W9L1 Mon endocrine disruptor

Question 1

What is an Endocrine Disruptor

Answer 1

Endocrine disruptor: an exogenous agent that interferes with synthesis, secretion, transport, binding + action or elimination of natural hormones in body which are responsible for maintenance of homeostasis, reproduction, development +/or behaviour

Question 2

Source of endocrine disruptor

Answer 2

§ Natural chemical (phytochemical): from soy, hops, clover; weak + generally act through oestrogen pathway
§ Synthetic chemical (xenochemical): plastics, drugs, household products, pesticides; bioaccumulate in fatty tissues

Question 3

Exposure to EDC

Answer 3

• Route of exposure: occupational/ agricultural/ service/ commercial industries (nail salon, hairdresser),
  ingestion (food – plastics, water – pesticides, cosmetics),
  absorption (skin, cosmetics),
  inhalation (air, dust)

Question 4

Controversal with EDC

Answer 4

– 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 5

Bisphenols BPA, BPF, BPS)

Answer 5

• Plastic bottles & containers, food can linings, epoxy resins, till receipts
• Few studies on replacers – BPF, BPS. Mainly oestrogenic actions

Question 6

Parabens

Answer 6

• Preservatives, anti-microbial agents, cosmetics, suncream, personal care products
• Similar structure to bisphenols, 5-fold higher in women. Mainly oestrogenic actions

Question 7

Phthalates (MEHP, DEHP)

Answer 7

• Soft toys, flooring, medical equipment/tubing, personal care products, food packaging
• Mainly anti-androgenic and oestrogenic actions

Question 8

Persistent Organic Pollutants (POPs)

Answer 8

• Consists of ‘superfamilies’- PBB, PCB, PCDD, PCDF & PFAS – Some banned since 1979
• Flame retardants, foams, plasticware, paints, lubricants, metal & paper production
• Very long half-life in the environment! Mainly oestrogenic and anti-androgenic actions

Question 9

Pesticides, Herbicides and Insecticides

Answer 9

• Organochlorines, organophosphates, pyrethroids e.g. DDT/DDE (banned 1972), Atrazine…
• Often chemical mixtures – Oestrogenic, anti-oestrogenic, androgenic, anti-androgenic actions

Question 10

Mechanisms of Action

Answer 10

endocrine disruptors bind to steroid hormone receptors + mimic hormones = block hormone binding
§ Can alter signalling + gene expression without binding
§ Influence production/metabolism of hormones, hormone receptor production/action + enzyme-related hormone functions
§ Oestrogenic pathway: BPA, DES, methoxychlor
§ Androgenic pathway: DDE, vinclozolin
§ Actions not fully understood; have independent effects outside of normal steroid pathway
* EDCs elicit effects at much lower doses (pM to fM concentration) vs. normal hormones (nM to pM)

Question 11

Target Organs and Tissues

Answer 11

: brain (sexual behaviour), thyroid (metabolism), thymus (immune system), breast (cancer), pancreas (obesity)
§ Male: testis + penis (hypospadias + cancer)
§ Female: ovarian function (PCOS, endometriosis, cancer) + pregnancy (foetal growth reduction, preterm + still birth)
§ EDCs affect neurons of hypothalamus, pituitary or gonads

Question 12

Effect of EDCs in wildlife

Answer 12

§ Amphibians + fish living in polluted water = frog deformities/infertility + abnormal ovaries
§ Alligators in Florida (1990s): lake full of DDT + pesticides = feminisation of males (tiny penis, low T4, high E2), abnormal ovaries
§ Bald eagles (1997): DDT (food chain) caused fragile eggshells + failed hatchings
§ Deer, otters + sea lions: PCB + DDT effects on fertility (bioaccumulation in blubber)
§ Issues understanding EDC effects: measure toxic/lethal not subtle effects, length of exposure vs. time of measurement, environment levels difficult to measure, background contamination = hard to show direct effect

Question 13

EDCs effect During Foetal Development

Answer 13

Most sensitive period of exposure
§ Effects:
-placental function + transfer,
-thyroid function,
-bipotential gonad differentiation,
-deficits in IQ + memory,
-neurobehavioural + delayed neuromuscular development postnatally

