API

Relationship: 2072

Title

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Decreased, cholesterol leads to Decreased, 11KT

Upstream event

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Decreased, cholesterol

Downstream event

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Decreased, 11KT

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
PPARalpha Agonism Impairs Fish Reproduction adjacent High Not Specified

Taxonomic Applicability

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Term Scientific Term Evidence Link
teleost fish teleost fish High NCBI
Vertebrates Vertebrates Low NCBI

Sex Applicability

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Sex Evidence
Male High
Female Low

Life Stage Applicability

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Key Event Relationship Description

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The cholesterol molecule is the precursor for all steroid hormone synthesis. Cholesterol is obtained from de novo synthesis within cells or uptake of extracellular cholesterol (Eacker et al., 2008), however the dependence on either source varies by species (Klinefelter et al., 2014). Cholesterol is then transported into the inner mitochondrial membrane via the steroidogenic acute regulatory protein (StAR). Cholesterol is then converted to pregnenolone via the enzyme cytochrome P450 side-chain cleavage (cyp11a1). This is the rate-limiting step of steroidogenesis (Arukwe, 2008). Pregnenolone is then used to produce all other steroid hormones. 11-KT is synthesized from testosterone primarily using the enzymes CYP11β1 and HSD11β2 (Yazawa et al., 2008).

Evidence Supporting this KER

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Time

Dose

Decreased Cholesterol?

Decreased

11-KT?

Citation

Species

48 hours

1.7, 33, & 70 mg/g Bezafibrate

No

No

Velasco-Santamaría et al. 2011

Danio Rerio

7 days

33 & 70 mg/g Bezafibrate

Yes

No

21 days

1.7 & 33 mg/g Bezafibrate

Yes

No

21 days

70 mg/g Bezafibrate

Yes

Yes

67 days

10 ug/L Gemfibrozil

Decreased ex vivo 11-KT production unless supplemented with 25OH-cholesterol

Fraz et al. 2018

Danio Rerio

21 days

0.04 mg/L Gemfibrozil

Yes

No

Lee et al. 2019

Oryzias latipes

21 days

0.4 & 3.7 mg/L Gemfibrozil

Yes

Yes

Biological Plausibility

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The process of steroid hormone biosynthesis is well understood, and cholesterol is the precursor for all steroid hormones.

Empirical Evidence

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Dose Concordance

In male zebrafish bezafibrate lowers cholesterol in lower doses than 11KT (Velasco-Santamaría et al. 2011).

In male medaka gemfibrozil lowers cholesterol in a lower dose than 11KT (Lee et al. 2019)

Temporal Concordance

Male zebrafish fed bezafibrate show lowered cholesterol days before lowered 11KT (Velasco-Santamaría et al. 2011).

Incidence Concordance

Fraz et al. (2018) show reduced ex vivo production of 11KT in male Zebrafish, due to gemfibrozil exposure, is corrected by addition of 25-hydroxycholesterol. This means the decreased steroid synthesis is due to decreased cholesterol availability. Addition of human chorionic gonadotropin, which binds to the LHCG receptor to promote 11KT synthesis, does not correct the decrease in 11KT.

Uncertainties and Inconsistencies

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Although Al-Habsi et al. (2016) show female zebrafish exposed to gemfibrozil and/or atorvastatin have decreased cholesterol and testosterone, decreased testosterone was not seen in males. Although several papers show 11KT is generally correlated with testosterone concentrations (Spanò et al., 2004; Maclatchy & Vanderkraak 1995; Lorenzi et al., 2008), it’s uncertain if 11KT was actually affected.

11KT levels can have high variability between fish. Although Lee et al. (2019) shows a decrease in testosterone and 11KT in a 21-day study, steroid measurements from the 155-day study showed no significant effects. This is possibly due to limited samples size (n=3-5).

