Antagonism, Estrogen receptor

80-05-7

IISBACLAFKSPIT-UHFFFAOYSA-N

Bisphenol A

BPA 4,4’-Propane-2,2-diyldiphenol Phenol, 4,4'-(1-methylethylidene)bis- (4,4'-Dihydroxydiphenyl)dimethylmethane 2,2-Bis(4'-hydroxyphenyl) propane 2,2'-Bis(4-hydroxyphenyl)propane 2,2-BIS-(4-HYDROXY-PHENYL)-PROPANE 2,2-Bis(4-hydroxyphenyl)propane 2,2-Bis(p-hydroxyphenyl)propane 2,2-Di(4-Hydroxyphenyl) Propane 2,2-DI(4-HYDROXYPHENYL)PROPANE 2,2-Di(4-phenylol)propane 4,4'-(1-Methylethylidene)bisphenol 4,4'-Bisphenol A 4,4'-DIHYDROXYPHENYL-2,2-PROPANE 4,4'-isopropilidendifenol 4,4'-Isopropylidendiphenol 4,4'-Isopropylidene bisphenol 4,4-ISOPROPYLIDENE DIPHENYL 4,4'-Isopropylidenebis[phenol] 4,4'-isopropylidenediphenol 4,4'-Methylethylidenebisphenol Bis(4-hydroxyphenyl)dimethylmethane Bis(p-hydroxyphenyl)propane BIS[PHENOL], 4,4'-(1-METHYLETHYLIDENE)- BISPHENOL, 4,4'-(1-METHYLETHYLIDENE)- BISPHENOL-A Diphenol methylethylidene Diphenylolpropane Hidorin F 285 Isopropylidenebis(4-hydroxybenzene) NSC 1767 NSC 17959 p,p'-Bisphenol A p,p'-Dihydroxydiphenylpropane P,P'-ISOPROPYLIDENE DIPHENOL p,p'-Isopropylidenebisphenol p,p'-Isopropylidenediphenol Parabis Parabis A Phenol, 4,4'-isopropylidenedi- Pluracol 245 Rikabanol β,β'-Bis(p-hydroxyphenyl)propane

DTXSID7020182

PR:000007204

PR estrogen receptor

GO:0017146

GO NMDA selective glutamate receptor complex

GO:0030284

GO estrogen receptor activity

GO:0004972

GO NMDA glutamate receptor activity

GO:0099536

GO synaptic signaling

WIKI decreased

Bisphenol A

2019-12-29T18:38:03

WCS_9606

common toxicological species human

10116

NCBI rat

10090

NCBI mouse

WCS_9606

common toxicological species humans

10095

NCBI mice

9685

NCBI cat

9606

NCBI Homo sapiens

Antagonism, Estrogen receptor

Molecular

Site of action: The site of action for the molecular initiating event is the liver (hepatocytes). Responses at the macromolecular level: Estrogen receptor antagonists have been shown to interact with the ligand binding domain of ERs. However, those interactions occur at different contact sites than those of estrogen agonists, leading to a different conformation in the transactivation domain (Brzozowski et al. 1997; Katzenellenbogen 1996). Characterization of chemical properties: Two broad categories of ER antagonists have been described. Type I, like tamoxifen act as mixed agonists and antagonists. Type II, like ICI164384 are pure antagonists (Katzenellenbogen 1996). Due to their potential utility for treating estrogen-dependent breast cancers and other estrogen-related disease states as well as concerns regarding endocrine disruption, there is an extensive body of literature on the identification and design of chemical structures that act as ER antagonists (e.g., (Brooks et al. 1987; Brooks and Skafar 2004; Lloyd et al. 2006; Sodero et al. 2012; Vedani et al. 2012; Wang et al. 2006).

<ul> <li>The BG1luc estrogen receptor transactivation test method for identifying estrogen receptor agonists and antagonists (OECD Test Guideline 457) has been validated by the National Toxicology Program Interagency Center for Evaluation of Alternative Toxicological Methods (NICEATM) and Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) as an appropriate assay for detecting ER antagonism. (OECD, 2012b).</li> <li>Other human ER-based transactivation assays that have been used to detect ERα antagonism include the T47D-Kbluc assay (Wilson et al. 2004); ERα CALUX assay (van der Burg et al. 2010); MELN assay (Witters et al. 2010); and the yeast estrogen screen (YES; (De Boever et al. 2001)). Each of these assays have undergone some level of validation.</li> <li>In aquatic ecotoxicology, vitellogenin synthesis in primary fish liver cells and liver slices has also been used to screen for anti-estrogenic activity (e.g., (Bickley et al. 2009; Navas and Segner 2006; Schmieder et al. 2000; Schmieder et al. 2004; Sun et al. 2010). Although these approaches have generally not been subject to as much formal validation as human ER-based transactivation assays, in the case of fish-specific AOPs linked to this key event, these measures of anti-estrogenicity may be more directly relevant to predicting other key events in the pathway.</li> </ul>

Taxonomic applicability: Steroid receptors, including ER are thought to have evolved in the chordate lineage (Baker 1997, 2003; Thornton 2001). An ER ortholog has been isolated from a mollusk species, but no ER orthologs have been detected in arthropods or nematodes (Thornton et al. 2003). Broadly speaking, most vertebrates can be expected to have functional ERs, while most invertebrates do not, although there may be exceptions within the mollusk lineage and evolutionarily-related organisms.

