Endocrine Disruptors

2. How do EDCs act?

• 2.1 What are the mechanisms involved in EDC action?
• 2.2 What are the major life stages when EDCs could act?
• 2.3 What are the relationships between the EDC dose and effect?

2.1 What are the mechanisms involved in EDC action?

The source document for this Digest states:

Research has clearly shown that EDCs can act at multiple sites via multiple mechanisms of action. Receptor-mediated mechanisms have received the most attention, but other mechanisms (e.g., hormone synthesis, transport, and metabolism) have been shown to be equally important. For most associations reported between exposure to EDCs and a variety of biologic outcomes, the mechanism(s) of action are poorly understood. This makes it difficult to distinguish between direct and indirect effects and primary versus secondary effects of exposure to EDCs. It also indicates that considerable caution is necessary in extrapolating from in vitro data to in vivo effects, in predicting effects from limited in vivo data, and in extrapolating from experimental data to the human situation. A collective weight of evidence is essential in determining under what conditions observed effects resulting from exposure to EDCs occur via endocrine-mediated mechanisms. This document outlines a number of criteria that can be used as a basis for attribution of an effect to an endocrine-mediated mechanism.

Source & ©: IPCS "Global Assessment of the state-of-the-science of Endocrine disruptors "
 Executive Summary (Chapter 1) page 1 section 1.2

For further details on the mechanism of endocrine disruption in humans and wildlife, see IPCS  Chapter 2, section 2.3., page 5.

The endocrine system:

For details on :	See IPCS assessment:
Criteria that can be used to assess whether an effect can be attributed to a suspected endocrine disruptor	Chapter 3, section 3.16, page 32,Chapter 7, sections 7.1 - 7.3, page 123.
The hypothalamic-pituitary-gonadal (HPG) axis in mammals	Chapter 3, section 3.3.1, page 13
Factors which modify the sensitivity of a target cell to its stimulating hormone	Chapter 3, section 3.3.2, page 14.
Transport and metabolism of hormones	Chapter 3, section 3.3.3, page 14
Paracrine systems that act as local satellites of the major endocrine axes, to serve local needs	Chapter 3, section 3.3.4, page 14.
Programming of the brain during development to become either a male or a female	Chapter 3, section 3.3.5, page 14.
The role of androgens in sex differentiation of the genitalia	Chapter 3, section 3.3.6, page 15.
The HPG axis in nonmammalian vertebrates, which are surprisingly similar to mammals	Chapter 3, section 3.3.7, page 16.
The hypothalamic-pituitary-adrenal (HPA) axis in mammals that responds to stress and has other endocrine functions	Chapter 3, section 3.4.1, page 17
The HPA axis in nonmammals that has actions similar to those in mammals	Chapter 3, section 3.4.2, page 17
The hypothalamic-pituitary-thyroid (HPT) axis in mammals which regulates metabolic activity	Chapter 3, section 3.5.1, page 17
The HPT axis of nonmammals that is very similar to that of mammals	Chapter 3, section 3.5.2, page 18.
The pineal gland that is responsive to light and affects the rhythms of the body	Chapter 3, section 3.6, page 18.
New pathways of communication and functional overlap between the various endocrine systems that are still being discovered	Chapter 3, section 3.10, page 19.
Effects of sex steroids on systems other than reproduction, (the brain, digestive system, immune system and adipose tissue) and interactions with other endocrine axes that target these tissues	Chapter 3, section 3.10, page 19. Chapter 3, section 3.11, page 20.

2.2 What are the major life stages when EDCs could act?

The source document for this Digest states:

Despite an overall lack of knowledge of mechanisms of action of EDCs, there are several examples where the mechanism of action is clearly related to direct perturbations of endocrine function and ultimately to adverse in vivo effects. These examples also illustrate the following important issues:

• Exposure to EDCs during the period when “programming” of the endocrine system is in progress may result in a permanent change of function or sensitivity to stimulatory/inhibitory signals,
• Exposure in adulthood may be compensated for by normal homeostatic mechanisms and may therefore not result in any significant or detectable effects,
• Exposure to the same level of an endocrine signal during different life history stages or during different seasons may produce different effects,
• Because of cross talk between different components of the endocrine systems, effects may occur unpredictably in endocrine target tissues other than the system predicted to be affected.

Considerable data are available on the early molecular events involved in hormone response, but there is little knowledge of the relationship between these molecular events and the potential for adverse health outcomes. Until such data become available, it will remain difficult and controversial to attribute adverse effects due to endocrine-mediated pathways.

