Midterm 3 Flashcards
MOA of Atrazine
Imbalance in steroid levels
Alters LH and FSH so effecting hypothalamus/pituitary hormone secretion
Adverse effects (gonad development)
Why is Atrazine used? What is the concentrations in BC?
Broadleaf weed control on crops (corn, blueberries…)
Detected in 71-75% waterways in BC
Where is Atraine banned? Why? Maximum concentrations of pesticides in water?
EU banned Atrazine due to persistent groundwater contamination.
Maximum level of 0.1 ug/L
Concentrations of Atrazine in Canada vs US
Canada: 5 ug/L
US: 3 ug/L
What is Endocrinology?
The study of the endocrine glands and their secretions (hormones)
What are endocrine glands?
Ductless glands that secrete hormones into the blood
Expanded Definition/Funciton of Hormones
- Hormones are not necessarily produced by ductless glands - hormones can be secreted by small groups of cells or even by individual cells
- Secretion from an endocrine gland or cell is not uni-hormonal - multiple active chemicals are produced by a cell
- Most hormones have multiple production sites
- Hormones are not only secreted into the bloodstream - they are not always blood borne - they can be released into lymph or extracellular fluids
- Hormone action cannot by stereotyped - it vaires according to the state of the target site. This may be determined by the receptors expressed in the target cell/ Action dependent on the state of the target - must be a receptor on the cell.
- Hormones do not always act on distant target sites - they can have paracrine or autocrine effects
Necessity of Multicellular Organisms for Hormones
The evolution of multicellular organisms made it necessary to have coordinating systems to regulate and integrate the function of different cells
Mechanisms of Water Soluble Hormone Action
(All amino acid-based hormones except thyroid hormone)
- Cannot enter target cells
- Act on plasma membrane receptors
- Coupled by G proteins to intracellular second messengers that mediate the target cell’s response
Mechanisms of Lipid Soluble Hormone Action
(Steroid and Thyroid Hormones)
- Act on intracellular receptors that directly activare genes
Mechanism of Xenobiotic Disruption of Endocrine Systems
- Hormone action exerted via Binding Receptors:
- Can be initiated by chemicals if able to bind to receptor and generate hormone response
- Can by blocked by chemical if binds and blocks receptor site without induction of hormone
Other Mechanisms or Xenobiotic Disruption of Endocrine System
Hormone synthesis, secretion, transport, or elimination
Consequences of Receptor-Mediated Signalling
- Hormones act at low levels
- Largest effect at lower doses
- Saturation of receptors and thus effect at high doses
- Desensitization and down-regulation of receptors at high-hormone levels (bind to gene decreases transcription levels - decrease hormonal effects)
- EDCs act via receptors are subject to same conequences
How is Hormonal action Life-Stage Specific
- Low doses matter
- Effects at high dose does not predict effects at low dose
- Early life exposure produce adverse effects in adulthood
Traditional Toxicology Concepts
- The higher the dose, the more toxic
- Endpoints: gene mutations, weight loss, death, and tested at high levels
Chemicals with Endocrine Activity Act Via Principles of Endocrinology and thus:
- May act at low doses
- Should by expected to have non-monotonic dose responses
- Will have tissue specific and time specific effects
- Will show different effects and dose responses during development relative to adults
- WIll likely NOT have a threshold
Evidence of EDC Effects in Wildlife and Humans
Mammals: reproductive and immune function Baltic Seals (organochlorines - PCB)
Birds: egg shell thinning (DDT)
Reptiles: Apopka alligators gonadal and devel. abnormalities (organochlorines)
Fish: ALtered steroid levels, gonad size, and reproduction (industrial and municipal effluents)
Invertebrates: Masculinization of marine gastropods (TBT)
Humans (controversial) - reproductive effects (sperm count, puberty, cancers)
3 Lines of Evidence Fuel Concerns over Endocrine Disruptors
- Increase trends of many endocrine-related disorders in humans
- Observations of endocrine-related effects in wildlife populations
- Lab studies linking chemicals with endocrine effects to disease outcomes
BPA as Developmentally Inducing Human Disease
- Reproductive/ Endocrine System - breast or prostate cancer, endometriosis, infertility, diabetes, early puberty, obesity
- Pulmono-cardiovascular System - heart disease, hypertension, stroke
How Many Endocrine Axes Disrupted by Environmental Contaminants?
Reproductive axis: Estrogenic/ anti-estrogenic and Androgenic/ anti-androgenic
Stress Axis: Anto-adrenal
Thyroid Axis: thyroidogenic/ anti-thyroidogenic
Definition of EDS
A substance that has the ability to disrupt the synthesis, secretion, transport, binding, action or elimination of hormones in an organism or its progent that is responsible for the maintenance of homeostasis, reproduction, development, or behaviour of an organism
3 Testing and Assessment Strategies
Mammalian
Ecotoxicity tests
Non-animal tests
EDTA Task Force replaced by EDTA Advisory Group to:
Begin assessment of endocrine disruptors
Examine case reports from OECD countries
Review conceptual framework
OECD Tests to Identify EDS
In vitro: estrogen and androgen receptor binding affinity, human estrogen receptor transcriptional activation, androgen or thyroid transactivation
In vivo: Uterotrophic and Hershberger (rats), amphibian metamorphosis assay…
In vivp (extended/ transgenerational) - rodent, fish, frog, bird, invertebrates
Countries Implementing EDS Testing
US, Japan, EU require information about the endocrine disrupting effects of chemicals
Canada: No mandatory testing strategy and OECD test guidelines
Pulp Mill Effluent Effects
Fish downstream of pulp and paper mill effluent -> sex steroids (decrease gonad size and delayed sexual maturity)
MOA for Hormone Mimic/Blocker
Brain (Telencephalon and hypothalamus) -> Pituitary (GnRH) -> Gonad (FSH and LH) -> Estradiol Testosterone