CL:0000182

CL hepatocyte

<ul> <li>Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, et al. 1997. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753-758.</li> <li>Katzenellenbogen B. 1996. Estrogen receptors: Bioactivities and interactions with cell signaling pathways. Biology of Reproduction 54:287-293.</li> <li>Brooks SC, Wappler NL, Corombos JD, Doherty LM, Horwitz JP. 1987. Estrogen structure-fuction relationships. Berlin:Walter de Gruyter & Co., 443-466.</li> <li>Brooks SC, Skafar DF. 2004. From ligand structure to biological activity: Modified estratrienes and their estrogenic and antiestrogenic effects in mcf-7 cells. Steroids 69:401-418.</li> <li>Lloyd DG, Smith HM, O'Sullivan T, Knox AS, Zisterer DM, Meegan MJ. 2006. Antiestrogenically active 2-benzyl-1,1-diarylbut-2-enes: Synthesis, structure-activity relationships and molecular modeling study for flexible estrogen receptor antagonists. Medicinal chemistry 2:147-168.</li> <li>Sodero AC, Romeiro NC, da Cunha EF, de Oliveira Magalhaaes U, de Alencastro RB, Rodrigues CR, et al. 2012. Application of 4d-qsar studies to a series of raloxifene analogs and design of potential selective estrogen receptor modulators. Molecules 17:7415-7439.</li> <li>Vedani A, Dobler M, Smiesko M. 2012. Virtualtoxlab - a platform for estimating the toxic potential of drugs, chemicals and natural products. Toxicology and applied pharmacology 261:142-153.</li> <li>Wang CY, Ai N, Arora S, Erenrich E, Nagarajan K, Zauhar R, et al. 2006. Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach. Chemical research in toxicology 19:1595-1601.</li> <li>Denny JS, Tapper MA, Schmieder PK, Hornung MW, Jensen KM, Ankley GT, et al. 2005. Comparison of relative binding affinities of endocrine active compounds to fathead minnow and rainbow trout estrogen receptors. Environmental toxicology and chemistry / SETAC 24:2948-2953.</li> <li>Lee HK, Kim TS, Kim CY, Kang IH, Kim MG, Jung KK, et al. 2012. Evaluation of in vitro screening system for estrogenicity: Comparison of stably transfected human estrogen receptor-alpha transcriptional activation (oecd tg455) assay and estrogen receptor (er) binding assay. The Journal of toxicological sciences 37:431-437.</li> <li>Rider CV, Hartig PC, Cardon MC, Lambright CR, Bobseine KL, Guillette LJ, Jr., et al. 2010. Differences in sensitivity but not selectivity of xenoestrogen binding to alligator versus human estrogen receptor alpha. Environmental toxicology and chemistry / SETAC 29:2064-2071.</li> <li>OECD. 2012b. Test no. 457: Bg1luc estrogen receptor transactivation test method for identifying estrogen receptor agonists and antagonists:OECD Publishing.</li> <li>Wilson VS, Bobseine K, Gray LE, Jr. 2004. Development and characterization of a cell line that stably expresses an estrogen-responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicological sciences : an official journal of the Society of Toxicology 81:69-77.</li> <li>van der Burg B, Winter R, Weimer M, Berckmans P, Suzuki G, Gijsbers L, et al. 2010. Optimization and prevalidation of the in vitro eralpha calux method to test estrogenic and antiestrogenic activity of compounds. Reproductive toxicology 30:73-80.</li> <li>Witters H, Freyberger A, Smits K, Vangenechten C, Lofink W, Weimer M, et al. 2010. The assessment of estrogenic or anti-estrogenic activity of chemicals by the human stably transfected estrogen sensitive meln cell line: Results of test performance and transferability. Reproductive toxicology 30:60-72.</li> <li>De Boever P, Demare W, Vanderperren E, Cooreman K, Bossier P, Verstraete W. 2001. Optimization of a yeast estrogen screen and its applicability to study the release of estrogenic isoflavones from a soygerm powder. Environmental health perspectives 109:691-697.</li> <li>Bickley LK, Lange A, Winter MJ, Tyler CR. 2009. Evaluation of a carp primary hepatocyte culture system for screening chemicals for oestrogenic activity. Aquatic toxicology 94:195-203.</li> <li>Navas JM, Segner H. 2006. Vitellogenin synthesis in primary cultures of fish liver cells as endpoint for in vitro screening of the (anti)estrogenic activity of chemical substances. Aquatic toxicology 80:1-22.</li> <li>Schmieder P, Tapper M, Linnum A, Denny J, Kolanczyk R, Johnson R. 2000. Optimization of a precision-cut trout liver tissue slice assay as a screen for vitellogenin induction: Comparison of slice incubation techniques. Aquatic toxicology 49:251-268.</li> <li>Schmieder PK, Tapper MA, Denny JS, Kolanczyk RC, Sheedy BR, Henry TR, et al. 2004. Use of trout liver slices to enhance mechanistic interpretation of estrogen receptor binding for cost-effective prioritization of chemicals within large inventories. Environmental science & technology 38:6333-6342.</li> <li>Sun L, Wen L, Shao X, Qian H, Jin Y, Liu W, et al. 2010. Screening of chemicals with anti-estrogenic activity using in vitro and in vivo vitellogenin induction responses in zebrafish (danio rerio). Chemosphere 78:793-799.</li> <li>Baker ME. 1997. Steroid receptor phylogeny and vertebrate origins. Molecular and cellular endocrinology 135:101-107.</li> <li>Baker ME. 2003. Evolution of adrenal and sex steroid action in vertebrates: A ligand-based mechanism for complexity. BioEssays : news and reviews in molecular, cellular and developmental biology 25:396-400.</li> <li>Thornton JW. 2001. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proceedings of the National Academy of Sciences of the United States of America 98:5671-5676.</li> <li>Thornton JW, Need E, Crews D. 2003. Resurrecting the ancestral steroid receptor: Ancient origin of estrogen signaling. Science 301:1714-1717.</li> </ul> AOPWiki 2016-11-29T18:41:22