Question 14

EDC effect on adult development

Answer 14

§ Effects:
-thyroid function,
- ↑cancer incidence,
-abnormal production of ovarian steroids + disruption of folliculogenesis,
-organ morphology/function, behavioural differences (feminisation), ↓stress respond
§ Hayes’ study on male frogs + Atrazine: feminised + become hermaphrodites
Many Studies are done on male

Question 15

EDC effect on Gamete/Embryo Development

Answer 15

§ 4 day exposure of embryo to normal amounts of BPA found in environment can change metabolic profile of embryo (↑obesity)
§ Unknown subtle effects or if effects different b/w males + females

Question 16

Multi- + TransGenerational Effects

Answer 16

§ Can affect germ cells, gametes (sperm + oocytes)
§ EDCs → prenatal exposure → programming (↑obesity) → transgenerational effects
§ Hypospadias: inappropriate exposure to EDCs from mother (requires balance b/w oestrogen + androgens)

Question 17

Diethylstilbesterol (DES) effect on human fertility

Answer 17

synthetic oestrogen prescribed to pregnant women in 1940s-1970s to prevent miscarriage
Ø Girls: vaginal + uterine malformations, breast cancer, clear cell adenocarcinoma (CCA)
Ø Boys: undescended testes, sperm abnormalities

Question 18

Oral contraceptive pill effect

Answer 18

– Taken for decades by millions of women
– Numerous side-effects
– High concentrations in urine → recycled water and used for daily life
– Effects on cancer incidence and feminisation (humans and animals

Question 19

Bisphenol A (BPA)

Answer 19

• 1997 until ‘Chapel Hill consensus’ vs Government 2006
• Earlier puberty
• Fetal uterine development (HOXA10), folliculogenesis
• Changes in breast and testis development (↑ hypospadias and cryptorchidism)
• Brain structure- feminisation of male brains (fetal)
• ↑ mammary and prostate cancers
• ↓ sperm counts, motility and testosterone
• Altered behaviours
• Obesity- most evidence of all EDCs

Question 20

Persistent Organic Pollutants (POPs) PBBs/PBDEs:

Answer 20

Perinatal exposure →
– Earlier puberty in breastfed girls
– Modulation of puberty feedback loops
– Neurological and behavioural issues

Question 21

Persistent Organic Pollutants (POPs) PCBs

Answer 21

Children exposed prenatally ↑ incidence of
– Perturbed thyroid function
– Abnormal sperm morphology, ↓ motility
– Intrauterine growth retardation (IUGR)
– Delayed development milestones
– Neurological and behavioural issues, Lower IQs

Question 22

Persistent Organic Pollutants (POPs) PCDDs (dioxins)/PCDFs (furans):

Answer 22

Perinatal exposure →
– Earlier puberty in breastfed girls
– Modulation of puberty feedback loops
– Neurological and behavioural issues
– High heat releases dioxins → plastics in microwave
– Dioxins are carcinogens- very toxic to cells
– Recurrent abortion
– IUGR

Question 23

Pesticides/herbicides/insecticides effect on fetrility

Answer 23

Females
• CCA of vagina and cervix
• Irregular uterine bleeding
• Recurrent abortion
• IUGR
• Abnormalities within most major systems
• Brain sex
Males
– Sperm morphology and motility abnormalities
– Testis size, function
– Brain sex?
Effects of Persistent Organic Pollutants (POPs)

Question 24

Future of EDCs

Answer 24

• Human fertility: raise awareness of exposures + concentrations, association with infertility/diseases, greater reliance on ART
• Research: agreement on appropriate methodology, end points + subtle effects; identify effects of single EDCs + EDC mixtures; long-term + transgenerational effects on fertility + all diseases
• Green chemistry: ↑testing + replacement chemicals in products, recycling + environmentally friendly policies
• Education of general public + policy makers: awareness, legislation, easy mitigation strategies

Question 25

EDCs: Mitigation Strategies

Answer 25

§ Read product labels (‘paraben free’) + green chemistry products
§ Fresh produce (wash fruit + veg), fewer processed/canned/pre-packaged foods, eat ‘lower on food chain, limit fatty/oily foods (bioaccumulation), drink out of glass/hard plastic bottles
§ Never heat food in soft plastic containers
§ Avoid smoke, strong chemicals, pesticides, excessive cosmetics + ventilate homes/offices