Relationship: 128: Agonism, Estrogen receptor leads to Increase, Vitellogenin synthesis in liver

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Taxonomic applicability: Oviparous vertebrates.

Life stage: This KER is applicable to all life stages following the differentiation of the liver. Larvae prior to liver differentiation should not be included.

Sex: This KER is applicable to both sexes.

Evidence Supporting this KER

Original text - unknown contributor

High degree of plausibility in fathead minnow, zebrafish and other cyprinid species.

Added by C. Baettig June 24, 2024

In egg laying vertebrates such as fish vitellogenin (VTG) synthesis occurs in the female liver after activation of estrogen receptors (ERs), including ERα and ERβ isoforms, by endogenous steroids and a variety of exogenous chemicals that bind to ERs (e.g., Brock & Shapiro, 1983; Denslow et al., 1999; Miracle et al., 2006). In mature female fish VTG is incorporated into growing oocytes by the ovary and is converted into yolk protein. However, neither adult male fish nor juvenile fish normally produce VTG, but the hepatic ER is present in males, as are the genes that encode for vtg expression and can therefore be induced by exogenous compounds (Heppell et al., 1995).

Agonism of the ER is expected to increase vtg transcription and translation and under high estrogen stimulation the fold increase of vtg transcripts increases by orders of magnitude (Brock & Shapiro, 1983). As such, induction of VTG levels in male fish has been used extensively as a biomarker of estrogen exposure (Wheeler et al., 2005).

Original text - unknown contributor

A wide range of studies using adult fish show that induction of plasma vitellogenin (VTG) occurs within 21 days in vivo aquatic exposure to estrogen receptor agonists (eg 17beta-estradiol and 4-tert pentylphenol) as shown during the successful validation of the OECD Test Guideline 229 and related protocols. A smaller number of experiment studies with fish have shown that within the OECD Test Guideline 2010, larval fish can also show induction of whole body VTG levels within 21 days aquatic exposure to estrogen receptor agonists.

Added by C. Baettig June 24, 2024

There are numerous publications supporting this relationship including multiple review articles (e.g., Matozzo et al., 2008; Palmer & Selcer, 1996; Verderame & Scudiero, 2017). A few specific examples are listed below.

• Estradiol and diarylpropionitrile (DPN), an ERβ selective agonist, induced a dose-dependent increase in VTG synthesis in rainbow trout hepatocytes (Leaños-Castañeda & Van Der Kraak, 2007).
• DPN has also been shown to increase ERα and vtg expression and synthesis post-injection in Mozambique tilapia in vivo (Davis et al., 2010).
• A study focusing on benzophenone derivatives found that BP1 (2,4-dihydroxybenzophenone), BP2 (2,2′,4,4′-tetrahydroxybenzophenone), and THB (2,4,4′-trihydroxybenzophenone) were human ERα (hERα) and hERβ and rainbow trout ERα (rtERα) and rtERβ agonists. To investigate ER activation profiles of the derivatives in vitro tests, i.e., competitive binding, reporter gene based assays, vitellogenin (Vtg) induction in isolated rainbow trout hepatocytes, and proliferation based assays were completed. hERβ was more strongly activated, which is an inverse finding to natural ligand 17β-estradiol (E2) where hERα is more strongly activated. BPs were more active in rtERα than in hERα assays. Significant VTG induction was detected in hERα, hERβ, rtERα, and rtERβ cultures (Molina-Molina et al., 2008).
• Tollefsen et al. (2003) looked at multiple endogenous (e.g., estrone (E1), estradiol (E2), and estriol (E3)) and exogenous estrogens (e.g., ethynyloestradiol (EE2), diethylstilbestrol (DES), genistein, zearalenone, bisphenol A) and found they induced dose-dependent VTG synthesis in Atlantic salmon hepatocytes.
• Shen et al. (2021) used in silico methods to screen 1056 pesticides for potential agonistic activity. They found 72 pesticides to be potential ER agonists, 14 of which have been previously reported as ER agonists. To test whether these pesticides were ER agonists, 10 were selected from the list, three that were previously reported as ER agonists and seven previously unreported as ER agonists. They found all 10 pesticides exhibited ERα agonistic activity in human or zebrafish cells and of the 10, seven also induced vtg1 and vtg2 mRNA in zebrafish.
• Xu et al (2020) also showed increase in plasma VTG following exposure to aryloxy-phenoxypropionate (APP) herbicides, after measuring the binding patterns of quizalofop-P-ethyl (QPE), clodinafop-propargyl (CP) and haloxyfop-P (HP) with ERα.
• In male fathead minnows exposed to E2 and 1H,1H,10H,10H-perfluorodecane-1,10-diol (FC-10 diol) for 21 days expression of hepatic esr1 and vtg were both significantly increased (Ankley et al. in prep).
• In male fathead minnows exposed to methoxychlor, a weak estrogen agonist, there was a clear induction of VTG (Ankley et al. 2001). In the same study exposure to methyltestosterone, a synthetic androgen, caused a significant induction of VTG in both male and female fathead minnows. This level of induction in female fathead minnows resulted in a dose-dependent increase in VTG, to concentrations approximately 10-fold higher than those observed in control fish. These funding were likely due to the conversion of methyltestosterone to methylestradiol (Hornung et al., 2004).

