lecture 25: reproduction and environmental endocrine disruptors Flashcards Preview

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Flashcards in lecture 25: reproduction and environmental endocrine disruptors Deck (24):

What is an endocrine disruptor?

  • an exogenous agent that interferes with synthesis, secretion, transport, binding and action or elimination of natural hormones in the body which are responsible for the maintenance of homeostasis, reproduction, development and/or behaviour 
  • natural chemical (phytochemical) 
  • synthetic chemical (xenochemical) 


Where are EDs found?

  • plants - soy, hops, clover 
    • genistein 
  • human-made 
    • plastics 
    • drugs
    • household products 
    • industrial chemicals 
    • pesticides 
  • animal oil and fat bioaccumulation 


What are common EDs?

  • OCP, Tamoxifen, and Diethylstilbesterol (DES) 
  • polychlorinated biphenyls (PCBs) 
    • paints, lubricants, coatings of electrical wires, plastic bottles, food can linings, dental sealants 
  • bisphenol A (BPA) 
    • plastic bottles and containers, food can linings, epoxy resins, till receipts 
  • polybrominated biphenyls (PBB) and diphenyl ethers (PBDE) 
    • flame retardants, plasticware component, plastic foams 
  • phthalates 
    • soft toys, flooring, medical equipment/tubing, cosmetics e.g. DEHP
  • parabens 
    • preservatives, antimicrobial agents, cosmetics, suncream 
  • dioxins and furans 
    • animal feed, wood preservative, dioxins – microwaved plastics containers 
  • pesticides and herbicides (organochlorines)
    • e.g. DDT, DDE, atrazine, endosulfan, chlorpyrifos 


What are possible mechanisms of action of EDs?

  • bind steroid hormone receptors and mimic 
  • block hormone binding 
  • alter cell-signalling and gene expression without binding 
  • influence production or metabolism of hormones 
  • influence hormone receptor production or action 
  • influence enzyme-related hormone functions 
  • epigenetic effects- germ cells 


What is current thinking about EDs?

  • routes of exposure 
    • occupational, agricultural, household items
    • ingestion (food, water, cosmetics)
    • absorption (skin, cosmetics)
    • inhalation (air, dust) 
  • controversial 
    • relatively new (1990s)
    • few studies in humans 
    • hard to show direct effect, background contamination 
    • lab studies usually only use very high doses 
    • natural levels difficult to measure 


What are pathways affected by EDs?

  1. oestogenic - DES, BPA, methoxychlor 
  2. androgenic- DDE, vinclozolin 
  • steroid receptors (oestrogen and androgen) 
  • independent effects
  • not fully understood 
  • concentrations required 
    • normal hormones (nM or pM) 
    • EDs (pM to fM), elicit effects and much lower doser 


How can EDs affect the hypothalamic-pituitary-gonadal axis?

  • hypothalamic neurons 
  • pituitary 
  • targets (gonads) 


What are ED target tissues?

  • organs with gonadal hormone receptors?
  • females = mammary glands, reproductive tract
  • males = reproductive tract
  • both sexes = external genitalia, brain, skeleton, thyroid, kidney, and immune system


What are effects of EDs during embryonic development?

  • pre-implantation - little research undertaken 
  • generally lethal toxic effects
  • sex skewing?
  • unknown subtle effects or if different between males and females 


What are effects of EDs during foetal development?

  • most sensitive period of exposure
    • organ development 
    • data from wildlife, lab animals, cell culture, accidental exposure
  • effects
    • placental function and transfer
    • thyroid 
    • bipotential gonad differentiation 
    • deficits in IQ and memory
    • neurobehavioural, delayed neuromuscular development post-natally 


What are the effects of EDs during adult life?

  • thyroid function 
  • increased cancer incidence 
  • aberrant production of ovarian steroids and disruption of folliculogenesis 
  • organ morphology or function 
  • behavioural differences - feminisation 
    • breeding issues of male frogs (Atrazine)
  • immunological, decreased stress response 


What are the trans-generation/gamete effects of EDs?

  • can affect germ cells, gametes (sperm and oocytes)
  • direct effects on the foetus 
  • data from rodent studies 


What are effects of EDs in different species?

  • amphibians and fish 
    • frog deformities/infertility 
  • alligators in florida (1990s) - lake full of DDT and pesticides →
    • males tiny penises, low T4, high E2
    • females abnormal ovaries 
  • bald eagles (1997) - DDT caused fragile eggshells 
    • failed hatching 
  • deer, otters and sea lions (1990s) - PCB and DDT effects on fertility 


What are effects of EDs in humans?

  • fertility issues 
    • reduced fertility (both sexes)
    • low sperm count
    • menstrual cycle disturbances 
    • increased time-to-pregnancy
    • spontaneous abortion 
    • stillbirths
    • development defects
  • increased rates of breast/prostate cancer?
  • neuroendocrinology - behavioural issues 
  • thyroid function impacting metabolism 
  • obesity epidemic?


What are effects of oestrogens: DES and the Oral Contraceptive Pill?

