37
In: Endocrine Disrupters
T. Grotmol, A. Bernhoft, G.S. Eriksen and T.P. Flaten, eds.
Oslo: The Norwegian Academy of Science and Letters, 2006.
Animal exposure to endocrine disrupters – synthetic
chemical contaminants and natural compounds in the diet
Aksel Bernhoft
National Veterinary Institute, Department of Food and Feed Hygiene, Section of
Toxicology, P.O. Box 8156 Dep, NO-0033 Oslo, Norway
E-mail: [email protected]
Telephone: +47 23 21 62 60
Telefax: +47 23 21 62 01
Abstract
Domestic and wild animals are dietary exposed to synthetic and natural
compounds acting as endocrine disrupters. Persistent organic pollutants
(POPs), including old pesticides like DDT, as well as PCBs, dioxins and
furans, are important synthetic endocrine disrupting contaminants with
their world wide distribution. Fish-eating animals and others at the top of
marine food webs are those mostly exposed to POPs. Domestic grasseating animals may be exposed to synthetic endocrine disrupting chemicals
in roughage or drinking water via recent use of pesticides, manure from
hormone treated animals or sewage sludge. Grass-eating animals are exposed to phytoestrogens, whereof particularly sheep and also cattle may be
affected. Pigs are sensitive to the mycoestrogen zearalenone and may also
develop symptoms after intake of amounts of phytoestrogens in soybeans.
Disturbed thyroid function may occur in pigs and ruminants fed goitrogenic
glucosinolates present in common fodder plants in the Brassica family. In
wild ruminants, adverse effects due to herbal endocrine disrupters are not
reported, which may indicate less exposure or adaptation.
Introduction – the term endocrine disrupter
The topic of this chapter is dietary exposure of domestic and wild animals to
synthetic chemical contaminants and natural compounds which may disrupt endocrine functions. Within the wild animals, terrestrial mammals will be focused
as other chapters of this book cover such exposures to fish, birds and Arctic
marine mammals. Furthermore, pharmaceutical substances and feed additives
with endocrine disrupting effects are also covered in a separate chapter.
The term endocrine disrupter is often used in relation to exogenous estrogenic
compounds and to reproductive effects, but exogenous compounds changing
other endocrine functions are also endocrine disrupters. On the other hand, not
38
all exogenous compounds eliciting reproductive effects are endocrine disrupters
as such effects may be produced by several other mechanisms than endocrine
disruption. Thus, to be classified as an endocrine disrupter the compounds’ mechanism of action should be known or at least suggested. As such mechanisms
may not be understood to detail, several compounds may be “misclassified”. For
several practical purposes, a mechanism of action may be of less importance
than a thorough description of the effects produced by the chemical compound.
Several of, in particular, the synthetic chemical contaminants may elicit their
effects via various mechanisms and an attempt to define these chemicals as
endocrine disrupters will restrict the description and also the total toxicological
signification of the compounds. However, mechanistic approaches are certainly
of great importance for the basic and comprehensive toxicological knowledge.
But incomplete mechanistic knowledge may imply a wrong track in risk
management. For less toxicologically complicated compounds as several of the
natural ones, the classification term endocrine disrupter may be more adequate.
Basic modes of action
The basic modes of action of endocrine disrupters are 1) interaction with
(steroid) hormone receptors, 2) modification of synthesis, transport, storage or
metabolism of hormones, 3) perturbation of hypothalamic-pituitary release of
tropic hormones (neuroendocrine regulation) and in addition, 4) miscellaneous
other less characterised modes of action (1).
The diversity of endocrine disrupters available for animal exposure in general
are in addition to several pharmaceutical substances and some feed additives covered separately, several pesticides, industrial chemicals, industrial by-products,
phyto-estrogens and -antithyroids, and mycoestrogens.
Synthetic endocrine disrupting contaminants
Several pesticides are classified as endocrine disrupters. Handbook of pesticide
toxicology (2) lists about 15 fungicides, 15 insecticides and 15 herbicides termed endocrine disrupters. Most of these pesticides are categorised as endocrine
disrupters via a single mechanism of action but some of them are involved in
more than one mechanism. For example the fungicides vinclozolin and procymidone, and the herbicide linuron block the androgen receptor and do also perturb
the neuroendocrine regulation of estrogenic production. The insecticides o,p’DDT and methoxychlor agonise the estrogenic receptors and do also perturb the
neuroendocrine regulation of estrogenic production. More than 20 of the endocrine disrupting pesticides listed perturb the neuroendocrine regulation of
thyroid function, thus, other mechanisms than via reproductive steroid hormone
regulation are commonly present. In addition, a range of the about 45 pesticides
may also elicit adverse effects not explained by the endocrine disrupter mechanisms.
