lecture 25: reproduction and environmental endocrine disruptors

Question 1

What is an endocrine disruptor?

Answer 1

• 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)

Question 2

Where are EDs found?

Answer 2

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

Question 3

What are common EDs?

Answer 3

• 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

Question 4

What are possible mechanisms of action of EDs?

Answer 4

• 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

Question 5

What is current thinking about EDs?

Answer 5

• 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

Question 6

What are pathways affected by EDs?

Answer 6

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

Question 7

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

Answer 7

• hypothalamic neurons
• pituitary
• targets (gonads)

Question 8

What are ED target tissues?

Answer 8

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

Question 9

What are effects of EDs during embryonic development?

Answer 9

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

Question 10

What are effects of EDs during foetal development?

Answer 10

• 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

Question 11

What are the effects of EDs during adult life?

Answer 11

• 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

Question 12

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

Answer 12

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

Question 13

What are effects of EDs in different species?

Answer 13

• 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

Question 14

What are effects of EDs in humans?

Answer 14

• 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?

Question 15

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

Answer 15

• 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?)

Question 16

What are the effects of BPA?

Answer 16

• 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

Question 17

What are effects of PCBs, PBBs, PBDEs?

Answer 17

• 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

Question 18

What are effects of phthalates, dioxins and furans?

Answer 18

• 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

Question 19

What are general effects of pesticides?

Answer 19

• 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

Question 20

What are effects of pesticides on reproduction?

Answer 20

• 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?

Question 21

What is exposure and dosage of EDs?

Answer 21

• 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

Question 22

What is current legislation over EDs?

Answer 22

• 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

Question 23

What are measures to lower exposure to EDs?

Answer 23

• 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

Question 24

What is current research focus?

Answer 24

• 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