  • DES effects
    • a synthetic oestrogen prescribed to pregnant women in the 1950s/60s to prevent miscarriage 
    • 300+ cases clear cell adenocarcinoma (CCA) documented in women exposed in utero to DES 
    • girls - vaginal and uterine malformation, breast cancer
    • boys - undescended testes, sperm abnormalities 
    • banned in the 1970s
  • OCP
    • taken for decades by millions of women 
    • numerous side-effects 
    • high concentrations in urine → recycled water
    • effects on cancer incidence and feminisation (humans and animals?) 


What are the effects of BPA?

  • exposure →
    • 'chapel hill consensus' vs government 2006
    • earlier puberty 
    • foetal uterine development (HOXA10), folliculogenesis 
    • changes in breast and testis development (increased hypospadia and cryptorchidism) 
    • brain structure - feminisation of male brains (foetal)
    • increased mammary and prostate cancers 
    • decreased sperm counts, motility and testosterone 
    • altered behaviours 
    • obesity - most evidence of all EDs
  • the problem is BPA in the urine of 93% of surveyed Americans over the age of six. If you don't have BPA in your body, you're not living in the modern world. - time magazine, 2010 
  • dose (µg/kg/day) → effects (measured in studies of mice or rats)
    • 0.025 → permanent changes to genital tract
    • 0.025 → changes in breast tissue that predispose cells to hormones and carcinogens 
    • 1 → long-term adverse reproductive and carcinogenic effects 
    • 2 → increased prostate weight 30% 
    • 2 → lower bodyweight, increase of anogenital distance in both genders, signs of early puberty and longer oestrus 
    • 2.4 → decline in testicular testosterone 
    • 2.5 → breast cells predisposed to cancer 
    • 10 → prostate cells more sensitive to hormones and cancer 
    • 10 → decreased maternal behaviours 
    • 30 → reversed the normal sex differences in brain structure and behaviour 
    • 50 → adverse neurological effects occur in non-human primates 
    • 50 → disrupts ovarian development 
  • the current U.S. human exposure limit set by the EPA is 50µg/kg/day


What are effects of PCBs, PBBs, PBDEs?

  • PCBs - children exposed prenatally increased incidence of 
    • pertubed thyroid function 
    • abnormal sperm morphology, decreased motility 
    • intrauterine growth retardation (IUGR) 
    • abnormal skin pigmentation 
    • delayed development milestones 
    • neurological and behavioural issues, lower IQs 
  • PBBs and PBDEs - perinatal exposure → 
    • earlier puberty in breastfed girls 
    • modulation of puberty feedback loops 
    • neurological and behavioural issues 


What are effects of phthalates, dioxins and furans?

  • phthalates 
    • increased male infant reproductive tract defects
    • abnormal sperm characteristics 
    • defects in male infant neurological development 
  • dioxins and furans 
    • high heat releases dioxins → food (plastics in microwave)
    • dioxins are carcinogens - very toxic to cells 
    • recurrent abortion
    • IUGR


What are general effects of pesticides?

  • on reproductive system (F0 and F1) - often detectable in reproductive tissues and fluids
  • teratogenic - birth defects
  • carcinogenic - cancer in tissues 
  • oncogenic - tumour-forming (not always cancerous) 
  • mutagenic - permanent changes in genetic structure, inheritable 
  • neurotoxic - poisioning/modulating nervous system 
  • immunosuppressive - block natural immune response 


What are effects of pesticides on reproduction?

  • females 
    • CCA of vagina and cervix 
    • irregular uterine bleeding 
    • reccurent abortion 
    • IUGR 
    • abnormalities within most major systems 
    • brain sex?
  • males
    • sperm morphology and motility abnormalities 
    • testis size, function 
    • brain sex?


What is exposure and dosage of EDs?

  • exposure sources and method 
    • occupational, agricultural, household items
    • multiple routes 
  • lethal vs sub-lethal 
    • most evidence is only level of toxicity!
    • subtle effects rarely investigated 
  • acute vs chronic exposure 
    • unknown effects
    • combined effects of multiple EDs unknown 
  • poor safety measures and training 
    • country specific 


What is current legislation over EDs?

  • banned
    • DES (1970s), PCB (1977), and DDT (1972 Western countries) 
  • differences between countries 
    • some countries minimal laws (developing nations) 
    • wester countries can't agree e.g. BPA
    • limited uses in certain products 
  • USA - Food Quality Protection Act (1996) 
    • requries environmental protection agency (EPA) to develop screening programmes- decade of disaster 
    • however est. 87,000+ commerical chemicals
  • many still not even known or regulated 


What are measures to lower exposure to EDs?

  • read labels on products - plastics etc 
  • organic fresh produce? known source. wash fruit and veg before eating 
  • use fewer processed, pre-canned/pre-packaged foods where possible 
  • eat lower on food chain, less fatty foods and non-oily deep water fish (avoid salmon, tuna etc)
  • drink out of hard plastic bottles 
  • NEVER heat food in plastics in the microwave 
  • avoid 
    • smoke, strong chemicals (glues, paints, carpet cleaners), pesticides, make-up, hairspray and colourings. Smell = high concentration 


What is current research focus?

  • WHO and UN (2013) report of recommendations
    • testing, research, reporting, collaborative approach
  • generally
    • numerous species 
    • timing and length of exposure 
    • toxic and subtle effects
    • half-life and metabolites 
    • longitudinal and multigenerational 
    • mechanisms of action 
    • monitoring and environmental concentrations 
    • potential diagnostics, sensitivty of detection 
  • much more needed