Mycoestrogen

Mycoestrogens are xenoestrogens produced by fungi. They are sometimes referred to as mycotoxins,[1] though this labelling has been called a misnomer by some because of their steroidal characteristics.[2] Among important mycoestrogens are zearalenone, zearalenol and zearalanol.[3] Although all of these can be produced by various Fusarium species,[4][5] zearalenol and zearalanol may also be produced endogenously in ruminants that have ingested zearalenone.[6][7] Alpha-zearalanol is also produced semisynthetically, for veterinary use; such use is prohibited in the European Union.[8]

Mechanism of action

Mycoestrogens act as agonists of the estrogen receptors, ERα and ERβ.

Affinities of estrogen receptor ligands for the ERα and ERβ

Ligand	Other names	Relative binding affinities (RBA, %)^a		Absolute binding affinities (Ki, nM)^a		Action
		ERα	ERβ	ERα	ERβ
Estradiol	E2; 17β-Estradiol	100	100	0.115 (0.04–0.24)	0.15 (0.10–2.08)	Estrogen
Estrone	E1; 17-Ketoestradiol	16.39 (0.7–60)	6.5 (1.36–52)	0.445 (0.3–1.01)	1.75 (0.35–9.24)	Estrogen
Estriol	E3; 16α-OH-17β-E2	12.65 (4.03–56)	26 (14.0–44.6)	0.45 (0.35–1.4)	0.7 (0.63–0.7)	Estrogen
Estetrol	E4; 15α,16α-Di-OH-17β-E2	4.0	3.0	4.9	19	Estrogen
Alfatradiol	17α-Estradiol	20.5 (7–80.1)	8.195 (2–42)	0.2–0.52	0.43–1.2	Metabolite
16-Epiestriol	16β-Hydroxy-17β-estradiol	7.795 (4.94–63)	50	?	?	Metabolite
17-Epiestriol	16α-Hydroxy-17α-estradiol	55.45 (29–103)	79–80	?	?	Metabolite
16,17-Epiestriol	16β-Hydroxy-17α-estradiol	1.0	13	?	?	Metabolite
2-Hydroxyestradiol	2-OH-E2	22 (7–81)	11–35	2.5	1.3	Metabolite
2-Methoxyestradiol	2-MeO-E2	0.0027–2.0	1.0	?	?	Metabolite
4-Hydroxyestradiol	4-OH-E2	13 (8–70)	7–56	1.0	1.9	Metabolite
4-Methoxyestradiol	4-MeO-E2	2.0	1.0	?	?	Metabolite
2-Hydroxyestrone	2-OH-E1	2.0–4.0	0.2–0.4	?	?	Metabolite
2-Methoxyestrone	2-MeO-E1	<0.001–<1	<1	?	?	Metabolite
4-Hydroxyestrone	4-OH-E1	1.0–2.0	1.0	?	?	Metabolite
4-Methoxyestrone	4-MeO-E1	<1	<1	?	?	Metabolite
16α-Hydroxyestrone	16α-OH-E1; 17-Ketoestriol	2.0–6.5	35	?	?	Metabolite
2-Hydroxyestriol	2-OH-E3	2.0	1.0	?	?	Metabolite
4-Methoxyestriol	4-MeO-E3	1.0	1.0	?	?	Metabolite
Estradiol sulfate	E2S; Estradiol 3-sulfate	<1	<1	?	?	Metabolite
Estradiol disulfate	Estradiol 3,17β-disulfate	0.0004	?	?	?	Metabolite
Estradiol 3-glucuronide	E2-3G	0.0079	?	?	?	Metabolite
Estradiol 17β-glucuronide	E2-17G	0.0015	?	?	?	Metabolite
Estradiol 3-gluc. 17β-sulfate	E2-3G-17S	0.0001	?	?	?	Metabolite
Estrone sulfate	E1S; Estrone 3-sulfate	<1	<1	>10	>10	Metabolite
Estradiol benzoate	EB; Estradiol 3-benzoate	10	?	?	?	Estrogen
Estradiol 17β-benzoate	E2-17B	11.3	32.6	?	?	Estrogen
Estrone methyl ether	Estrone 3-methyl ether	0.145	?	?	?	Estrogen
ent-Estradiol	1-Estradiol	1.31–12.34	9.44–80.07	?	?	Estrogen
Equilin	7-Dehydroestrone	13 (4.0–28.9)	13.0–49	0.79	0.36	Estrogen