2017-09-16T10:14:46

inhibition, EKR1/2 signaling pathway

Cellular

AOPWiki 2024-01-25T21:13:59

2024-01-25T21:13:59

Inhibition, NMDARs

Molecular

Biological state: L-glutamate (Glu) is a neurotransmitter with important role in the regulation of brain development and maturation processes. Two major classes of Glu receptors, ionotropic and metabotropic, have been identified. Due to its physiological and pharmacological properties, Glu activates three classes of ionotropic receptors named: α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA receptors), 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine (kainate receptors) and N-methyl-D-aspartate (NMDA receptors, NMDARs), which transduce the postsynaptic signal. Ionotropic glutamate receptors are integral membrane proteins formed by four large subunits that compose a central ion channel pore. In case of NMDA receptors, two NR1 subunits are combined with either two NR2 (NR2A, NR2B, NR2C, NR2D) subunits and less commonly are assembled together with a combination of NR2 and NR3 (A, B) subunits (reviewed in Traynelis et al., 2010). To be activated NMDA receptors require simultaneous binding of both glutamate to NR2 subunits and of glycine to either NR1 or NR3 subunits that provide the specific binding sites named extracellular ligand-binding domains (LBDs). Apart from LBDs, NMDA receptor subunits contain three more domains that are considered semiautonomous: 1) the extracellular amino-terminal domain that plays important role in assembly and trafficking of these receptors; 2) the transmembrane domain that is linked with LBD and contributes to the formation of the core of the ion channel and 3) the intracellular carboxyl-terminal domain that influences membrane targeting, stabilization, degradation and post-translation modifications. Biological compartments: The genes of the NMDAR subunits are expressed in various tissues and are not only restricted to the nervous system. The level of expression of these receptors in neuronal and non-neuronal cells depends on: transcription, chromatin remodelling, mRNA levels, translation, stabilization of the protein, receptor assembly and trafficking, energy metabolism and numerous environmental stimuli (reviewed in Traynelis et al., 2010). In hippocampus region of the brain, NR2A and NR2B are the most abundant NR2 family subunits. NR2A-containing NMDARs are mostly expressed synaptically, while NR2B-containing NMDARs are found both synaptically and extrasynaptically (Tovar and Westbrook, 1999). General role in biology: NMDA receptors, when compared to the other Glu receptors, are characterized by higher affinity for Glu, slower activation and desensitisation kinetics, higher permeability for calcium (Ca2+) and susceptibility to potential-dependent blockage by magnesium ions (Mg2+). NMDA receptors are involved in fast excitatory synaptic transmission and neuronal plasticity in the central nervous system (CNS). Functions of NMDA receptors: 1. They are involved in cell signalling events converting environmental stimuli to genetic changes by regulating gene transcription and epigenetic modifications in neuronal cells (Cohen and Greenberg, 2008). 2. In NMDA receptors, the ion channel is blocked by extracellular Mg2+ and Zn2+ ions, allowing the flow of Na+ and Ca2+ ions into the cell and K+ out of the cell which is voltage-dependent. Ca2+ flux through the NMDA receptor is considered to play a critical role in pre- and post-synaptic plasticity, a cellular mechanism important for learning and memory (Barria and Malinow, 2002). 3. The NMDA receptors have been shown to play an essential role in the strengthening of synapses and neuronal differentiation, through long-term potentiation (LTP), and the weakening of synapses, through long-term depression (LTD). All these processes are implicated in the memory and learning function (Barria and Malinow, 2002).

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? No OECD methods are available to measure the activation state of NMDA receptors. The measurement of the activation or the inhibition of NMDA receptors is done indirectly by recording the individual ion channels that are selective to Na+, K+ and Ca+2 by the patch clamp technique. This method relies on lack of measurable ion flux when NMDA ion channel is closed, whereas constant channel specific conductance is recorded at the open state of the receptor (Blanke and VanDongen, 2009). Furthermore, this method is based on the prediction that activation or inhibition of an ion channel results from an increase in the probability of being in the open or close state, respectively. The whole-cell patch clamp recording techniques have also been used to study synaptically-evoked NMDA receptor-mediated excitatory or inhibitory postsynaptic currents (EPSCs and IPSCs, respectively) in brain slices and neuronal cells, allowing the evaluation of the activated or inhibited state of the receptor (Ogdon and Stanfield, 2009; Zhao et al., 2009). Microelectrode array (MEA) recordings are used to measure electrical activity in cultured neurons in response to NMDA receptor activation or inactivation (Keefer et al., 2001, Gramowski et al., 2000 and Gopal, 2003; Johnstone et al., 2010). MEAs can also be applied in higher throughput platforms to facilitate screening of numerous chemical compounds based on electrical activity measurements (McConnell et al., 2012).