Quantitative Understanding of the Linkage

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Response-response Relationship

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Velasco-Santamaría et al. (2011) sampled male zebrafish fed several doses of bezafibrate (1.7, 33, & 70 mg BZF/g food) at several timepoints (48 hours, 7 days, and 21 days). Decreased plasma cholesterol is observed after 7 days to 33 mg/g. However, 11-KT isn’t significantly decreased until 21 days to 70 mg/g. There is a positive linear correlation between cholesterol and 11KT (r=0.291, p=0.0004). These decreases are observed without significant changes to cyp11a1 or StAR.

Male medaka exposed to gemfibrozil for 21 days show decreased cholesterol with doses of 0.03, 0.3, and 3.0 mg/L. However, decreases in 11KT is only significant at doses of 0.3 and 3.0 mg/L (Lee et al. 2019).

Time-scale

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Decreases in cholesterol in Zebrafish due to bezafibrate exposure can be seen after 7 days, however, decreases in plasma 11-KT aren’t significant until 14 days later (Velasco-Santamaría et al. 2011).

A six-week exposure to gemfibrozil, a cholesterol-lowering pharmaceutical, is sufficient to lower 11-KT levels in the plasma, testes, and whole-body samples of male Zebrafish (Fraz et al. 2018). A 21-day exposure to gemfibrozil is sufficient to lower plasma cholesterol and 11-KT levels in male Japanese Medaka (Lee et al. 2019).

 

Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Decreases in plasma cholesterol are correlated with a slight increase in StAR in zebrafish (Velasco-Santamaría et al. 2011). This is a possible compensatory mechanism to increase the amount of cholesterol in the mitochondria.

Domain of Applicability

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Taxanomic Applicability: The understanding of steroid hormone biosynthesis is developed from human and rodent studies but is generally conserved among vertebrates. Cyp11a1, which performs the first step of converting cholesterol to steroid hormones, is only found in vertebrates (Slominski et al., 2015). However, the relationship may not be relevant or studied in organisms in which 11KT isn't a primary androgen. 11KT is particularly relevant teleost fish as it is the dominant androgen and involved in testicular development and courtship behavior (Brantley et al., 1993; Barannikova et al., 2004; Gemmell et al., 2019). Evidence supporting this KER comes from a few fish species, including zebrafish and medaka, but is biologically plausible for all teleost fish.

Sex Applicability: Male and female fish use the same biological processes to produce steroids and express the necessary enzymes. In most fish species 11KT is significantly lower in females versus males, however a a few species of the order Perciformes show no sexual dimorphism (Lokman et al. 2002). In species with sexual dimorphism, males could show more significant effects resulting from lowered 11-KT than females. Decreased production of 11-KT in females may not be detectable due to low baseline production, however there are few studies available showing the relationship between cholesterol and 11KT in female fish. 

Life-Stage Applicability:

 

References

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Al-Habsi, A.A., A. Massarsky, T.W. Moon (2016) “Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (Danio rerio)”, Comparative Biochemistry and Physiology, Part B, Vol. 199, Elsevier, pp. 87-96. http://dx.doi.org/10.1016/j.cbpb.2015.11.009

Arukwe, A. (2008) “Steroidogenic acute regulatory (StAR) protein and cholesterol side-chain cleavage (P450scc)-regulated steroidogenesis as an organ-specific molecular and cellular target for endocrine disrupting chemical in fish”, Cell Biology and Toxicology, Vol. 24, Springer, pp. 527-540. https://doi.org/10.1007/s10565-008-9069-7

Barannikova, I.A., L.V. Bayunova, T.B. Semenkova (2004) “Serum levels of testosterone, 11-ketotestosterone and oestradiol-17β in three species of sturgeon during gonadal development and final maturation induced by hormonal treatment”, Journal of Fish Biology, Vol. 64(5), Wiley-Blackwell, pp. 1330-1338. https://doi.org/10.1111/j.0022-1112.2004.00395.x