Equilenin	6,8-Didehydroestrone	2.0–15	7.0–20	0.64	0.62	Estrogen
17β-Dihydroequilin	7-Dehydro-17β-estradiol	7.9–113	7.9–108	0.09	0.17	Estrogen
17α-Dihydroequilin	7-Dehydro-17α-estradiol	18.6 (18–41)	14–32	0.24	0.57	Estrogen
17β-Dihydroequilenin	6,8-Didehydro-17β-estradiol	35–68	90–100	0.15	0.20	Estrogen
17α-Dihydroequilenin	6,8-Didehydro-17α-estradiol	20	49	0.50	0.37	Estrogen
Δ^8-Estradiol	8,9-Dehydro-17β-estradiol	68	72	0.15	0.25	Estrogen
Δ^8-Estrone	8,9-Dehydroestrone	19	32	0.52	0.57	Estrogen
Ethinylestradiol	EE; 17α-Ethynyl-17β-E2	120.9 (68.8–480)	44.4 (2.0–144)	0.02–0.05	0.29–0.81	Estrogen
Mestranol	EE 3-methyl ether	?	2.5	?	?	Estrogen
Moxestrol	RU-2858; 11β-Methoxy-EE	35–43	5–20	0.5	2.6	Estrogen
Methylestradiol	17α-Methyl-17β-estradiol	70	44	?	?	Estrogen
Diethylstilbestrol	DES; Stilbestrol	129.5 (89.1–468)	219.63 (61.2–295)	0.04	0.05	Estrogen
Hexestrol	Dihydrodiethylstilbestrol	153.6 (31–302)	60–234	0.06	0.06	Estrogen
Dienestrol	Dehydrostilbestrol	37 (20.4–223)	56–404	0.05	0.03	Estrogen
Benzestrol (B2)	–	114	?	?	?	Estrogen
Chlorotrianisene	TACE	1.74	?	15.30	?	Estrogen
Triphenylethylene	TPE	0.074	?	?	?	Estrogen
Triphenylbromoethylene	TPBE	2.69	?	?	?	Estrogen
Tamoxifen	ICI-46,474	3 (0.1–47)	3.33 (0.28–6)	3.4–9.69	2.5	SERM
Afimoxifene	4-Hydroxytamoxifen; 4-OHT	100.1 (1.7–257)	10 (0.98–339)	2.3 (0.1–3.61)	0.04–4.8	SERM
Toremifene	4-Chlorotamoxifen; 4-CT	?	?	7.14–20.3	15.4	SERM
Clomifene	MRL-41	25 (19.2–37.2)	12	0.9	1.2	SERM
Cyclofenil	F-6066; Sexovid	151–152	243	?	?	SERM
Nafoxidine	U-11,000A	30.9–44	16	0.3	0.8	SERM
Raloxifene	–	41.2 (7.8–69)	5.34 (0.54–16)	0.188–0.52	20.2	SERM
Arzoxifene	LY-353,381	?	?	0.179	?	SERM
Lasofoxifene	CP-336,156	10.2–166	19.0	0.229	?	SERM
Ormeloxifene	Centchroman	?	?	0.313	?	SERM
Levormeloxifene	6720-CDRI; NNC-460,020	1.55	1.88	?	?	SERM
Ospemifene	Deaminohydroxytoremifene	2.63	1.22	?	?	SERM
Bazedoxifene	–	?	?	0.053	?	SERM
Etacstil	GW-5638	4.30	11.5	?	?	SERM
ICI-164,384	–	63.5 (3.70–97.7)	166	0.2	0.08	Antiestrogen
Fulvestrant	ICI-182,780	43.5 (9.4–325)	21.65 (2.05–40.5)	0.42	1.3	Antiestrogen
Propylpyrazoletriol	PPT	49 (10.0–89.1)	0.12	0.40	92.8	ERα agonist
16α-LE2	16α-Lactone-17β-estradiol	14.6–57	0.089	0.27	131	ERα agonist
16α-Iodo-E2	16α-Iodo-17β-estradiol	30.2	2.30	?	?	ERα agonist
Methylpiperidinopyrazole	MPP	11	0.05	?	?	ERα antagonist
Diarylpropionitrile	DPN	0.12–0.25	6.6–18	32.4	1.7	ERβ agonist
8β-VE2	8β-Vinyl-17β-estradiol	0.35	22.0–83	12.9	0.50	ERβ agonist
Prinaberel	ERB-041; WAY-202,041	0.27	67–72	?	?	ERβ agonist
ERB-196	WAY-202,196	?	180	?	?	ERβ agonist
Erteberel	SERBA-1; LY-500,307	?	?	2.68	0.19	ERβ agonist
SERBA-2	–	?	?	14.5	1.54	ERβ agonist
Coumestrol	–	9.225 (0.0117–94)	64.125 (0.41–185)	0.14–80.0	0.07–27.0	Xenoestrogen
Genistein	–	0.445 (0.0012–16)	33.42 (0.86–87)	2.6–126	0.3–12.8	Xenoestrogen
Equol	–	0.2–0.287	0.85 (0.10–2.85)	?	?	Xenoestrogen
