TOXI LEC

• Endocrine glands


  Collections of specialized cells that synthesize, store, and release their secretions directly into the bloodstream
• Adenohypophysis


  Each type of endocrine cell is under the control of a specific releasing hormone from the hypothalamus
• Toxicants


  Can influence the synthesis, storage, and release of hypothalamic releasing hormones, adenohypophyseal-releasing hormones, and the endocrine gland-specific hormones
• Endocrine system


  • A complex network of glands and organs that uses hormones to control and coordinate your body's metabolism, energy level, reproduction, growth and development, and response to injury, stress, and mood

  
• Hormones released by the hypothalamus


  • Thyrotropin-releasing hormone (TRH)
  • Gonadotropin-releasing hormone (GnRH)
  • Growth hormone-releasing hormone (GHRH)
  • Corticotrophin-releasing hormone (CRH)
  • Somatostatin
  • Dopamine
  • Vasopressin
  • Oxytocin
• Hypothalamic dysfunction


  Can be caused by surgery, brain injury, brain tumors, radiation treatment, nutritional problems, extreme weight loss, vascular problems in the brain, genetic disorders, infections and swelling
• Pineal body


  Produces the hormone melatonin, which helps regulate the body's circadian rhythm
• Hormones released by the anterior pituitary gland


  • ACTH
  • FSH
  • GH
  • LH
  • Prolactin
  • TSH
• Pituitary tumors


  Can be induced by sustained uncompensated hormonal imbalances leading to increased synthesis and secretion of pituitary hormones
• Mechanisms of thyroid toxicity


  • Blockade of iodine uptake
  • Inhibition of thyroperoxidase
  • Blockade of thyroid hormone release
  • Hepatic microsomal enzyme induction
• Thyroid C cells


  Morphologic alterations and proliferative lesions can be caused by sustained hypercalcemic stimulus and long term hypercalcemia
• Mechanisms of parathyroid toxicity


  • Ozone - compensatory hypertrophy and hyperplasia
  • Aluminum - minimal elevation of iPTH
  • L-asparaginase - selectively destroy chief cells
  • Rotenone - adenoma
• Thymus


  Where lymphocytes from the bone marrow mature and become specialized T-cells
• Hormones produced by the thymus


  • Thymopoeitin
  • Thymosin
  • Thymulin
  • Thymic humoral factor
• Hormones produced by the adrenal cortex


  • Cortisol
  • Aldosterone
• Hormones produced by the adrenal medulla


  • Epinephrine
  • Norepinephrine
• Adrenal cortical toxicity


  Many adrenal cortical toxic compounds are lipophilic and can accumulate in the lipid-rich adrenal cortical cells, impairing steroidogenesis. Adrenal cortical cells also have enzymes capable of metabolizing xenobiotics, leading to activation of toxins and generation of ROS. Blockage of the action of adrenocorticoids at peripheral sites or by inhibition of synthesis and/or secretion of hormone can also occur.
• Adrenal medullary toxicity


  Can lead to proliferative lesions such as pheochromocytoma and tumors
• Hormones produced by the pancreas


  • Pancreatic enzymes (lipase, protease, amylase)
  • Insulin
  • Glucagon
  • Gastrin
  • Amylin
• Toxic responses of the reproductive system


  The gonads possess a dual function: an endocrine function involving the secretion of sex hormones and a non-endocrine function relating to the production of germ cells (gametogenesis). Gametogenic and secretory functions of either the ovary or testes are dependent on the secretion of FSH and LH from the pituitary. The blood–testis barrier between the lumen of an interstitial capillary and the lumen of a seminiferous tubule impedes or prevents the free exchange of chemicals/drugs between the blood and the fluid inside the seminiferous tubules. Xenobiotics can act directly on the hypothalamus and the adenohypophysis.
• Beta cells


  Help control appetite and gastric emptying
• Substances that can cause hyperplasia, metaplasia, malignant transformation, acute pancreatic injury


  • Alcohol
  • Alloxan
  • Azaserine
  • Streptozotocin
• Substances that can cause acute pancreatitis


  • Azathioprine
  • Estrogens
  • Furosemide
  • Methyldopa
  • Pentamidine
  • Procainamide
  • Sulfonamides
  • Thiazide diuretics
• Gonads


  • Possess a dual function: an endocrine function involving the secretion of sex hormones and a non-endocrine function relating to the production of germ cells (gametogenesis)
• Gametogenic and secretory functions of ovary or testes