Original text - unknown contributor

There are generally few inconsistencies for experimental studies using model fish species dervied from pathogen-free laboratory cultures. However, there can some uncertainties where wild fish have been used for experimental purposes.

Added by C. Baettig June 24, 2024

• Some uncertainty remains regarding which ER subtypes regulate vtg gene expression in the liver of fish. In general, the literature suggests a close interplay between ER subtypes, primarily ERα and Erβ, in the regulation of vitellogenesis. Consequently, at present, the key event relationship is generalized to impacts on all ER subtypes, even though it remains possible that impacts on a particular sub-type may drive the effect on vitellogenin transcription and translation.
• Using selective agonists and antagonists for ERα and ERβ, it was concluded that ERβ was primarily responsible for inducing vitellogenin production in rainbow trout and that compounds exhibiting ERα selectivity would not be detected using a vitellogenin ELISA bioassay (Leaños-Castañeda & Van Der Kraak, 2007). However, a subsequent study conducted in tilapia concluded that agonistic and antagonistic characteristics of mammalian, isoform-specific ER agonists and antagonists, cannot be reliably extrapolated to piscine ERs (Davis et al., 2010).
• Based on RNA interference knock-down experiments Nelson and Habibi (2010) proposed a model in which all ER subtypes are involved in E2-mediated vitellogenesis, with ERβ isoforms stimulating expression of both vitellogenin and ERα gene expression, and ERα helping to drive vitellogenesis, particularly as it becomes more abundant following sensitization.

References

Navas, J.M., 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

Thorpe, K.L., Benstead, R., Hutchinson, T.H., Tyler, C.R. (2007). Associations between altered vitellogenin concentrations and adverse health effects in fathead minnow (Pimephales promelas). Aquatic Toxicology 85: 176-183

• Brock, M. L., & Shapiro, D. (1983). Estrogen regulates the absolute rate of transcription of the Xenopus laevis vitellogenin genes. Journal of Biological Chemistry, 258(9), 5449-5455.
• Davis, L., Katsu, Y., Iguchi, T., Lerner, D., Hirano, T., & Grau, E. (2010). Transcriptional activity and biological effects of mammalian estrogen receptor ligands on three hepatic estrogen receptors in Mozambique tilapia. The Journal of steroid biochemistry and molecular biology, 122(4), 272-278.
• Denslow, N. D., Chow, M. C., Kroll, K. J., & Green, L. (1999). Vitellogenin as a biomarker of exposure for estrogen or estrogen mimics. Ecotoxicology, 8, 385-398.
• Hornung, M. W., Jensen, K. M., Korte, J. J., Kahl, M. D., Durhan, E. J., Denny, J. S., Henry, T. R., & Ankley, G. T. (2004). Mechanistic basis for estrogenic effects in fathead minnow (Pimephales promelas) following exposure to the androgen 17α-methyltestosterone: conversion of 17α-methyltestosterone to 17α-methylestradiol. Aquatic Toxicology, 66(1), 15-23. https://doi.org/https://doi.org/10.1016/j.aquatox.2003.06.004
• Leaños-Castañeda, O., & Van Der Kraak, G. (2007). Functional characterization of estrogen receptor subtypes, ERα and ERβ, mediating vitellogenin production in the liver of rainbow trout. Toxicology and applied pharmacology, 224(2), 116-125.
• Matozzo, V., Gagné, F., Marin, M. G., Ricciardi, F., & Blaise, C. (2008). Vitellogenin as a biomarker of exposure to estrogenic compounds in aquatic invertebrates: A review. Environment International, 34(4), 531-545. https://doi.org/https://doi.org/10.1016/j.envint.2007.09.008
• Miracle, A., Ankley, G., & Lattier, D. (2006). Expression of two vitellogenin genes (vg1 and vg3) in fathead minnow (Pimephales promelas) liver in response to exposure to steroidal estrogens and androgens. Ecotoxicology and environmental safety, 63(3), 337-342.
• Molina-Molina, J.-M., Escande, A., Pillon, A., Gomez, E., Pakdel, F., Cavaillès, V., Olea, N., Aït-Aïssa, S., & Balaguer, P. (2008). Profiling of benzophenone derivatives using fish and human estrogen receptor-specific in vitro bioassays. Toxicology and applied pharmacology, 232(3), 384-395.
• Nelson, E. R., & Habibi, H. R. (2010). Functional Significance of Nuclear Estrogen Receptor Subtypes in the Liver of Goldfish. Endocrinology, 151(4), 1668-1676. https://doi.org/10.1210/en.2009-1447
• Palmer, B. D., & Selcer, K. W. (1996). Vitellogenin as a biomarker for xenobiotic estrogens: a review. Environmental Toxicology and Risk Assessment: Biomarkers and Risk Assessment: Fifth Volume, 3-22.
• Shen, C., Zhu, K., Ruan, J., Li, J., Wang, Y., Zhao, M., He, C., & Zuo, Z. (2021). Screening of potential oestrogen receptor α agonists in pesticides via in silico, in vitro and in vivo methods. Environmental Pollution, 270, 116015.
• Tollefsen, K.-E., Mathisen, R., & Stenersen, J. (2003). Induction of vitellogenin synthesis in an Atlantic salmon (Salmo salar) hepatocyte culture: a sensitive in vitro bioassay for the oestrogenic and anti-oestrogenic activity of chemicals. Biomarkers, 8(5), 394-407.
• Verderame, M., & Scudiero, R. (2017). Estrogen-dependent, extrahepatic synthesis of vitellogenin in male vertebrates: A mini-review. Comptes Rendus Biologies, 340(3), 139-144. https://doi.org/https://doi.org/10.1016/j.crvi.2017.01.005
• Wheeler, J. R., Gimeno, S., Crane, M., Lopez-Juez, E., & Morritt, D. (2005). Vitellogenin: a review of analytical methods to detect (anti) estrogenic activity in fish. Toxicology Mechanisms and Methods, 15(4), 293-306.
• Xu, Y., Feng, R., Wang, L., Dong, L., Liu, R., Lu, H., & Wang, C. (2020). Computational and experimental investigations on the interactions of aryloxy-phenoxy-propionate herbicides to estrogen receptor alpha in zebrafish. Ecotoxicology and environmental safety, 189, 110003.