Daidzein	–	0.07 (0.0018–9.3)	0.7865 (0.04–17.1)	2.0	85.3	Xenoestrogen
Biochanin A	–	0.04 (0.022–0.15)	0.6225 (0.010–1.2)	174	8.9	Xenoestrogen
Kaempferol	–	0.07 (0.029–0.10)	2.2 (0.002–3.00)	?	?	Xenoestrogen
Naringenin	–	0.0054 (<0.001–0.01)	0.15 (0.11–0.33)	?	?	Xenoestrogen
8-Prenylnaringenin	8-PN	4.4	?	?	?	Xenoestrogen
Quercetin	–	<0.001–0.01	0.002–0.040	?	?	Xenoestrogen
Ipriflavone	–	<0.01	<0.01	?	?	Xenoestrogen
Miroestrol	–	0.39	?	?	?	Xenoestrogen
Deoxymiroestrol	–	2.0	?	?	?	Xenoestrogen
β-Sitosterol	–	<0.001–0.0875	<0.001–0.016	?	?	Xenoestrogen
Resveratrol	–	<0.001–0.0032	?	?	?	Xenoestrogen
α-Zearalenol	–	48 (13–52.5)	?	?	?	Xenoestrogen
β-Zearalenol	–	0.6 (0.032–13)	?	?	?	Xenoestrogen
Zeranol	α-Zearalanol	48–111	?	?	?	Xenoestrogen
Taleranol	β-Zearalanol	16 (13–17.8)	14	0.8	0.9	Xenoestrogen
Zearalenone	ZEN	7.68 (2.04–28)	9.45 (2.43–31.5)	?	?	Xenoestrogen
Zearalanone	ZAN	0.51	?	?	?	Xenoestrogen
Bisphenol A	BPA	0.0315 (0.008–1.0)	0.135 (0.002–4.23)	195	35	Xenoestrogen
Endosulfan	EDS	<0.001–<0.01	<0.01	?	?	Xenoestrogen
Kepone	Chlordecone	0.0069–0.2	?	?	?	Xenoestrogen
o,p'-DDT	–	0.0073–0.4	?	?	?	Xenoestrogen
p,p'-DDT	–	0.03	?	?	?	Xenoestrogen
Methoxychlor	p,p'-Dimethoxy-DDT	0.01 (<0.001–0.02)	0.01–0.13	?	?	Xenoestrogen
HPTE	Hydroxychlor; p,p'-OH-DDT	1.2–1.7	?	?	?	Xenoestrogen
Testosterone	T; 4-Androstenolone	<0.0001–<0.01	<0.002–0.040	>5000	>5000	Androgen
Dihydrotestosterone	DHT; 5α-Androstanolone	0.01 (<0.001–0.05)	0.0059–0.17	221–>5000	73–1688	Androgen
Nandrolone	19-Nortestosterone; 19-NT	0.01	0.23	765	53	Androgen
Dehydroepiandrosterone	DHEA; Prasterone	0.038 (<0.001–0.04)	0.019–0.07	245–1053	163–515	Androgen
5-Androstenediol	A5; Androstenediol	6	17	3.6	0.9	Androgen
4-Androstenediol	–	0.5	0.6	23	19	Androgen
4-Androstenedione	A4; Androstenedione	<0.01	<0.01	>10000	>10000	Androgen
3α-Androstanediol	3α-Adiol	0.07	0.3	260	48	Androgen
3β-Androstanediol	3β-Adiol	3	7	6	2	Androgen
Androstanedione	5α-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Etiocholanedione	5β-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Methyltestosterone	17α-Methyltestosterone	<0.0001	?	?	?	Androgen
Ethinyl-3α-androstanediol	17α-Ethynyl-3α-adiol	4.0	<0.07	?	?	Estrogen
Ethinyl-3β-androstanediol	17α-Ethynyl-3β-adiol	50	5.6	?	?	Estrogen
Progesterone	P4; 4-Pregnenedione	<0.001–0.6	<0.001–0.010	?	?	Progestogen
Norethisterone	NET; 17α-Ethynyl-19-NT	0.085 (0.0015–<0.1)	0.1 (0.01–0.3)	152	1084	Progestogen
Norethynodrel	5(10)-Norethisterone	0.5 (0.3–0.7)	<0.1–0.22	14	53	Progestogen
Tibolone	7α-Methylnorethynodrel	0.5 (0.45–2.0)	0.2–0.076	?	?	Progestogen
Δ^4-Tibolone	7α-Methylnorethisterone	0.069–<0.1	0.027–<0.1	?	?	Progestogen
3α-Hydroxytibolone	–	2.5 (1.06–5.0)	0.6–0.8	?	?	Progestogen
3β-Hydroxytibolone	–	1.6 (0.75–1.9)	0.070–0.1	?	?	Progestogen
Footnotes: ^a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Sources