The cellular expression of the NMDAR subunits has been studied in both adult human cortex and hippocampus (Scherzer et al., 1998) as well as during the development of the human hippocampal formation (Law et al., 2003). The whole-cell patch clamp recording techniques have been used in NMDA receptors expressed in human TsA cells (derivative of the human embryonic kidney cell line HEK-293) (Ludolph et al., 2010). Cell-attached single-channel recordings of NMDA channels has been carried out in human dentate gyrus granule cells acutely dissociated from slices prepared from hippocampi surgically removed from human patients (Lieberman and Mody, 1999). It is important to note that in invertebrates the glutamatergic synaptic transmission has inhibitory and not excitatory role like in vertebrates. This type of neurotransmission is mediated by glutamate-gated chloride channels that are members of the ‘cys-loop’ ligand-gated anion channel superfamily found only in invertebrates. The subunits of glutamate-activated chloride channel have been isolated from C. elegans and from Drosophila (Blanke and VanDongen, 2009).

CL:0000540

CL neuron

High High High

Barria A, Malinow R. (2002) Subunit-specific NMDA receptor trafficking to synapses. Neuron 35: 345-353. Blanke ML, VanDongen AMJ. (2009) Activation Mechanisms of the NMDA Receptor. In: Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press; Chapter 13. Available from: <a rel="nofollow" target="_blank" class="external free" href="http://www.ncbi.nlm.nih.gov/books/NBK5274/">http://www.ncbi.nlm.nih.gov/books/NBK5274/</a> Cohen S, Greenberg ME. (2008) Communication between the synapse and the nucleus in neuronal development, plasticity, and disease. Ann Rev Cell Dev Biol 24: 183-209. Gopal K. (2003) Neurotoxic effects of mercury on auditory cortex networks growing on microelectrode arrays: a preliminary analysis. Neurotoxicol Teratol. 25: 69-76. Gramowski A, Schiffmann D, Gross GW. (2000) Quantification of acute neurotoxic effects of trimethyltin using neuronal networks cultures on microelectrode arrays. Neurotoxicology 21: 331-342. Johnstone AFM, Gross GW, Weiss D, Schroeder O, Shafer TJ. (2010). Use of microelectrode arrays for neurotoxicity testing in the 21st century Neurotoxicology 31: 331-350. Keefer E, Norton S, Boyle N, Talesa V, Gross G. (2001) Acute toxicity screening of novel AChE inhibitors using neuronal networks on microelectrode arrays. Neurotoxicology 22: 3-12. Law AJ, Weickert CS, Webster MJ, Herman MM, Kleinman JE, Harrison PJ. (2003) Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation. Eur J Neurosci. 18: 1197-1205. Lieberman DN, Mody I. (1999) Properties of single NMDA receptor channels in human dentate gyrus granule cells. J Physiol. 518: 55-70. Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O, Weigt HU, Fegert JM, Boeckers TM, Föhr KJ. (2010) Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations. Br J Pharmacol. 160: 283-291. McConnell ER, McClain MA, Ross J, LeFew WR, Shafer TJ (2012). Evaluation of multi-well microelectrode arrays for neurotoxicity screening using a chemical training set Neurotoxicology 33: 1048-1057. Ogdon D, Stanfield P. (2009) Patch clamp techniques for single channel and whole-cell recording. Chapter 4, pages 53-78. <a rel="nofollow" target="_blank" class="external free" href="http://www.utdallas.edu/~tres/microelectrode/microelectrodes_ch04.pdf">http://www.utdallas.edu/~tres/microelectrode/microelectrodes_ch04.pdf</a> Scherzer CR, Landwehrmeyer GB, Kerner JA, Counihan TJ, Kosinski CM, Standaert DG, Daggett LP, Veliçelebi G, Penney JB, Young AB. (1998) Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: hippocampus and cortex. J Comp Neurol. 390: 75-90. Tovar KR, Westbrook GL. (1999) The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci. 19: 4180–4188. Traynelis S, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 62: 405-496. Zhao Y, Inayat S, Dikin DA, Singer JH, Ruoff RS, Troy JB. (2009) Patch clamp technique: review of the current state of the art and potential contributions from Nanoengineering. Proc. IMechE 222, Part N: J. Nanoengineering and Nanosystems 149. DOI: 10.1243/17403499JNN149 AOPWiki 2016-11-29T18:41:23