Brantley, R.K., J.C. Wingfield, A.H. Bass (1993) “Sex steroid levels in Porichthys notatus, a fish with alternative reproductive tactics, and a review of the hormonal bases for male dimorphism among teleost fishes”, Hormones and Behavior, Vol. 27(3), Elsevier, pp. 332-347. https://doi.org/10.1006/hbeh.1993.1025

Eacker, S. M. et al. (2008) “Hormonal regulation of testicular steroid and cholesterol homeostasis”, Molecular Endocrinology, Vol. 22(3), pp. 623-635. https://doi.org/10.1210/me.2006-0534

Fraz, S., A.H. Lee, J.Y. Wilson (2018) “Gemfibrozil and carbamazepine decrease steroid production in zebrafish testes (Danio rerio)”, Aquatic Toxicology, Vol. 198, Elsevier, pp. 1-9. https://doi.org/10.1016/j.aquatox.2018.02.006

Gemmell, N.J. et al. (2019) “Natural sex change in fish”, in Sex Determination in Vertebrates, Vol. 134, Academic Press, pp. 71-117. doi: 10.1016/bs.ctdb.2018.12.014.

Klinefelter, G.R., J.W. Laskey, R.P. Amann (2014) “Statin drugs markedly inhibit testosterone production by rat Leydig cells in vitro: Implications for men”, Reproductive Toxicology, Vol. 45, Elsevier, pp. 52-58. https://doi.org/10.1016/j.reprotox.2013.12.010

Lee, G. et al. (2019) “Effects of gemfibrozil on sex hormones and reproduction related performances of Oryzias latipes following long-term (155 d) and short-term (21 d) exposure”, Ecotoxicology and Environmental Safety, Vol. 173, Elsevier, pp. 174-181. https://doi.org/10.1016/j.ecoenv.2019.02.015

Lokman, P.M. et al. (2002) “11-Oxygenated androgens in female teleosts: prevalence, abundance, and life history implications”, General and Comparative Endocrinology, Vol. 129, Academic Press, pp. 1-12. doi: 10.1016/s0016-6480(02)00562-2

Lorenzi, V. et al. (2008) “Diurnal patterns and sex differences in cortisol, 11-ketotestosterone, testosterone, and 17β-estradiol in the bluebanded goby (Lythrypnus dalli)”, General and Comparative Endocrinology, Vol. 155(2)., Elsevier, pp. 438-446. https://doi.org/10.1016/j.ygcen.2007.07.010

MacLatchy, D.L., G.J. Vanderkraak (1995) “The phytoestrogen β-sitosterol alters the reproductive endocrine status of goldfish”, Toxicology and Applied Pharmacology, Vol. 134(2), Elsevier, pp. 305-312. https://doi.org/10.1006/taap.1995.1196

Slominski, A.T. et al. (2015) “Novel activities of CYP11A1 and their potential physiological significance”, The Journal of Steroid Biochemistry and Molecular Biology, Vol. 151, Elsevier, pp. 25-37. https://doi.org/10.1016/j.jsbmb.2014.11.010

Spanó, L. et al. (2004) “Effects of atrazine on sex steroid dynamics, plasma vitellogenin concentration and gonad development in adult goldfish (Carassius auratus)”, Aquatic Toxicology, Vol. 66(4), Elsevier, pp. 369-379. https://doi.org/10.1016/j.aquatox.2003.10.009

Velasco-Santamaría, Y.M. et al. (2011) “Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (Danio rerio)”, Aquatic Toxicology, Vol. 105, Elsevier, pp. 107-118. doi:10.1016/j.aquatox.2011.05.018

Yazawa, T. (2008) “Cyp11b1 is induced in the murine gonad by luteinizing hormone/human chorionic gonadotropin and involved in the production of 11-ketotestosterone, a major fish androgen: Conservation and evolution of the androgen metabolic pathway”, Endocrinology, Vol. 149(4), Oxford Academy, pp. 1786-1792. https://doi.org/10.1210/en.2007-1015