Relationship: 336: Increase, Vitellogenin synthesis in liver leads to Increase, Plasma vitellogenin concentrations

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Taxonomic applicability: Oviparous vertebrates synthesize yolk precursor proteins that are transported in the circulation for uptake by developing oocytes. Many invertebrates also synthesize vitellogenins that are taken up into developing oocytes via active transport mechanisms. However, invertebrate vitellogenins are transported in hemolymph or via other transport mechanisms rather than plasma.

Life stage: This KER is applicable to all life stages following the differentiation of the liver. Embryos prior to liver differentiation should not be included.

Sex: This KER is applicable to both sexes. However, as males do not have the ability to clear plasma VTG via uptake into the oocytes the outcome is more likely to be problematic in males. Therefore, this KER has more relevance in males both in the context of monitoring for exogenous estrogens and potential biological consequences of elevated VTG.

Evidence Supporting this KER

Original text - unknown contributor

High level of physiological plausibility in fish.

Added by C. Baettig on June 24, 2024

The liver is the primary source of VTG synthesis and production and after it is synthesized it is secreted into the blood (Wallace, 1985). Vitellogenin transcription and translation results in protein production, although there is a delay between expression of vtg and actual production/detection of VTG (e.g., Korte et al. 2000).

• In male tilapia, 48 hours after 17β-estradiol (E2) treatment, vtg hepatic mRNA expression was elevated as was plasma VTG (Davis et al., 2008).
• In time course studies an increase in vtg mRNA synthesis precedes increases in plasma VTG concentration. For example, a study using male fathead minnows injected with E2, vtg mRNA was detected in the liver within 4 hours, reached a maximum around 48 hours, and returned to normal levels after 6 days.  Plasma VTG was detectable within 16 hours of treatment, reached  maximum levels at about 72 hours, and did not return to normal levels for at least 18 days (Korte et al., 2000).
• Similar results were observed in a flow-through experiment using sheepshead minnows exposed to E2 and p-nonylphenol. A dose dependent increase in hepatic vtg mRNA initially occurred followed by plasma VTG increase. Their results further supported that hepatic vtg mRNA rapidly diminishes after termination of estrogenic exposure, but plasma VTG clearance is concentration and time dependent (Hemmer et al., 2002).
• Bowman et al. (2000) also found a time lag between vtg, which was elevated after 4 hours while induction of plasma VTG wasn’t detected until 24 hours in male sheepshead minnows injected with E2.
• During waterborne exposures to 17α-ethinylestradiol (EE2), male fathead minnows showed a strong increase of vtg mRNA within 3 days (first sampling time point in the study), which remained elevated for the entirety of the 35-day exposure. Although plasma VTG was first detectable on day 3 it did not significantly increase until day 14 further illustrating the lag between vtg mRNA and plasma increase (Schmid et al., 2002).
• In male fathead minnows exposed to E2 and FC-10 diol for 21 days, expression of hepatic vtg was significantly increased as was the plasma VTG (Ankley et al. in prep).

There are no known inconsistencies between these KERs which are not readily explained on the basis of the expected dose, temporal, and incidence relationships between these two KERs. This applies across a significant body of literature in which these two KEs have been measured.

Quantitative Understanding of the Linkage

Models and statistical relationships that define quantitative relationships between circulating E2 concentrations and circulating VTG concentrations have been developed (Ankley et al., 2008; Li et al., 2011; Murphy et al., 2009; Murphy et al., 2005). However, much of this work has focused on decreased VTG as a function of decreased E2, rather than induction.

Due to the timeline between induction of mRNA transcription, translation, and the appearance of protein in plasma, as well as variable rates of uptake of VTG from plasma into oocytes, a precise quantitative relationship describing all steps of vitellogenesis transcription/translation has not been described.

However, studies in fish suggest that that the temporal lag between mRNA transcription and increased plasma concentrations takes place within 24 hours. For example, in fish injected with E2 there is generally an increase of vtg mRNA beginning around 4 hours whereas plasma VTG isn’t measurable until 16-24 hours (Bowman et al., 2000; Korte et al., 2000). Additionally, in waterborne exposure of estrone (E1) in juvenile rainbow trout, elevated vtg mRNA occurred on day 4 of exposure while plasma VTG was elevated on day 5 (Osachoff et al., 2016).

There is no known feedback as plasma VTG does not appear to regulate expression levels in the liver.