2017-09-16T10:14:24

Aberrant, synaptic formation and plasticity

Organ

AOPWiki 2024-01-25T21:18:46

2024-01-25T21:18:46

Decrease of neuronal network function

Neuronal network function, Decreased

Organ

Biological state: There are striking differences in neuronal network formation and function among the developing and mature brain. The developing brain shows a slow maturation and a transient passage from spontaneous, long-duration action potentials to synaptically-triggered, short-duration action potentials. Furthermore, at this precise developmental stage the neuronal network is characterised by "hyperexcitability”, which is related to the increased number of local circuit recurrent excitatory synapses and the lack of γ-amino-butyric acid A (GABAA)-mediated inhibitory function that appears much later. This “hyperexcitability” disappears with maturation when pairing of the pre- and postsynaptic partners occurs and synapses are formed generating population of postsynaptic potentials and population of spikes followed by developmental GABA switch. Glutamatergic neurotransmission is dominant at early stages of development and NMDA receptor-mediated synaptic currents are far more times longer than those in maturation, allowing more calcium to enter the neurons. The processes that are involved in increased calcium influx and the subsequent intracellular events seem to play a critical role in establishment of wiring of neural circuits and strengthening of synaptic connections during development (reviewed in Erecinska et al., 2004). Neurons that do not receive glutaminergic stimulation are undergoing developmental apoptosis. During the neonatal period, the brain is subject to profound alterations in neuronal circuitry due to high levels of synaptogenesis and gliogenesis. For example, in neuroendocrine regions such as the preoptic area-anterior hypothalamus (POA-AH), the site of gonadotropin-releasing hormone (GnRH) system is developmentally regulated by glutamatergic neurons. The changes in the expression of the N-methyl-D-aspartate (NMDA) receptor subunits NR1 and NR2B system begin early in postnatal development, before the onset of puberty, thereby playing a role in establishing the appropriate environment for the subsequent maturation of GnRH neurons (Adams et al., 1999). Biological compartments: Neural network formation and function happen in all brain regions but it appears to onset at different time points of development (reviewed in Erecinska et al., 2004). Glutamatergic neurotransmission in hippocampus is poorly developed at birth. Initially, NMDA receptors play important role but the vast majority of these premature glutamatergic synapses are “silent” possibly due to delayed development of hippocampal AMPA receptors. In contrast, in the cerebral cortex the maturation of excitatory glutamatergic neurotransmission happens much earlier. The “silent” synapses disappear by PND 7-8 in both brain regions mentioned above. There is strong evidence suggesting that NMDA receptor subunit composition controls synaptogenesis and synapse stabilization (Gambrill and Barria, 2011). It is established fact that during early postnatal development in the rat hippocampus, synaptogenesis occurs in parallel with a developmental switch in the subunit composition of NMDA receptors from NR2B to NR2A. It is suggested that early expression of NR2A in organotypic hippocampal slices reduces the number of synapses and the volume and dynamics of spines. In contrast, overexpression of NR2B does not affect the normal number and growth of synapses. However, it does increase spine motility, adding and retracting spines at a higher rate. The C terminus of NR2B, and specifically its ability to bind CaMKII, is sufficient to allow proper synapse formation and maturation. Conversely, the C terminus of NR2A was sufficient to stop the development of synapse number and spine growth. These results indicate that the ratio of synaptic NR2B over NR2A controls spine motility and synaptogenesis, and suggest a structural role for the intracellular C terminus of NR2 in recruiting the signalling and scaffolding molecules necessary for proper synaptogenesis. Interestingly, it was found that genetic deletion of NR3A accelerates glutamatergic synaptic transmission, as measured by AMPAR-mediated postsynaptic currents recorded in hippocampal CA1. Consistent, the deletion of NR3A accelerates the expression of the glutamate receptor subunits NR1, NR2A, and GluR1 sugesting that glutamatergic synapse maturation is critically dependent upon activation of NMDA-type glutamate receptors (Henson et al., 2012). General role in biology: The development of neuronal networks can be distinguished into two phases: an early ‘establishment’ phase of neuronal connections, where activity-dependent and independent mechanisms could operate, and a later ‘maintenance’ phase, which appears to be controlled by neuronal activity (Yuste and Sur, 1999). These neuronal networks facilitate information flow that is necessary to produce complex behaviors, including learning and memory (Mayford et al., 2012).

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? In vivo: The recording of brain activity by using electroencephalography (EEG), electrocorticography (ECoG) and local field potentials (LFP) assists towards the collection of signals generated by multiple neuronal cell networks. Advances in computer technology have allowed quantification of the EEG and expansion of quantitative EEG (qEEG) analysis providing a sensitive tool for time-course studies of different compounds acting on neuronal networks' function (Binienda et al., 2011). The number of excitatory or inhibitory synapses can be functionally studied at an electrophysiological level by examining the contribution of glutamatergic and GABAergic synaptic inputs. The number of them can be determined by variably clamping the membrane potential and recording excitatory and inhibitory postsynaptic currents (EPSCs or IPSCs) (Liu, 2004). In vitro: Microelectrode array (MEA) recordings are also used to measure electrical activity in cultured neurons (Keefer et al., 2001, Gramowski et al., 2000; Gopal, 2003; Johnstone et al., 2010). MEAs can be applied in high throughput platforms to facilitate screening of numerous chemical compounds (McConnell et al., 2012). Using selective agonists and antagonists of different classes of receptors their response can be evaluated in a quantitative manner (Novellino et al., 2011; Hogberg et al., 2011). Patch clamping technique can also be used to measure neuronal network activity.In some cases, if required, planar patch clamping technique can also be used to measure neuronal networks activity (e.g., Bosca et al., 2014).

In vitro studies in brain slices applying electrophysiological techniques showed significant variability among species (immature rats, rabbits and kittens) related to synaptic latency, duration, amplitude and efficacy in spike initiation (reviewed in Erecinska et al., 2004).