Mycoestrogens are produced by various strains of fungi, many of which fall under the genus fusarium. Fusarium fungi are filamentous fungi that are found in the soil and are associated with plants and some crops, especially cereals.[9] Zearalenone is mainly produced by F. graminearum and F. culmorum strains, which inhabit different areas depending on temperature and humidity. F. graminearum prefers to inhabit warmer and more humid locations such as Eastern Europe, Northern America, Eastern Australia, and Southern China in comparison to F. colmorum which is found in colder Western Europe.[10]

Health effects

Mycoestrogens mimic natural estrogen in the body by acting as estrogen receptor (ER) ligands.[9] Mycoestrogens have been identified as endocrine disruptors due to their high binding affinity for ERα and ERβ, exceeding that of well known antagonists such as bisphenol A and DDT.[11] Studies have been performed that strongly suggest a relationship between detectable levels of mycoestrogen and growth and pubertal development. More than one study has shown that detectable levels of zearalenone and its metabolite alpha-zearalanol in girls are associated with significantly shorter heights at menarche.[1][11] Other reports have documented premature onset of puberty in girls. Estrogen are known to cause decreased body weight in model animals, and the same effect has been seen in rats exposed to zearalenone.[12] Interactions of ZEN and its metabolite with human androgen receptors (hAR) have also been documented.[10]

Metabolism

Zearalenone has two major phase I metabolites: α-zearalenol and β-zearalenol.[12][10] When exposed orally ZEN is absorbed by the intestinal lining and metabolized there as well as in the liver.[12] Research into the metabolism of ZEN has been difficult because of the significant difference in biotransformation between species making comparison challenging.

Phase I

The first transformation of metabolism of ZEN will reduce the ketone group to an alcohol via aliphatic hydroxylation and result in the formation of the two zearalenol metabolites. This process is catalyzed by 3 α- and 3 β-hydroxy steroid dehydrogenase (HSD). CYP450 enzymes will then catalyze aromatic hydroxylation at the 13 or 15 position resulting in 13- or 15- catechols. Steric hindrance of at the 13 position is suspected to be the reason that in humans and rats there is more of the 15-catechol present. The catechols are the processed into mono-ethyl esters by catechol-o-methyl transferase (COMT) and S-adenosyl methionine (SAM). After this transformation they may be metabolized further to quinones which can cause the formation of reactive oxygen species (ROS) and cause covalent modification of DNA.[13]

Phase II

In phase-II metabolizing includes glucuronidation and sulfation of the mycoestrogen compound. Glucuronidation is the major phase II metabolic pathway. The transferase UGT (5'-diphosphate glucuronosyltransferase) adds a glucuronic acid group sourced from uridine 5'-diphosphate glucuronic acid (UDPGA).[13]

Excretion

Mycoestrogens and their metabolites are largely excreted in urine in humans and in feces in other animal systems.[13]

In food

Mycoestrogens are commonly found in stored grain. They can come from fungi growing on the grain as it grows, or after harvest during storage. Mycoestrogens can be found in silage.[14] Some estimates state that 25% of global cereal production and 20% of global plant production may be at some point contaminated by mycotoxins of which mycoestrogens, especially those from fusarium strains, may make up a significant portion.[10] Among mycoestrogens that contaminate plants are ZEN and its phase I metabolites. The limit for ZEN in unprocessed cereals, milling products, and cereal foodstuffs is 20-400 μg/kg (depending on the product in question).[10]

Types

• trans ZEN isomer[15]