References

• Ankley, G. T., Miller, D. H., Jensen, K. M., Villeneuve, D. L., & Martinović, D. (2008). Relationship of plasma sex steroid concentrations in female fathead minnows to reproductive success and population status. Aquatic Toxicology, 88(1), 69-74. https://doi.org/https://doi.org/10.1016/j.aquatox.2008.03.005
• Bowman, C. J., Kroll, K. J., Hemmer, M. J., Folmar, L. C., & Denslow, N. D. (2000). Estrogen-induced vitellogenin mRNA and protein in sheepshead minnow (Cyprinodon variegatus). General and Comparative Endocrinology, 120(3), 300-313.
• Davis, L. K., Pierce, A. L., Hiramatsu, N., Sullivan, C. V., Hirano, T., & Grau, E. G. (2008). Gender-specific expression of multiple estrogen receptors, growth hormone receptors, insulin-like growth factors and vitellogenins, and effects of 17β-estradiol in the male tilapia (Oreochromis mossambicus). General and Comparative Endocrinology, 156(3), 544-551.
• Hemmer, M. J., Bowman, C. J., Hemmer, B. L., Friedman, S. D., Marcovich, D., Kroll, K. J., & Denslow, N. D. (2002). Vitellogenin mRNA regulation and plasma clearance in male sheepshead minnows,(Cyprinodon variegatus) after cessation of exposure to 17β-estradiol and p-nonylphenol. Aquatic Toxicology, 58(1-2), 99-112.
• Korte, J. J., Kahl, M. D., Jensen, K. M., Pasha, M. S., Parks, L. G., LeBlanc, G. A., & Ankley, G. T. (2000). Fathead minnow vitellogenin: Complementary DNA sequence and messenger RNA and protein expression after 17β‐estradiol treatment. Environmental Toxicology and Chemistry: An International Journal, 19(4), 972-981.
• Li, Z., Kroll, K. J., Jensen, K. M., Villeneuve, D. L., Ankley, G. T., Brian, J. V., Sepúlveda, M. S., Orlando, E. F., Lazorchak, J. M., Kostich, M., Armstrong, B., Denslow, N. D., & Watanabe, K. H. (2011). A computational model of the hypothalamic - pituitary - gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol and 17β-trenbolone. BMC Systems Biology, 5(1), 63. https://doi.org/10.1186/1752-0509-5-63
• Murphy, C. A., Rose, K. A., Rahman, M. S., & Thomas, P. (2009). Testing and applying a fish vitellogenesis model to evaluate laboratory and field biomarkers of endocrine disruption in Atlantic croaker (Micropogonias undulatus) exposed to hypoxia. Environmental toxicology and chemistry, 28(6), 1288-1303. https://doi.org/https://doi.org/10.1897/08-304.1
• Murphy, C. A., Rose, K. A., & Thomas, P. (2005). Modeling vitellogenesis in female fish exposed to environmental stressors: predicting the effects of endocrine disturbance due to exposure to a PCB mixture and cadmium. Reproductive Toxicology, 19(3), 395-409. https://doi.org/https://doi.org/10.1016/j.reprotox.2004.09.006
• Osachoff, H. L., Brown, L. L. Y., Tirrul, L., van Aggelen, G. C., Brinkman, F. S. L., & Kennedy, C. J. (2016). Time course of hepatic gene expression and plasma vitellogenin protein concentrations in estrone-exposed juvenile rainbow trout (Oncorhynchus mykiss). Comparative Biochemistry and Physiology Part D: Genomics and Proteomics, 19, 112-119. https://doi.org/https://doi.org/10.1016/j.cbd.2016.02.002
• Schmid, T., Gonzalez-Valero, J., Rufli, H., & Dietrich, D. R. (2002). Determination of vitellogenin kinetics in male fathead minnows (Pimephales promelas). Toxicology Letters, 131(1), 65-74. https://doi.org/https://doi.org/10.1016/S0378-4274(02)00043-7
• Wallace, R. A. (1985). Vitellogenesis and oocyte growth in nonmammalian vertebrates. Oogenesis, 127-177.

Relationship: 254: Increase, Plasma vitellogenin concentrations leads to Increase, Renal pathology due to VTG deposition

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Original text - unknown contribution

Publish studies specifically relate to fish, although it is plausible that the same response may occur in the aquatic life-stages of amphibians.

Added by C. Baettig on June 24, 2024

Taxonomic applicability: Oviparous vertebrates that synthesize yolk precursor proteins and have functional kidneys.

Life stage: This KER is applicable to all life stages following the differentiation of the liver and kidney.

Sex: This KER is applicable to both sexes.

Evidence Supporting this KER

Original text - unknown contribution

High level of biological plausibility in fish.

Added by C. Baettig on June 24, 2024

When large quantities of VTG are circulating hyalin material can accumulate in the kidneys which can cause significant pathology (Folmar et al., 2001; Herman & Kincaid, 1988; Palace et al., 2002). Additionally, eosinophilic material is known to accumulate in kidney tubules and has been proposed to be due to high circulating VTG (Hahlbeck et al., 2004). Similarly, cilia proliferation observed in renal tubules is assumed to be related to increased absorption of circulating vitellogenin (Zha et al., 2008).

Original text - unknown contribution

Laboratory in vivo aquatic exposures of fish (fathead minnow) to 17alpha-ethinylestradiol led to renal pathology within 16 weeks, concomitant with macroscopic evidence of osmoregulatory dysfunction and morbidity (Laenge et al., 2001).