UBERON:0000955

UBERON brain

High Mixed

High

During brain development

High High High High

Adams MM, Flagg RA, Gore AC., Perinatal changes in hypothalamic N-methyl-D-aspartate receptors and their relationship to gonadotropin-releasing hormone neurons. Endocrinology. 1999 May;140(5):2288-96. Binienda ZK, Beaudoin MA, Thorn BT, Ali SF. (2011) Analysis of electrical brain waves in neurotoxicology: γ-hydroxybutyrate. Curr Neuropharmacol. 9: 236-239. Bosca, A., M. Martina, and C. Py (2014) Planar patch clamp for neuronal networks--considerations and future perspectives. Methods Mol Biol, 2014. 1183: p. 93-113. Erecinska M, Cherian S, Silver IA. (2004) Energy metabolism in mammalian brain during development. Prog Neurobiol. 73: 397-445. Gambrill AC, Barria A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc Natl Acad Sci U S A. 2011:108(14):5855-60. Gopal K. (2003) Neurotoxic effects of mercury on auditory cortex networks growing on microelectrode arrays: a preliminary analysis. Neurotoxicol Teratol. 25: 69-76. Gramowski A, Schiffmann D, Gross GW. (2000) Quantification of acute neurotoxic effects of trimethyltin using neuronal networks cultures on microelectrode arrays. Neurotoxicology 21: 331-342. Henson MA, Larsen RS, Lawson SN, Pérez-Otaño I, Nakanishi N, Lipton SA, Philpot BD. (2012) Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS One. 7(8). Hogberg HT, Sobanski T, Novellino A, Whelan M, Weiss DG, Bal-Price AK. (2011) Application of micro-electrode arrays (MEAs) as an emerging technology for developmental neurotoxicity: evaluation of domoic acid-induced effects in primary cultures of rat cortical neurons. Neurotoxicology 32: 158-168. Johnstone AFM, Gross GW, Weiss D, Schroeder O, Shafer TJ. (2010) Use of microelectrode arrays for neurotoxicity testing in the 21st century Neurotoxicology 31: 331-350. Keefer E, Norton S, Boyle N, Talesa V, Gross G. (2001) Acute toxicity screening of novel AChE inhibitors using neuronal networks on microelectrode arrays. Neurotoxicology 22: 3-12. Liu G. (2004) Local structural balance and functional interaction of excitatory and inhibitory synapses in hippocampal dendrites. Nat Neurosci. 7: 373-379. Mayford M, Siegelbaum SA, Kandel ER. (2012) Synapses and memory storage. Cold Spring Harb Perspect Biol. 4. pii: a005751. McConnell ER, McClain MA, Ross J, LeFew WR, Shafer TJ. (2012) Evaluation of multi-well microelectrode arrays for neurotoxicity screening using a chemical training set. Neurotoxicology 33: 1048-1057. Novellino A, Scelfo B, Palosaari T, Price A, Sobanski T, Shafer TJ, Johnstone AF, Gross GW, Gramowski A, Schroeder O, Jügelt K, Chiappalone M, Benfenati F, Martinoia S, Tedesco MT, Defranchi E, D'Angelo P, Whelan M. (2011) Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals. Front Neuroeng. 4: 4. Yuste R, Peinado A, Katz LC. (1992) Neuronal domains in developing neocortex. Science 257: 665-669. AOPWiki 2016-11-29T18:41:24

2018-05-28T11:36:00

autism-like behavior

Individual

AOPWiki 2024-01-25T21:20:23

2024-01-25T21:20:23

<upstream-id>65f55046-755e-450e-bf76-89b5c9689287</upstream-id> <downstream-id>3b7a6240-d249-4cbc-92a7-ea26ec169aac</downstream-id>

AOPWiki 2024-01-25T21:21:21

2024-01-25T21:21:21

<upstream-id>3b7a6240-d249-4cbc-92a7-ea26ec169aac</upstream-id> <downstream-id>5e218405-dc58-4bae-b3b5-068315962aa8</downstream-id>

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Estrogen antagonism leading to increased risk of autism-like behavior

Kanglong Cui

Open for adoption

2.6

Autism spectrum disorder (ASD), also known as autism, is a common, highly hereditary and heterogeneous neurodevelopmental disorder. The prevalence of ASD is high globally and rising from 758 per 100,000 in 2010 to 1,000 in 2022[1, 2]. Emerging evidence suggests that environmental factors contribute to the occurrence and development of ASD and that approximately 41% of the etiology of ASD are related to environmental factors directly or indirectly, for example, by the interaction with genetic factors[3-5]. Epidemiologic studies have found association between exposure to environmental endocrine disruptors (EDCs) and ASD[6-9] On AOP-Wiki, there have been 14 reported AOPs linked to neurodevelopmental toxicity. These encompass a range of adverse outcomes, including learning and memory impairment (5 AOPs), cognitive dysfunction (4 AOPs), neural tube defects (3 AOPs), hearing loss (1 AOP), and periventricular heterotopia (1 AOP). Intriguingly, no AOPs directly related to ASD have been identified yet. We chose two widespread plastic-derived EDCs, diethylhexyl phthalate (DEHP) and bisphenol A (BPA), as stressors. Using public datasets and network-based approach, we constructed a chemical-gene-phenotype-disease network (CGPDN) and developed a preliminary AOP of GDM using literature mining. In this AOP, estrogen antagonism was identified as the MIE, and four KEs, including decreased NMDAR expression (KE1), ERK1/2 signaling pathway inhibition (KE2), aberrant synaptic formation and plasticity (KE3), and decreased neuronal network function system (KE4), were selected to connect estrogen antagonism and ASD (AO). The weight of evidence (WoE) of overall AOP was assessed based on the biological plausibility, empirical support, and evidence supporting essentiality of the KEs and KERs according to the OECD handbook of AOP. As a result, both the biological plausibility and evidence supporting essentiality were rated as “High”, empirical support was rated as “Moderate”, indicating “Moderate” confidence in this AOP. But we have no quantitative understanding of relationships between two key events, so, in the future, we can conduct some experiments about it.

