Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion

Molecular diameter, lipophilicity and hydrophilicity exclusion affinity limits exist for small molecule carrier-mediated diffusion or transport through channel pores or interaction with the cell surface glycocalyx. The molecular structure lipophilicity limit for non-specific carrier-mediated transmembrane diffusion through polarity-selective transport channels of the cell membrane is L(external structure) ∙ H(polar group)(-1) of ≥ 1.07. The cell membrane channel pore size is > 0.752 and < 0.758 nm based on a 3-D ellipsoid model (biphenyl), and within the molecular diameter size range 0.744 and 0.762 nm based on a 2-D elliptical model (alkanol). The adjusted van der Waals diameter (vdWD, adj; nm) for the subset of halogenated vapors is predictive of the required MAC for anesthetic potency at an initial (-) Δ C(micro) effect. The molecular structure L ∙ H(polar group)(-1) for Neu5Ac is 0.080, and the L ∙ H(polar group)(-1) interval range for the cell surface glycocalyx hydrophilicity barrier interaction is 0.101 (Saxitoxin, Stx; L(internal structure) ∙ H(polar group)(-1)) - 0.092 (m-xylenediamine, L(external structure) · H(polar group)). Differential predictive effective pressure mapping of gene activation or repression reveals that p-dioxin exposure results in activation of AhR-Erβ (Arnt)/Nrf-2, Pparδ, Errγ (LxRα), Dio3 (Dio2) and Trα limbs, and due to high affinity Dio2 and Dio3 (OH-TriCDD, L(ext) · H(-1): 1.91–4.31) exothermy-antagonism (Δ contraction) with high affinity T(4)/rT(3)-TRα-mediated agonism (Δ expansion). co-planar PCB metabolite exposure (L(ext) · H(-1): 1.95–3.91) results in activation of AhR (Erα/β)/Nrf2, Rev-Erbβ, Errα, Dio3 (Dio2) and Trα limbs with a Δ C(micro) contraction of 0.89 and Δ C(micro) expansion of 1.05 as compared to p-dioxin. co-, ortho-planar PCB metabolite exposure results in activation of Car/PxR, Pparα (Srebf1,—Lxrβ), Arnt (AhR-Erβ), AR, Dio1 (Dio2) and Trβ limbs with a Δ C(micro) contraction of 0.73 and Δ C(micro) expansion of 1.18 (as compared to p-dioxin). Bisphenol A exposure (L(ext struct) ∙ H(-1): 1.08–1.12, BPA–BPE, Errγ; BPAF, L(ext struct) ∙ H(-1): 1.23, CM Erα, β) results in increased duration at P(eff) for Timm8b (P(eff) 0.247) transcription and in indirect activation of the AhR/Nrf-2 hybrid pathway with decreased duration at P(eff) 0.200 (Nrf1) and increased duration at P(eff) 0.257 (Dffa). The Bpa/Bpaf convergent pathway C(micro) contraction-expansion response increase in the lower P(eff) interval is 0.040; in comparison, small molecule hormone Δ C(micro) contraction-expansion response increases in the lower P(eff) intervals for gene expression ≤ 0.168 (Dex· GR) ≥ 0.156 (Dht · AR), with grade of duration at P(eff) (min·count) of 1.33x10(5) (Dex/Cort) and 1.8–2.53x10(5) (Dht/R1881) as compared to the (-) coupled (+) Δ C(micro) P(eff) to 0.136 (Wnt5a, Esr2) with applied DES (1.86x10(6)). The subtype of trans-differentiated cell as a result of an applied toxin or toxicant is predictable by delta-C(micro) determined by P(eff) mapping. Study findings offer additional perspective on the basis for pressure regulated gene transcription by alterations in cell micro-compliance (Δ contraction-expansion, C(micro)), and are applicable for the further predictive modeling of gene to gene transcription interactions, and small molecule modulation of cell effective pressure (P(eff)) and its potential.