Added by C. Baettig on June 24, 2024

• Male summer flounder injected with 17β-estradiol (E2) had increased levels of circulating VTG. The accumulation of VTG resulted in obstruction or rupture of renal glomeruli (Folmar et al., 2001).
• Male rare minnow exposed to 17α-ethinylestradiol (EE2) and 4-nonylphenol (NP) had significantly increased plasma VTG concentrations, as did females after EE2 exposure. This resulted in hemorrhages in male kidney tubules, hypertrophy of tubular epithelia, and accumulated eosinophilic material in renal tissue (Zha et al., 2007).
• Elevated levels of VTG and kidney hypertrophy in juvenile three-spined sticklebacks was observed after exposure to E2 and EE2 (Hahlbeck et al., 2004).
• Male fathead minnows experimentally exposed to EE2 within a whole lake experiment showed 9000-fold higher VTG concentrations than fish captured from the same lake prior to the EE2 additions. Edema in the interstitium between kidney tubules and eosinophilic deposits in the kidney tubule lumen were also observed in the EE2-exposed male fatheads (Palace et al., 2002).
• After exposure to bisphenol A VTG levels increased in fathead minnows resulting in glomerular epithelial cell hyperplasia, hyaline droplets in glomeruli, glomerular mesangial membrane thickening, intravascular proteinaceous fluid, tubular dilation, and dilation of Bowman’s spaces (Mihaich et al., 2012).
• Fathead minnow embryos exposed to EE2 exhibited increased whole body VTG levels and tubular degeneration and dilation and glomerulonephritis/glomerulosclerosis was observable after 16 weeks (Länge et al., 2001).
• In male fathead minnows exposed to E2 and an estrogenic PFAS, FC-10 diol, for 21 days plasma VTG was significantly increased. Neuropathy in the kidneys of diol-exposed fish was observed, specifically tubule dilation, tubule protein, enlarged glomeruli, glomerular protein, and thickened basement membranes. Additionally, interstitial and intravascular proteinaceous fluid was significantly elevated (Ankley et al. in prep).

Original text - unknown contribution

None that the author of this entry is aware of.

Added by C. Baettig on June 24, 2024

Although the accumulation of hyalin material/lipoprotein within the kidneys has been confirmed to be partially caused by accumulated VTG, some of the accumulated proteins do not respond to VTG antibody (e.g., Folmar et al., 2001). Because male fish will also express other estrogen inducible proteins such as vitelline envelope and zona radiata some renal pathology could be caused by these related proteins rather than VTG (Johan Hyllner et al., 1994; Oppen‐Berntsen et al., 1994).

Proliferative kidney disease (PKD) in fish caused by the parasite Tetracapsuloides bryosalmonae results in significant kidney pathology. However, when PKD infection took place under simultaneous exposure to EE2, kidney pathology was less pronounced despite the fact that hepatic vtg was elevated in fish exposed to the estrogen (Bailey et al., 2019; Rehberger et al., 2020).

References

Herman, R.L., Kincaid, H.L. (1988) Pathological effects of orally administered 17beta-estradiol to rainbow trout. Aquaculture 72:165–172

Länge, R., Hutchinson, T.H., Croudace, C.P., Siegmund, F., Schweinfurth, H., Hampe, P., Panter, G.H., Sumpter, J.P. (2001) Effects of the synthetic estrogen 17 alpha-ethinylestradiol on the life-cycle of the fathead minnow (Pimephales promelas). Environ Toxicol Chem 20:1216-1227