References

1. Rivera-Núñez Z, Barrett ES, Szamreta EA, Shapses SA, Qin B, Lin Y, Zarbl H, Buckley B, Bandera EV (March 2019). "Urinary mycoestrogens and age and height at menarche in New Jersey girls". Environmental Health. 18 (1): 24. doi:10.1186/s12940-019-0464-8. PMC 6431018. PMID 30902092.
2. "Mycoestrogen - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2019-05-30.
3. Fink-Gremmels, J.; Malekinejad, H. (October 2007). "Clinical effects and biochemical mechanisms associated with exposure to the mycoestrogen zearalenone". Animal Feed Science and Technology. 137 (3–4): 326–341. doi:10.1016/j.anifeedsci.2007.06.008.
4. Richardson, Kurt E.; Hagler, Winston M.; Mirocha, Chester J. (September 1985). "Production of zearalenone, .alpha.- and .beta.-zearalenol, and .alpha.- and .beta.-zearalanol by Fusarium spp. in rice culture". Journal of Agricultural and Food Chemistry. 33 (5): 862–866. doi:10.1021/jf00065a024.
5. Hsieh HY, Shyu CL, Liao CW, Lee RJ, Lee MR, Vickroy TW, Chou CC (April 2012). "Liquid chromatography incorporating ultraviolet and electrochemical analyses for dual detection of zeranol and zearalenone metabolites in mouldy grains". Journal of the Science of Food and Agriculture. 92 (6): 1230–7. doi:10.1002/jsfa.4687. PMID 22012692.
6. Miles CO, Erasmuson AF, Wilkins AL, Towers NR, Smith BL, Garthwaite I, Scahill BG, Hansen RP (October 1996). "Ovine metabolism of zearalenone to α-zearalanol (zeranol)". Journal of Agricultural and Food Chemistry. 44 (10): 3244–50. doi:10.1021/jf9601325.
7. Kennedy DG, Hewitt SA, McEvoy JD, Currie JW, Cannavan A, Blanchflower WJ, Elliot CT (1998). "Zeranol is formed from Fusarium spp. toxins in cattle in vivo". Food Additives and Contaminants. 15 (4): 393–400. doi:10.1080/02652039809374658. PMID 9764208.
8. Thevis M, Fusshöller G, Schänzer W (2011). "Zeranol: doping offence or mycotoxin? A case-related study". Drug Testing and Analysis. 3 (11–12): 777–83. doi:10.1002/dta.352. PMID 22095651.
9. Ding X, Lichti K, Staudinger JL (June 2006). "The mycoestrogen zearalenone induces CYP3A through activation of the pregnane X receptor". Toxicological Sciences. 91 (2): 448–55. doi:10.1093/toxsci/kfj163. PMC 2981864. PMID 16547076.
10. Bryła M, Waśkiewicz A, Ksieniewicz-Woźniak E, Szymczyk K, Jędrzejczak R (April 2018). "Fusarium Mycotoxins in Cereals and Their Products-Metabolism, Occurrence, and Toxicity: An Updated Review". Molecules. 23 (4). doi:10.3390/molecules23040963. PMC 6017960. PMID 29677133.
11. Bandera EV, Chandran U, Buckley B, Lin Y, Isukapalli S, Marshall I, King M, Zarbl H (November 2011). "Urinary mycoestrogens, body size and breast development in New Jersey girls". The Science of the Total Environment. 409 (24): 5221–7. Bibcode:2011ScTEn.409.5221B. doi:10.1016/j.scitotenv.2011.09.029. PMC 3312601. PMID 21975003.
12. Hueza IM, Raspantini PC, Raspantini LE, Latorre AO, Górniak SL (March 2014). "Zearalenone, an estrogenic mycotoxin, is an immunotoxic compound". Toxins. 6 (3): 1080–95. doi:10.3390/toxins6031080. PMC 3968378. PMID 24632555.
13. Mukherjee D, Royce SG, Alexander JA, Buckley B, Isukapalli SS, Bandera EV, Zarbl H, Georgopoulos PG (2014-12-04). "Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study". PLOS One. 9 (12): e113632. Bibcode:2014PLoSO...9k3632M. doi:10.1371/journal.pone.0113632. PMC 4256163. PMID 25474635.
14. González Pereyra ML, Alonso VA, Sager R, Morlaco MB, Magnoli CE, Astoreca AL, Rosa CA, Chiacchiera SM, Dalcero AM, Cavaglieri LR (April 2008). "Fungi and selected mycotoxins from pre- and postfermented corn silage". Journal of Applied Microbiology. 104 (4): 1034–41. doi:10.1111/j.1365-2672.2007.03634.x. PMID 18005347.
15. Marin S, Ramos AJ, Cano-Sancho G, Sanchis V (October 2013). "Mycotoxins: occurrence, toxicology, and exposure assessment". Food and Chemical Toxicology. 60: 218–37. doi:10.1016/j.fct.2013.07.047. PMID 23907020.