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KE essentiality assessment of the AOP that Estrogen antagonism leading to increased risk of autism-like behavior <table align="center" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="border-bottom:2px solid black; border-left:none; border-right:none; border-top:2px solid black; width:931px"> <ol> <li style="text-align:justify">MIE: Antagonism, estrogen</li> </ol> Supporting Data: Estrogen can bind to estrogen receptors and activate the ERK signaling pathway, leading to an increase in the density of synapses and dendritic spines, inducing LTP, and promoting synaptic plasticity[17, 19, 38]. Antagonizing the estrogen effect can inhibit the ERK signaling pathway[10]，also inhibit the increase in dendritic spines, the synaptic density and the induction of LTP[17, 19]. The prevalence of ASD is much higher in males than females, and multiple clinical and preclinical researches suggest that estrogen plays a role in inhibiting the development of ASD and protecting neuroprotection[39]. Potentially Inconsistent Data: N/A Evidence Rank: High Reference: Yang, Y.[17], Xu, X.[38], Wang, C.[10], Chen, X.[19], Crider, A.[39] <ol start="2"> <li style="text-align:justify">KE1: Decreasing, NMDAR expression</li> </ol> Supporting Data: Pharmacological enhancement or inhibition of NMDAR function can improve symptoms of ASD in humans. The activation of NMDAR is crucial for inducing synaptic plasticity[15]. Activation of NMDAR can rapidly improve synaptic plasticity inhibition caused by NGL-2 deficiency, as well as autism-like behaviors such as social interaction deficits and repetitive behaviors[40]. NMDAR activation can also improve social behavior impairments caused by CTTNBP2 deficiency[41]. Pharmacological enhancement of NMDAR function can improve symptoms of ASD in humans[42]. Potentially Inconsistent Data: N/A Evidence Rank: High References: Citri, A.[15], Um, S. M.[40], Shih, P. Y.[41], Lee, E. J[42]. </td> </tr> </tbody> </table>