Source & ©: IPCS "Global Assessment of the state-of-the-science of Endocrine disruptors "
 Executive Summary (Chapter 1) page 1 section 1.2

Critical points on Endocrine systems:

For details on:	See IPCS assessment:
Basic facts about homeostasis	Chapter 3, section 3.2.2, page 12
Programming of the endocrine axes, which are established during fetal/neonatal development	Chapter 3, section 3.2.3, page 12
Issues that are critical when considering the impact of EDCs	Chapter 3, section 3.2.4, page 13

How endocrine systems communicate with each other (cross talk):

For details on:	See IPCS assessment:
Cross talk between the various endocrine systems that may have different consequences at different stages of life	Chapter 3, section 3.9, page 19
Difficulties in predicting the reproductive consequences of a given chemical from its known sex steroid hormone activity or inactivity	Chapter 3, section 3.11, page 20

Mechanism of action of EDCs:

For details on anti-androgens:	See IPCS assessment:
Anti-androgens that inhibit the binding of natural androgens to the androgen receptor (AR)	Chapter 3, section 3.12.2, page 21
Anti-androgenic activity of vinclozolin, DDE, methoxychlor (MXC) metabolite HPTE, fenitrothion and procymidone in mammals	Chapter 3, section 3.12.2.1, page 21  Chapter 3, section 3.12.2.2, page 22
Sexual dimorphisms in fish that are affected by both androgens and estrogens	Chapter 3, section 3.12.2.3, page 22
Effects of vinclozolin on the pituitary-adrenal axis in mammals	Chapter 3, section 3.12.2.4, page 23

For details on estrogens:	See IPCS assessment:
Estrogenic activity of bisphenol A and DES that bind to the estrogen receptor (ER) in mammals	Chapter 3, section 3.12.3.1, page 23
Methoxychlor (MXC) has multiple EDC action, as an ER-a agonist, an ER-b antagonist and an AR antagonist	Chapter 3, section 3.12.3.2, page 24
Estrogenic activity of octylphenol, nonylphenol, bisphenol A, DDT, ethynyl estradiol and MXC in fish and frogs	Chapter 3, section 3.12.3.3, page 24

For details on inhibitors of steroid hormone synthesis:	See IPCS assessment:
Fungicides that can inhibit synthesis of steroid hormones in mammals	Chapter 3, section 3.12.4.1, page 25
Ketoconazole which if used as a therapeutic antiandrogen leads to gynecomastia (formation of breasts in males)	Chapter 3, section 3.12.4.2, page 25
Pharmaceutical agents for treatment of postmenopausal breast cancer that inhibit the enzyme aromatase, which converts androgen to estrogen	Chapter 3, section 3.12.4.3, page 25
Finasteride that inhibits the enzyme 5a -reductase, which converts testosterone to dihydrotestosterone	Chapter 3, section 3.12.4.3, page 25
Phthalates such as DEHP, DBP, BBP, di-isonyl phthalate that affect androgen synthesis in fetal males	Chapter 3, section 3.12.4.5, page 26

For details on AhR agonists:	See IPCS assessment:
Effects of dioxins and dioxin-like substances (TCDD, PCBs and PCDFs) that are mediated through the aryl hydrocarbon receptor (AhR)	Chapter 3, section 3.12.5, page 27

For details on eggshell thinning:	See IPCS assessment:
Proposed mechanisms for DDE-induced eggshell thinning	Chapter 3, section 3.12.6, page 28 Chapter 4, section 4.2.2.4, page 38

For details on atrazine and cancer:	See IPCS assessment:
Atrazine exposure delays puberty and accelerates reproductive aging in rats	Chapter 3, section 3.13, page 29

EDC-related mode of action in neurotoxicity & immunotoxicity:

For details on:	See IPCS Assessment:
Chemicals that alter neurotransmitter concentrations , such as PCBs , and are likely to influence neuroendocrine function and ultimately reproduction	Chapter 3, section 3.14.1, page 30
Aromatase in mammalian brains, its role in sexual differentiation and the influence of PCBs	Chapter 3, section 3.14.2, page 31
How immune responsiveness is affected by the balance between male and female sex hormones, estradiol and testosterone	Chapter 3, section 3.15, page 31

2.3 What are the relationships between the EDC dose and effect?

The source document for this Digest states:

The issue of dose-response relationships is perhaps the most controversial issue regarding EDCs. One of the reasons is that EDCs often act by mimicking or antagonizing the actions of naturally occurring hormones. These hormones (often more potent than exogenous EDCs) are present at physiologically functional concentrations, so the dose-response considerations for EDCs are often different than for other environmental chemicals, which are not acting directly on the endocrine system. Reports of low-dose effects of EDCs are highly controversial and the subject of intense research. dose-response relationships are likely to vary for different chemicals and endocrine mechanisms. Timing of exposure is absolutely critical to the understanding of dose-response relationships for EDCs. This is true for both wildlife and humans and for cancer as well as for developmental, reproductive, immunological, and neurological effects. Numerous examples exist in the literature where age at exposure is a known risk factor.

Source & ©: IPCS "Global Assessment of the state-of-the-science of Endocrine disruptors "
 Executive Summary (Chapter 1) page 2 section 1.3

The dose–response considerations for EDCs are often differen from other environmental chemicals. For details see IPCS Chapter 2, section 2.4, page 7. For low-dose effects on the prostate see IPCS Chapter 5, section 5.1.6.5.4, page 66.