• Bailey, C., von Siebenthal, E. W., Rehberger, K., & Segner, H. (2019). Transcriptomic analysis of the impacts of ethinylestradiol (EE2) and its consequences for proliferative kidney disease outcome in rainbow trout (Oncorhynchus mykiss). Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 222, 31-48. https://doi.org/https://doi.org/10.1016/j.cbpc.2019.04.009
• Folmar, L. C., Gardner, G. R., Schreibman, M. P., Magliulo-Cepriano, L., Mills, L. J., Zaroogian, G., Gutjahr-Gobell, R., Haebler, R., Horowitz, D. B., & Denslow, N. D. (2001). Vitellogenin-induced pathology in male summer flounder (Paralichthys dentatus). Aquatic Toxicology, 51(4), 431-441.
• Hahlbeck, E., Katsiadaki, I., Mayer, I., Adolfsson-Erici, M., James, J., & Bengtsson, B.-E. (2004). The juvenile three-spined stickleback (Gasterosteus aculeatus L.) as a model organism for endocrine disruption II—kidney hypertrophy, vitellogenin and spiggin induction. Aquatic Toxicology, 70(4), 311-326.
• Herman, R. L., & Kincaid, H. L. (1988). Pathological effects of orally administered estradiol to rainbow trout. Aquaculture, 72(1-2), 165-172.
• Johan Hyllner, S., Silvers, C., & Haux, C. (1994). Formation of the vitelline envelope precedes the active uptake of vitellogenin during oocyte development in the rainbow trout, Oncorhynchus mykiss. Molecular Reproduction and Development, 39(2), 166-175.
• Länge, R., Hutchinson, T. H., Croudace, C. P., Siegmund, F., Schweinfurth, H., Hampe, P., Panter, G. H., & Sumpter, J. P. (2001). Effects of the synthetic estrogen 17α‐ethinylestradiol on the life‐cycle of the fathead minnow (Pimephales promelas). Environmental Toxicology and Chemistry: An International Journal, 20(6), 1216-1227.
• Mihaich, E., Rhodes, J., Wolf, J., van der Hoeven, N., Dietrich, D., Hall, A. T., Caspers, N., Ortego, L., Staples, C., & Dimond, S. (2012). Adult fathead minnow, Pimephales promelas, partial life‐cycle reproductive and gonadal histopathology study with bisphenol A. Environmental toxicology and chemistry, 31(11), 2525-2535.
• Oppen‐Berntsen, D., Olsen, S., Rong, C., Taranger, G., Swanson, P., & Walther, B. (1994). Plasma levels of eggshell zr‐proteins, estradiol‐17β, and gonadotropins during an annual reproductive cycle of Atlantic salmon (Salmo salar). Journal of Experimental Zoology, 268(1), 59-70.
• Palace, V. P., Evans, R. E., Wautier, K., Baron, C., Vandenbyllardt, L., Vandersteen, W., & Kidd, K. (2002). Induction of vitellogenin and histological effects in wild fathead minnows from a lake experimentally treated with the synthetic estrogen, ethynylestradiol. Water Quality Research Journal, 37(3), 637-650.
• Rehberger, K., Wernicke von Siebenthal, E., Bailey, C., Bregy, P., Fasel, M., Herzog, E. L., Neumann, S., Schmidt-Posthaus, H., & Segner, H. (2020). Long-term exposure to low 17α-ethinylestradiol (EE2) concentrations disrupts both the reproductive and the immune system of juvenile rainbow trout, Oncorhynchus mykiss. Environment International, 142, 105836. https://doi.org/https://doi.org/10.1016/j.envint.2020.105836
• Zha, J., Sun, L., Zhou, Y., Spear, P. A., Ma, M., & Wang, Z. (2008). Assessment of 17α-ethinylestradiol effects and underlying mechanisms in a continuous, multigeneration exposure of the Chinese rare minnow (Gobiocypris rarus). Toxicology and applied pharmacology, 226(3), 298-308.
• Zha, J., Wang, Z., Wang, N., & Ingersoll, C. (2007). Histological alternation and vitellogenin induction in adult rare minnow (Gobiocypris rarus) after exposure to ethynylestradiol and nonylphenol. Chemosphere, 66(3), 488-495.

Relationship: 3258: Increase, Renal pathology due to VTG deposition leads to Increased Mortality

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Taxonomic applicability: All vertebrates with functional kidneys.

Life stage: This KER is applicable to all life stages following the differentiation of the kidney.

Sex: This KER is applicable to both sexes.

Evidence Supporting this KER

The kidneys perform a suite of physiological roles that are critical for organismal homeostasis including waste excretion, osmoregulation, and fluid homeostasis (Preuss, 1993). The renal system can incur damage from a variety of sources which can lead to a loss of renal functions such as decreased glomerular filtration rate or impaired clearance of waste products which can lead to death (McKee & Wingert, 2015).

For example, in fish exposed to estrogenic compounds there is evidence that excessive production of vitellogenin (VTG), which leads to renal failure, increases mortality in fish (Herman & Kincaid, 1988). Generally, the molecular mass of proteins in glomerular filtrate are lower than albumin but when proteins like VTG are deposited in the kidneys they cannot be resorbed and the excess protein can lead to glomerular rupturing or hemorrhaging (Tojo & Kinugasa, 2012). Ultimately these pathologies can cause acute renal failure resulting in mortality.

• Male summer flounder injected with 17β-estradiol (E2) had increased levels of circulating VTG. The accumulation of VTG resulted in obstruction or rupture of renal glomeruli. Glomerular injury including immunoreactive hyalin material within the glomerular capsule, increased drainage into Bowman’s space and renal tubules. Mortality observed after E2 treatment likely resulted from  acute renal failure associated with excessive VTG accumulation in the kidney (Folmar et al., 2001).
• High mortality was observed in rainbow trout fed E2. The accumulation of circulating VTG most likely resulted in hypertrophy of the kidneys (Herman & Kincaid, 1988). 
• Abdel-Tawwab et al. (2020) found that in European sea bass fed dietary zearalenone combined with exposure to a pathogen, Vibrio alginolyticus, increased mortality. A depletion of serum total protein, albumin, and globulin was observed in in zearalenone fed fish which resulted in kidney dysfunction and ultimately increased mortality.
• Exposure to microcystin-LR (MC-LR) resulted in kidney lesions consisting of coagulative tubular necrosis with a dilation of Bowman's space and caused mortality in rainbow trout (Kotak et al., 1996). Mortality is most likely due to MC-LR resulting in significantly dysregulating proteins related to ionic regulation (Shahmohamadloo et al., 2022).
• Laboratory in vivo aquatic exposures of fathead minnow to EE2 led to renal pathology within 16 weeks, concomitant with macroscopic evidence of osmoregulatory dysfunction and morbidity (Länge et al., 2001). 
• Proliferative kidney disease caused by Tetracapsuloides bryosalmonae in salmonid fish result in significant kidney lesions and often resulted in mortality (e.g., Bettge et al., 2009; Schmidt-Posthaus et al., 2015; Sterud et al., 2007).
• In male fathead minnows exposed to the estrogenic PFAS FC-10 diol for 21 days neuropathy in the kidneys was observed, specifically tubule dilation, tubule protein, enlarged glomeruli, glomerular protein, and thickened basement membranes. Additionally, interstitial and intravascular proteinaceous fluid was significantly elevated. Elevated mortality in males was also observed (Ankley et al. in prep).