<table border="1" cellpadding="1" cellspacing="1" style="width:500px"> <caption>KER biological plausibility assessment of AOP that Estrogen antagonism leading to increased risk of autism-like behavior</caption> <tbody> <tr> <td>KER</td> <td>Description</td> <td>Reference</td> <td>Evidence Rank</td> </tr> <tr> <td>Antagonism, estrogen→Inhibition, ERK1/2 signaling pathway</td> <td> BPA can inhibit the ERK signaling pathway by acting anti-estrogen effect[10]. The activation of the ERK pathway by estrogen binding to estrogen receptors plays an important role in neuroprotection[11-13].</td> <td> Wang, C.[10] Zhao, L.[11] Yang, L. C.[12] Lu, Y.[13]</td> <td>High</td> </tr> <tr> <td>Decreased, NMDAR expression→Aberrant, synaptic formation and plasticity</td> <td> NMDAR plays a critical role in forming the plasticity of the hippocampus, mice with NMDAR defects exhibit inhibited long-term potentiation of synapses[14, 15]. Compared to normal mice, mice with mutations in GluN2B (a subunit that consists NMDAR) show impaired plasticity in the hippocampus[16].</td> <td> Tsien, J. Z.[14] Citri, A.[15] Brigman, J. L.[16]</td> <td>Moderate</td> </tr> <tr> <td>Inhibition, ERK1/2 signaling pathway→Aberrant, synaptic formation and plasticity</td> <td> Inhibiting the ERK pathway can inhibit the increase in dendritic spine and synaptic density caused by estrogen[17, 18]. Inhibiting the ERK pathway can inhibit the induction of LTP in hippocampal neurons by estrogen[19].</td> <td> Hojo, Y.[18] Yang, Y.[17] Chen, X.[19]</td> <td>Moderate</td> </tr> <tr> <td>Aberrant, synaptic formation and plasticity→Decrease of neuronal network function</td> <td>Proper synaptic structure and formation of neuronal connections are necessary for normal brain development. Disruption of synaptic formation and plasticity in the hippocampus during development leads to structural and functional abnormalities in the hippocampus[20, 21].</td> <td> Harris, K. M.[21] Leuner, B.[20]</td> <td>Moderate</td> </tr> <tr> <td>Decrease of neuronal network function→autism-like behavior</td> <td> In ASD rat model, changes in hippocampal synaptic function-related proteins were found in life early phase[22]. Autopsy findings in individuals with ASD reveal reduced dendritic branching and neuron size in the hippocampus[23]. The hippocampus is involved in memory, spatial reasoning, and social interaction. structural and functional abnormalities in the hippocampus may lead to ASD through impairments in memory, spatial reasoning, and social interaction[24].</td> <td> Codagnone, M. G.[22] Raymond, G. V.[23] Banker, S. M.[24]</td> <td>Low</td> </tr> </tbody> </table>  KER empirical support assessment of AOP that Estrogen antagonism leading to increased risk of autism-like behavior <table align="center" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none; width:1106px"> <tbody> <tr> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:70px"> Stressor </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:159px"> Administration Dose </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:140px"> Study Type </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:159px"> Administration Time </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:132px"> Test Time </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:49px"> MIE </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:49px"> KE1 </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:49px"> KE2 </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:49px"> KE3 </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:49px"> KE4 </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:49px"> AO </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:3px solid black; height:30px; width:151px"> Reference </td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:70px"> DEHP </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:159px"> 100uM </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:140px"> in vitro (N2a Cell) </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:159px"> 24h </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:132px"> immediatelya </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:49px"> √ </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:28px; width:151px"> Qiu, F.[25] </td> </tr> <tr> <td style="height:28px; width:70px"> DEHP </td> <td style="height:28px; width:159px"> 300mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（rat） </td> <td style="height:28px; width:159px"> GD0-PND21 </td> <td style="height:28px; width:132px"> PND21 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> Dong, J.[26] </td> </tr> <tr> <td style="height:28px; width:70px"> DEHP </td> <td style="height:28px; width:159px"> 100 kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（rat） </td> <td style="height:28px; width:159px"> GD0-PND35 </td> <td style="height:28px; width:132px"> PND35 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:151px"> Li, Y.[27] </td> </tr> <tr> <td style="height:28px; width:70px"> DEHP </td> <td style="height:28px; width:159px"> 10 kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（rat） </td> <td style="height:28px; width:159px"> GD14-GD21 </td> <td style="height:28px; width:132px"> GD21 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> Sun, G. C.[28] </td> </tr> <tr> <td style="height:28px; width:70px"> DEHP </td> <td style="height:28px; width:159px"> 50mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（mice） </td> <td style="height:28px; width:159px"> GD3-GD17 </td> <td style="height:28px; width:132px"> PND63 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:151px"> Zhang, X.[29] </td> </tr> <tr> <td style="height:28px; width:70px"> DEHP </td> <td style="height:28px; width:159px"> 50mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（mice） </td> <td style="height:28px; width:159px"> GD7-PND21 </td> <td style="height:28px; width:132px"> PND42 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> Dai, Y.[30] </td> </tr> <tr> <td style="height:28px; width:70px"> DEHP </td> <td style="height:28px; width:159px"> 500mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（mice） </td> <td style="height:28px; width:159px"> GD11-PND0 </td> <td style="height:28px; width:132px"> PND16 months </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> Barakat, R.[31] </td> </tr> <tr> <td style="height:28px; width:70px"> BPA </td> <td style="height:28px; width:159px"> 0.05 mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（rat） </td> <td style="height:28px; width:159px"> GD9-PND0 </td> <td style="height:28px; width:132px"> PND21 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> Wang, C.[10] </td> </tr> <tr> <td style="height:28px; width:70px"> BPA </td> <td style="height:28px; width:159px"> 0.5 mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（rat） </td> <td style="height:28px; width:159px"> GD9-PND0 </td> <td style="height:28px; width:132px"> PND21 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> Wang, C.[10] </td> </tr> <tr> <td style="height:28px; width:70px"> BPA </td> <td style="height:28px; width:159px"> 0.03 mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（rat） </td> <td style="height:28px; width:159px"> GD15-PND7 </td> <td style="height:28px; width:132px"> PND70 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> Kawato, S.[32] </td> </tr> <tr> <td style="height:28px; width:70px"> BPA </td> <td style="height:28px; width:159px"> 50 mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（rat） </td> <td style="height:28px; width:159px"> GD1-PND3 </td> <td style="height:28px; width:132px"> PND21 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:151px"> Singha, S. P.[33] </td> </tr> <tr> <td style="height:28px; width:70px"> BPA </td> <td style="height:28px; width:159px"> 50 mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（rat） </td> <td style="height:28px; width:159px"> Gavage (42 Days) </td> <td style="height:28px; width:132px"> immediatelya </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> El Morsy, E. M.[34] </td> </tr> <tr> <td style="height:28px; width:70px"> BPA </td> <td style="height:28px; width:159px"> 1 mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（rat） </td> <td style="height:28px; width:159px"> Gavage (28 Days) </td> <td style="height:28px; width:132px"> immediatelya </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> Hu, F.[35] </td> </tr> <tr> <td style="height:28px; width:70px"> BPA </td> <td style="height:28px; width:159px"> 4 mg/kg·BW/d </td> <td style="height:28px; width:140px"> in vivo（mice） </td> <td style="height:28px; width:159px"> GD7—PND14 </td> <td style="height:28px; width:132px"> PND14 </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px"> √ </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:49px">   </td> <td style="height:28px; width:151px"> Xu, X.[36] </td> </tr> <tr> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:70px"> BPA </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:159px"> 0.05 mg/kg·BW/d </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:140px"> in vivo（mice） </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:159px"> Oral (2 months) </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:132px"> immediatelya </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:49px">   </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:49px"> √ </td> <td style="border-bottom:3px solid black; border-left:none; border-right:none; border-top:none; height:28px; width:151px"> Hyun, S. A.[37] </td> </tr> </tbody> </table> a. “immediately” means that after “Administration Time”, researchers test the results immediately.

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

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