39
Industrial by-products as polychlorinated dibenzo-dioxins and -furans, and
industrial chemicals as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), alkyl phenols and -ethoxylates, and phthalate esters are
classified as endocrine disrupters (1). PCBs, dioxins, furans and PBDEs may
disrupt normal endocrine function via various mechanisms. For PCBs, dioxins,
furans the affinity to the Ah-receptor plays a central role. Alkyl phenols have
primarily an agonistic effect on estrogenic receptors and phthalate esters an inhibitory effect on Sertoli cells.
Animals exposed to synthetic endocrine disrupting contaminants
Persistent organic pollutants (POPs), including old pesticides like DDT, as well
as PCBs, dioxins and furans, are important synthetic endocrine disrupting
contaminants, with their world wide distribution. However, it is well-known that
these compounds also act via mechanisms not covered by the endocrine disrupter term and the concert of various actions is expressed differently from those
via endocrine disruption alone. Fish-eating animals and other animals at or close
to the top of marine food webs are mostly exposed to POPs. Wild mink, otter,
some seal and whale species, polar bear, sea birds and birds of prey are animals
of concern. Concerning wild mink and otter, the dramatic regional decline in
their populations in the USA and Europe was suspected to be caused by environmental PCB exposure (3). Farmed mink fed fish may also be heavily exposed to
endocrine disrupter POPs, and the adverse effect of PCBs in the food web was
discovered in USA during the 1960s as reproductive failures and mortality
among farmed mink fed contaminated fish from the Great Lakes (4). Other farmed animals, except fish, are in general far less exposed to the environmentally
distributed POPs but some cases of accidental poisoning causing adverse effects
are reported. A recent case was the crisis in Belgium in 1999 where chicken,
hens, and pigs fed PCB contaminated feed resulted in reduced hatchability of
eggs, reduced viability of chicken and residues in animal products for human
exposure (5).
Domestic grass-eating animals may be unintentionally exposed to endocrine
disrupting pesticides if grazing on recently sprayed areas, or if silage or hay is
made from such grass. Pesticides may also contaminate the drinking water.
Herbivorous domestic animals may also be exposed to synthetic endocrine disrupters on pasture treated with manure from hormone treated animals or on
pasture treated with sewage sludge. Silage or hay from these grasses may also
contain residues of the endocrine disrupting chemicals (6). Manure and sewage
sludge also contain naturally occurring estrogenic hormones but their levels may
be reduced due to physical degradation.
Dependent on type of feeding stuff, carnivorous pet animals (dogs and cats)
may be exposed to various amounts of POPs and also other synthetic endocrine
disrupters following the human lifestyle.
40
Natural endocrine disrupting compounds
The natural endocrine disrupting compounds in animal diet include compounds
produced by plants and moulds. Lignans and isoflavonoids are phytoestrogens.
Lignans are minor components of the plant cell wall, found at highest concentrations in oil seeds – particularly in flaxseed, but also considerably present in
whole grains, cereal brans, legumes and other vegetables. The plant lignans are
converted by gastrointestinal microorganisms to the active compounds enterolactone or enterodiol (7).
The isoflavonoids are less prevalent than the lignans but more potent as
phytoestrogens. They occur in legumes, particularly in soybeans and products
thereof, as well as in alfalfa and some clover species. The isoflavonoids constitute a range of active compounds, where the isoflavones genistein and daidzein
(from soybeans and clover) and the coumestan compound coumestrol (in soybeans and alfalfa) are of major importance (7).
In plants most phytoestrogens occur in the glycosidic form. Before absorption
in the animals they are hydrolysed by gastrointestinal microorganisms. The extent of hydrolysis, absorption and further metabolism varies with animal species,
strain and other ingredients of the diet. The phytoestrogen content of edible
plants changes during season and also year by year. High nitrogen fertilizer
applications reduce the content of phytoestrogens. Some plants may induce their
production of phytoestrogens as a response to infections by insects, bacteria or
Fusarium moulds. Thus, Fusarium infected plants may contain both phyto- and
mycoestrogens (see below) (8).
The endocrine disrupting mould compound of concern is the mycoestrogen
zearalenone. The mycotoxin is produced by some Fusarium species infecting
grains and maize, and pasture grasses and legumes including alfalfa and clovers
(8). In general, the phyto- and mycoestrogenic compounds are far more potent
estrogenic compounds than the synthetic industrial contaminants and byproducts mentioned above. Zearalenone and phytoestrogens as genistein and
coumestrol stimulate the transcriptional activity of the estrogen receptors at
more than 100 times lower concentrations than the most estrogenic synthetic
chemicals (for example nonylphenol and o,p’-DDT) (9).
