on the lipoprotein transport system.
Left: lipoproteins LDL and HDL. Right: Hepatic and plasma cholesterol. 200 mg/ day is the recommended amount of cholesterol in diet/day while 400 mg/day is high and 600 mg/day is considered very high.
Fig 12.
Dynamics of gonadotropins (FSH and LH) and steroid hormones (E2 and P4) throughout the menstrual cycle in a population of individuals.
Grey lines represent the data for 100 individuals. The solid lines denote the average values across these cases, while the dashed lines define the ranges within which 95% of the values lie.
Fig 13.
Effects of varying k_Des activity (i.e., conversion of cholesterol to P5 by 20,22-desmolase) on hormone dynamics based on the standardized menstrual cycle model.
Fig 14.
Population-wide distributions of follicular phase lengths and corresponding dose-response curves.
Top panels: Frequency distributions and corresponding cumulative probabilities describing the relationship between dioxin serum levels (ppt) and follicular phase length. Bottom panel: Dose-response curve for a population, depicting the influence of dioxin serum level on the length of the follicular phase, expressed as the mean ± standard deviation.
Table 2.
Dose-response relationships of the processes versus dioxin dose. Sections highlighted in grey represent simulation-based predictions generated by applying values of the dose-response curve for cholesterol biosynthesis (unshaded; Fig 8) to the entire template model, including hepatic cholesterol storage, peripheral tissue usage, plasma dynamics, and steroid hormone production.
Fig 15.
Dose response curve of dioxin versus cholesterol biosynthesis, according to the template model.
Table 3.
Impact of diet on the various processes of the template model. The sections highlighted in grey represent simulation-based predictions generated by applying the dose-response curve for cholesterol biosynthesis (unshaded) to the template model.
Table 4.
Impact of diet and dioxin on the processes comprising the template model. Sections highlighted in grey represent simulation-based predictions generated by applying values of the dose-response curve for cholesterol biosynthesis (unshaded) to the template model.
Fig 16.
Example of a directed line graph G and its (edge-to-vertex) dual graph G*.
The vertices of G* correspond directly to the edges in G, as indicated by letters a – h. The edges of G* correspond to vertices in G if one edge is entering this vertex and another one is leaving it. For instance, vertex ② in G is represented in the directed dual graph G* through the edges from ⓐ to ⓒ and from ⓐ to ⓓ, because these edges meet head to tail at vertex ② in G.
Fig 17.
Cholesterol template model as dual graph.
New representation of the cholesterol template model (Fig 4), where variables (anchors) are in truth processes and edges either represent the moving of cholesterol ⓒ among processes or indicate inhibitory signals - - -|. Note that the arrows differ from the standards of typical proper model diagrams (Fig 6).
Fig 18.
Utilization of flux information (e.g., fromTable 4) to obtain information regarding cholesterol concentrations.
In this example, the concentration of interest is that of hepatic cholesterol.