  Dependent on the secretion of FSH and LH from the pituitary

  
• Blood-testis barrier


  Impedes or prevents the free exchange of chemicals/drugs between the blood and the fluid inside the seminiferous tubules
• Xenobiotics


  Can act directly on the hypothalamus and the adenohypophysis, leading to alterations in the secretion of hypothalamic releasing hormones and/or gonadotropins
• Steroid hormone biosynthesis


  Can occur in several endocrine organs including the adrenal cortex, ovary, and the testes
• Female reproductive processes that may be sites of xenobiotic interference


  • Oogenesis
  • Ovulation
  • Development of sexual receptivity
  • Coitus
  • Gamete and zygote transport
  • Fertilization
  • Implantation of the conceptus
• Xenobiotics


  May influence male reproductive organ structure, spermatogenesis, androgen hormone secretion, and accessory organ function
• Ovary


  • A woman's ovaries are located on both sides of the uterus, below the opening of the fallopian tubes
  • Estrogen (estradiol, estriol, estrone) - sexual development and maintain the reproductive system, bone maintenance, nitric oxide production, and brain function
  • Progesterone - prepares the endometrium for potential pregnancy after ovulation. While the body is producing high levels of progesterone, the body will not ovulate
  • Androgens
• Testis


  • A man's testes are located in a pouch that hangs suspended outside the male body
  • Testosterone - for secondary sexual characteristics, develop muscle mass and strength, fat distribution, bone mass, and sex drive, stimulates spermatogenesis
• Epididymis


  • Although most male reproductive toxicants disrupt spermatogenesis, post-testicular functions in the epididymis can be the primary target for toxicity, or the epididymis can exhibit changes as a secondary consequence to testicular events
  • Sperm, which are antigenically foreign, are protected from the host immune system by tight junctions, which comprise the blood testis and the blood epididymal barrier
  • Inflammation is the result if these barriers are compromised
• Endocrine-Disrupting Chemicals (EDCs)


  • Natural or human-made chemicals in the environment, food sources, personal care products, and manufactured products that may mimic, block, or interfere with the body's hormones
  • Even low doses of EDCs may be unsafe as the body's normal endocrine functioning involves very small changes in hormone levels, yet even these small changes can cause significant developmental and biological effects
  • Most EDCs are lipophilic and bioaccumulate in the adipose tissue, thus they have a very long half-life in the body

  
• Effects of EDCs


  • Developmental malformations
  • Interference with reproduction
  • Increased cancer risk
  • Disturbances in the immune and nervous system function
• Polychlorinated biphenyls (PCBs)


  • Mixtures of different congeners and positions of chlorine atoms around biphenyl rings, widely used as insulators in capacitors and transformers, hydraulic fluids, and in paints and related products
  • Noncoplanar PCBs structurally resemble to estradiol 17-β (E2) and hence can mimic estrogenic effects in the cell
  • Coplanar PCBs mimic dioxin in that they bind with relatively high affinity to the aryl hydrocarbon receptor (AHR) and results in a reduction in cytosolic estrogen level (i.e. anti-estrogenic effect)
• Organochlorine pesticides (OPs)


  • Such as DDT, endosulfan, lindane, mirex, dieldrin, chlordane - Their effects on male and female fertility as a consequence of estrogenic, anti-estrogenic, androgenic and antiandrogenic actions, obesity and metabolic disorders, thyroid homeostasis, hormone-sensitive cancers and hypothalamopituitary axis have been reported
  • Some OPs structurally resemble to E2 and thus can bind to estrogen receptor (ER) and mimic the effects of the endogenous ligand
  • Some xenohormones may display anti-estrogenic actions by binding to AHR and initiating transcription of cytochrome p450 enzymes that metabolize E2
• Plasticizers (Bisphenol A (BPA) and phthalates) and Nonylphenols


  • Provide flexibility and shape to plastic products, may leach out of the plastic material into the food chain and cause toxic effects esp in children and pregnant women
  • BPA and other phenols - linked to reduced egg quality and viability
  • Phthalates - interfere with the production of androgens
• Per- and polyfluoroalkyl substances (PFAS)


  Chemicals used as oil and water repellents and coatings for cookware and textiles, can affect our biology by mimicking fatty acids and their ability to interfere with hormone systems, exposure can cause adverse health effects
• Heavy metals


  Humans are exposed to arsenic, lead, and mercury, findings suggest that organometals may exert endocrine disruptive effects, esp on reproductive functions