A plant produced group of compounds which may disrupt endocrine function
in a different way than those with estrogenic effect are the goitrogenic glucosinolates. They are present in plants in the Brassica family, which includes
common fodder plants and vegetables as rape, cabbage and broccoli. The compounds are particularly present in their seeds. They interfere with the iodine
capture by the thyroid gland and with the synthesis of thyroxin (8).
Animals exposed to natural endocrine disrupting compounds
All grass-eating animals are exposed to phytoestrogens but not all seem to be
affected (8). Sheep are most commonly affected by isoflavones in clover, and
sheep as well as cattle may be affected by coumestans in alfalfa. Horses may
41
grass on pastures with phytoestrogenic plants without adverse effects. Pigs may
develop symptoms after intake of amounts of soybeans. Pigs are also relatively
sensitive to the mycoestrogen zearalenone and clinical symptoms and reproduction problems in sows due to this mycotoxin are frequently reported internationally. Cattle and sheep are less susceptible to zearalenone but effects are also
reported in these species. Wild ruminants are certainly also exposed to natural
endocrine disrupting compounds but reports on effects are lacking. More variation in the diet composition and possibly a degree of adaptation to these natural
bioactive compounds may make the wild ruminants more robust.
The goitrogenic glucosinolates are present particularly in the seeds of
common fodder plants and intoxication is a topic for domestic animals. The
compounds may induce hypothyroidism and goitre in pigs and ruminants (8).
Final comments
The effect of the endocrine disrupters is certainly related to dose and to the duration of exposure – a certain exposure level of natural endocrine disrupters may
even be beneficial. The animal susceptibility is also dependent on the stage of
development of the target tissues. Usually are pre- and post-natal exposures
more dramatic than at adulthood. Furthermore are exposures to other toxic compounds and the animals’ nutritional and immune status of major importance
(10).
The synthetic contaminants are in general weak endocrine disrupters compared with most of the natural compounds but the synthetic chemicals do often
elicit their effects via a more complicated register of mechanisms. Thus, endocrine disrupters may not be the accurate term to describing compounds with a
range of effects produced via various mechanisms. Due to the present broad
environmental occurrence and the complicated effect register, the synthetic
contaminants termed endocrine disrupters, in total seem to constitute global
animal health threats which are more extensive than those from the more perspicuous natural endocrine disrupters.
References
1. IPCS. Global Assessment of the State-of-the-Science of Endocrine Disruptors. International Programme on Chemical Safety, World Health Organization, 2002; 180pp.
2. Kavlock, R.J. Pesticides as endocrine-disrupting chemicals. In: Krieger R,
ed. Handbook of Pesticide toxicology, vol 1 Principles, 2nd edn. San Diego:
Academic Press, 2001: 727-746.
3. Gilbertson M. Effects on fish and wildlife populations. In: Kimbrough RD,
Jensen AA, eds. Halogenated biphenyls, terphenyls, naphtalenes, dibenzodioxins and related products, Amsterdam: Elsevier, 1989: 103-127.
42
4. Aulerich RJ, Ringer RK, Iwamoto S. Reproductive failure and mortality in
mink fed on Great lakes fish. J Reprod Fert Suppl 1973; 19: 365-376.
5. Hoogenboom LAP, Kan CA, Bovee TF, van der Weg G, Onstenk C, Traag
WA. Residues of dioxins and PCBs in fat of growing pigs and broilers fed
contaminated feed. Chemosphere 2004; 57: 35-42.
6. Radostits OM, Gay CC, Blood DC, Hinchcliff KW. Diseases caused by
inorganic and farm chemicals. In: Veterinary Medicine, 9th edn. London: WB
Saunders, 2000: 1573-1630.
7. Patisaul HB, Whitten PL. Dietary phytoestrogens. In: Naz RK, ed. Endocrine
disruptors. Effects on male and female reproductive systems, Boca Raton:
CRC Press, 1999: 89-123.
8. Radostits OM, Gay CC, Blood DC, Hinchcliff KW. Diseases caused by
toxins in plants, fungi, cyanophytes, clavibacteria, and venoms in ticks and
vertebrate animals. In: Veterinary Medicine, 9th edn. London: WB Saunders,
2000: 1631-1708.
9. Kuiper GGJM, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag
PT, van der Burg B, Gustafsson J-Å. Interation of estrogenic chemicals and
phytoestrogens with estrogen receptor b. Endocrinology 1998; 139: 42524263.
10. Sweeney T. Is exposure to endocrine disrupting compounds during fetal/
post-natal development affecting the reproductive potential of farm animals?
Domest Anim Endocrinol 2002; 23: 203-209.