References

• Abdel-Tawwab, M., Khalifa, E., Diab, A. M., Khallaf, M. A., Abdel-Razek, N., & Khalil, R. H. (2020). Dietary garlic and chitosan alleviated zearalenone toxic effects on performance, immunity, and challenge of European sea bass, Dicentrarchus labrax, to Vibrio alginolyticus infection. Aquaculture International, 28, 493-510.
• Bettge, K., Wahli, T., Segner, H., & Schmidt-Posthaus, H. (2009). Proliferative kidney disease in rainbow trout: time-and temperature-related renal pathology and parasite distribution. Diseases of aquatic organisms, 83(1), 67-76.
• Folmar, L. C., Gardner, G. R., Schreibman, M. P., Magliulo-Cepriano, L., Mills, L. J., Zaroogian, G., Gutjahr-Gobell, R., Haebler, R., Horowitz, D. B., & Denslow, N. D. (2001). Vitellogenin-induced pathology in male summer flounder (Paralichthys dentatus). Aquatic Toxicology, 51(4), 431-441.
• Herman, R. L., & Kincaid, H. L. (1988). Pathological effects of orally administered estradiol to rainbow trout. Aquaculture, 72(1-2), 165-172.
• Kotak, B. G., Semalulu, S., Fritz, D. L., Prepas, E. E., Hrudey, S. E., & Coppock, R. W. (1996). Hepatic and renal pathology of intraperitoneally administered microcystin-LR in rainbow trout (Oncorhynchus mykiss). Toxicon, 34(5), 517-525.
• Länge, R., Hutchinson, T. H., Croudace, C. P., Siegmund, F., Schweinfurth, H., Hampe, P., Panter, G. H., & Sumpter, J. P. (2001). Effects of the synthetic estrogen 17α‐ethinylestradiol on the life‐cycle of the fathead minnow (Pimephales promelas). Environmental Toxicology and Chemistry: An International Journal, 20(6), 1216-1227.
• McKee, R. A., & Wingert, R. A. (2015). Zebrafish Renal Pathology: Emerging Models of Acute Kidney Injury. Current Pathobiology Reports, 3(2), 171-181. https://doi.org/10.1007/s40139-015-0082-2
• Preuss, H. G. (1993). Basics of renal anatomy and physiology. Clinics in laboratory medicine, 13(1), 1-11.
• Schmidt-Posthaus, H., Hirschi, R., & Schneider, E. (2015). Proliferative kidney disease in brown trout: Infection level, pathology and mortality under field conditions. Diseases of aquatic organisms, 114(2), 139-146.
• Shahmohamadloo, R. S., Ortiz Almirall, X., Simmons, D. B. D., Poirier, D. G., Bhavsar, S. P., & Sibley, P. K. (2022). Fish tissue accumulation and proteomic response to microcystins is species-dependent. Chemosphere, 287, 132028. https://doi.org/https://doi.org/10.1016/j.chemosphere.2021.132028
• Sterud, E., Forseth, T., Ugedal, O., Poppe, T. T., Jørgensen, A., Bruheim, T., Fjeldstad, H.-P., & Mo, T. A. (2007). Severe mortality in wild Atlantic salmon Salmo salar due to proliferative kidney disease (PKD) caused by Tetracapsuloides bryosalmonae (Myxozoa). Diseases of aquatic organisms, 77(3), 191-198.
• Tojo, A., & Kinugasa, S. (2012). Mechanisms of glomerular albumin filtration and tubular reabsorption. Int J Nephrol, 2012, 481520. https://doi.org/10.1155/2012/481520

Relationship: 2013: Increased Mortality leads to Decrease, Population growth rate

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Taxonomic: All organisms must survive to reproductive age in order to reproduce and sustain populations. The additional considerations related to survival made above are applicable to other fish species in addition to zebrafish and fathead minnows with the same reproductive strategy (r-strategist as described in the theory of MaxArthur and Wilson (1967). The impact of reduced survival on population size is even greater for k-strategists that invest more energy in a lower number of offspring.

Life stage: Density dependent effects start to play a role in the larval stage of fish when free-feeding starts (Hazlerigg et al., 2014).

Sex: This linkage is independent of sex.

Key Event Relationship Description

Increased mortality in the reproductive population may lead to a declining population. This depends on the excess mortality due to the applied stressor and the environmental parameters such as food availability and predation rate. Most fish species are r-strategist, meaning they produce a lot of offspring instead of investing in parental care. This results in natural high larval mortality causing only a small percentage of the larvae to survive to maturity. If the excess larval mortality due to a stressor is small, the population dynamics might result in constant population size. Should the larval excess be more significant, or last on the long-term, this will affect the population. To calculate the long-term persistence of the population, population dynamic models should be used.

Evidence Supporting this KER

Survival rate is an obvious determinant of population size and is therefore included in population modeling (e.g., Miller et al., 2020).

