## Endocrine disrupting chemicals may affect sexual differentiation

Sexual differentiation in vertebrates can vary widely across species, with differences in both timing and the specific mechanisms involved. However, steroid hormones consistently play a key role in signalling the differentiation of tissues that define male and female characteristics. Given their crucial role in this process, exposure to external steroids or EDCs that mimic, block, or otherwise disrupt these hormonal signals during critical stages of development is likely to affect later reproductive and neuroendocrine functions. If an organism is exposed to these EDCs during a sensitive stage of its life cycle, it could lead to changes in differentiation of the brain, behaviour, and reproductive organs. In addition, if a sufficient number of individuals are impacted effects at the population level would be seen. For example, if EDCs result in altered oocyte maturation, in the individual this could result in difficulties to conceive, infertility or miscarriage. Consequently, with more infertile women in the population, there will be a reduction in birth rates and an impact on society in terms of increased healthcare requirements (a need for IVF) and a shift in the age demographic of the population that could have economic impacts.

There are few very specific examples of EDCs – natural or human-made – that could contribute to sex changes. The feminisation caused by estrogenic chemicals was observed in alligators living in some lakes in Florida, or in fish living in English rivers near sewage-treatment works.The most causative chemicals in effluents were the natural steroid estrogens 17ß-estradiol (E2) and estrone (E1), as well as the synthetic steroid estrogen ethinyl estradiol (EE2), which is the active ingredient of the contraceptive pill. As EE2 is used by many people it is therefore excreted by humans and, unfortunately, is incompletely degraded in sewage-treatment works. Subsequently, as EE2 can be present in water, it can be absorbed by the human body, where the chemical is able to interact with estrogen receptors. This interaction can disrupt natural hormone balance, potentially leading to various disorders. EE2 is an example of an xenoestrogen, an estrogen mimicking compound that is not produced by the body. They may be synthetic, like EE2, plasticizers or pesticides but natural compounds also have similarity to estrogen. Such phytoestrogens include genistein which can be found in soy.

While most research has concentrated on estrogens and their estrogenic effects, such as feminisation, there is also substantial evidence that chemicals with androgenic and anti-androgenic properties present in aquatic environments may affect sexual determination. This became apparent when it was discovered that certain effluents from paper and pulp mills were causing masculinisation in fish living downstream from where the effluent entered the river. Typical examples of chemicals that can interfere with androgen actions, and thus interrupt the normal masculinisation of male reproductive organs, are antiandrogens – a persistent DDT metabolite (p,p'-dichloro-diphenyl-trichloroethane) and vinclozolin.

In addition, some other chemicals, phthalates, can interfere with the synthesis of testosterone and thus disrupt normal masculinisation. These effects would not be possible without affecting androgen binding to androgen receptors caused by EDCs, subsequently leading to adverse physiological responses.

Taken together, sexual differentiation of several species can be affected by the binding of human-made chemicals to hormone receptors (especially estrogen and androgen receptors), which can subsequently lead to the changes in relevant cell signal pathways.