• Survival to reproductive maturity is a parameter of demographic significance. Assuming resource availability (i.e., food, habitat, etc.) is not limiting to the extant population, sufficient mortality in the reproductive population may ultimately lead to declining population trajectories.
• Under some conditions, reduced larval survival may be compensated by reduced predation and increased food availability, and therefore not result in population decline (Stige et al., 2019).

• According to empirical data, combined with population dynamic models, feeding larvae are the crucial life stage in zebrafish (and other r-strategists) for the regulation of the population. (Schäfers et al., 1993)
• In fathead minnow, natural survival of early life stages has been found to be highly variable and influential on population growth (Miller and Ankley, 2004)
• Rearick et al. (2018) used data from behavioural assays linked to survival trials and applied a modelling approach to quantify changes in antipredator escape performance of larval fathead minnows in order to predict changes in population abundance. This work was done in the context of exposure to an environmental oestrogen. Exposed fish had delayed response times and slower escape speeds, and were more susceptible to predation. Population modelling showed that this can result in population decline.
• In the context of fishing and fisheries, ample evidence of a link between increased mortality and a decrease of population size has been given. Important insights can result from the investigation of optimum modes of fishing that allow for maintaining a population (Alekseeva and Rudenko, 2018). Jacobsen and Essington (2018) showed the impact of varying predation mortality on forage fish populations.
• Boreman (1997) reviewed methods for comparing the population-level effects of mortality in fish populations induced by pollution or fishing.

• The extent to which larval mortality affects population size could depend on the fraction of surplus mortality compared to a natural situation.
• There are scenarios in which individual mortality may not lead to declining population size. These include instances where populations are limited by the availability of habitat and food resources, which can be replenished through immigration. Effects of mortality in the larvae can be compensated by reduced competition for resources (Stige et al., 2019).
• The direct impact of pesticides on migration behavior can be difficult to track in the field, and documentation of mortality during migration is likely underestimated (Eng 2017).

References

Alekseeva SM, Rudenko AI. 2018. Modeling of optimum fishing population. Marine Intellectual Technologies. 3(4):142-146.

Beaudouin, R., Goussen, B., Piccini, B., Augustine, S., Devillers, J., Brion, F., Pery, A.R., 2015. An individual-based model of zebrafish population dynamics accounting for energy dynamics. PloS one 10, e0125841.

Boreman J. 1997. Methods for comparing the impacts of pollution and fishing on fish populations. Transactions of the American Fisheries Society. 126(3):506-513.

Caswell, H., 2000. Matrix population models. Sinauer Sunderland, MA, USA.

Eng, M.L., Stutchbury, B.J.M. & Morrissey, C.A. Imidacloprid and chlorpyrifos insecticides impair migratory ability in a seed-eating songbird. Sci Rep 7, 15176 (2017)

Hazlerigg, C.R., Lorenzen, K., Thorbek, P., Wheeler, J.R., Tyler, C.R., 2012. Density-dependent processes in the life history of fishes: evidence from laboratory populations of zebrafish Danio rerio. PLoS One 7, e37550.

Jacobsen NS, Essington TE. 2018. Natural mortality augments population fluctuations of forage fish. Fish and Fisheries. 19(5):791-797.

MacArthur, R., Wilson, E., 1967. The Theory of Island Biogeography. Princeton: Princeton Univ. Press. 203 p.

Miller, D.H., Ankley, G.T., 2004. Modeling impacts on populations: fathead minnow (Pimephales promelas) exposure to the endocrine disruptor 17β-trenbolone as a case study. Ecotoxicology and Environmental Safety 59, 1-9.

Miller, D.H., Clark, B.W., Nacci, D.E. 2020. A multidimensional density dependent matrix population model for assessing risk of stressors to fish populations. Ecotoxicology and environmental safety 201, 110786

Pinceel, T., Vanschoenwinkel, B., Brendonck, L., Buschke, F., 2016. Modelling the sensitivity of life history traits to climate change in a temporary pool crustacean. Scientific reports 6, 29451.

Rearick, D.C., Ward, J., Venturelli, P., Schoenfuss, H., 2018. Environmental oestrogens cause predation-induced population decline in a freshwater fish. Royal Society open science 5, 181065.

Schäfers, C., Oertel, D., Nagel, R., 1993. Effects of 3, 4-dichloroaniline on fish populations with differing strategies of reproduction. In: Braunbeck, T. , Hanke, W and Segner, H. (eds) Ecotoxicology and Ecophysiology, VCH, Weinheim, 133-146.

Stige, L.C., Rogers, L.A., Neuheimer, A.B., Hunsicker, M.E., Yaragina, N.A., Ottersen, G., Ciannelli, L., Langangen, Ø., Durant, J.M., 2019. Density‐and size‐dependent mortality in fish early life stages. Fish and Fisheries 20, 962-976.Hazlerigg, C.R.E., Tyler, C.R., Lorenzen, K., Wheeler, J.R., Thorbek, P., 2014. Population relevance of toxicant mediated changes in sex ratio in fish: An assessment using an individual-based zebrafish (Danio rerio) model. Ecological Modelling 280, 76-88.

Stige, L.C., Rogers, L.A., Neuheimer, A.B., Hunsicker, M.E., Yaragina, N.A., Ottersen, G., Ciannelli, L., Langangen, O., Durant, J.M., 2019. Density- and size-dependent mortality in fish early life stages. Fish and Fisheries 20, 962-976.