EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011 Mini review: ENDOCRINE DISRUPTING COMPOUNDS EXPOSURE AND TESTIS DEVELOPMENT IN MAMMALS Biola F. Egbowona and Olajide A Mustapha a School of Science and Technology, Erasmus Darwin Building ERD 200, Nottingham Trent University, Clifton Lane, NG11 8NS, UK * corresponding author: [email protected] ABSTRACT In the last few decades, there is substantial evidence that male reproductive function is dete- riorating in humans and wildlife and this is associated with unintentional exposure to widely used synthetic chemicals. Subsequently, much has been done to show that certain chemicals in the environment adversely interfere with the developing fetal gonads of the laboratory ani- mals. Some in vitro studies have demonstrated treatment-induced reproductive problems in offspring exposed to endocrine disrupting compounds (EDC) which are similar to those ob- served in wildlife and human population. Few EDC studies have demonstrated that there are certain periods of gestation when the developing fetus is highly sensitive and at risk of small endocrine changes. Similar observations have been made in the sewage sludge model, how- ever, while animal studies have been insightful in providing valuable information about the range of effects that can be attributed to in utero exposure to EDCs, varying levels of mater- nal doses administered in different studies exaggerated extrapolation of these results to hu- man. Thus the EDC concentration representative of fetal exposure levels is uncertain because of the complexities of its nature. So far, the level of fetal exposure can only be roughly esti- mated. There is substantial evidence from animal data to prove that EDCs can adversely affect reproductive development and function in male and more has accumulated on the mechanisms by which they exert their effects. This paper therefore, reviews previous studies to highlight the extent to which testis development can be disrupted during fetal life. Keywords: endocrine disrupting compound, human direct exposure, humans, wildlife and male reproductive INTRODUCTION evidence have shown declines in human semen quality during the last 5-6 decades The adverse effects of environmental (Leto and Frensilli, 1981; Bostofte et al., disrupting compound (EDC) exposure on 1983). Several studies have reported diverse various aspects of human health and, espe- trends in male reproductive health, includ- cially, reproductive development during ing increasing incidence of testicular cancer fetal and early post-natal life, have been a (Forman and Moller, 1994), declining se- growing concern in most parts of the world. men quality (Andersen et al., 2000). Re- This is particularly evident from the emerg- ports have shown significant decreases in ing trends in human reproductive health sperm concentration (113 million/ml vs. 66 such as testicular cancer, decreasing sperm million/ml) and semen volume (3.40 ml vs. counts and or hypospadias/cryptorchidism, 2.75 ml) over the period between 1938 and which are collectively ‘termed testicular 1990 (Carlsen et al., 1992). A number of dysgenesis syndrome’ (TDS), over the last reports on the available data from cancer few decades. Clinical and epidemiological registries have been reviewed (Toppari et 173 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011 al., 1996) with evidence of an increase in effects, which include growth inhibition, testicular cancer in many countries includ- reproductive dysfunction and immune sys- ing England and Wales (Pike et al., 1987), tem impairment (Rhind, 2002) on many Scotland (Hakulinen et al., 1986), the Nor- animal species including ruminants and dic and Baltic countries (Adami et al., humans. They are often referred to as endo- 1994; Stone et al., 1991), Australia (Pearce crine disruptors; indicating their potential et al., 1987), New Zealand (Wilkinson et ability as either hormone agonists, or an- al., 1992; Spitz et al., 1986), and the United tagonists of the endogenous compounds. States (Harris and Steinberg, 1954). Their adverse effects may include im- Studies on wildlife species have re- paired testosterone secretion, (certain vealed various effects of environmental phthalates), altered metabolism (PCBs, compounds (Toppari et al., 1996). These polychlorinated bisphenyls hydrocarbons), include some key observations in gastro- blockage of hormone action (pesticides) or pods, fish, reptiles, and mammals (Ta- direct activation of androgen or estrogen ble 2A, B). Generally, some of the repro- receptors (several EDCs) (Rhind, 2002). ductive failures reported in wildlife include Animals may be exposed to relatively high decreased fertility, decreased hatching suc- concentrations of EDCs mostly through cess, birth deformities, metabolic abnor- feeding and water; they could be stored and malities, behavioural abnormalities, demas- concentrated mainly in the fat tissues (Eke- culinisation/feminisation of males, and de- lund et al., 1990; Ahel et al., 1993; Pojana feminisation/masculinisation of females et al., 2007). The accumulated fats may be (Hollander, 1997). A number of reproduc- utilised in periods of pregnancy and lacta- tive dysfunctions which were reported in tion when the animals’ energy requirements male offspring from animal studies have are particularly very high. This could exert been associated with maternal EDC expo- endocrine disrupting effects on the animals sure (Sweeney and Brooks 1996; Imajima (Bigsby et al., 1997) thus exposing their et al., 1997). Experimental evidence from embryos and neonates to relatively high many animal studies has also explained concentrations of EDCs. Detectable con- some of the anatomical and physiological centrations of EDCs were reported in body changes which may occur as a result of tissues from adults, young children and fe- EDC exposed in humans. These includes tuses (Fowler et al., 2008, 2009; Choi et al., oviductal malformations (Newbold et al., 2008), following absorption of the EDCs 1983) and a high incidence of uterine fi- from the environment. broids (Baird and Newbold, 2005; Cook et al., 2005). Environmental disrupting compounds (EDCs) Environmental disrupting compounds (EDCs) constitute a diverse range of an- thropogenic compounds, including organo- chlorine pesticides, polychlorinated bisphe- nyls (PCB), alkylphenol polyethoxylates, phytoestrogens, bisphenol-A, phthalates, dioxins, polybrominated diphenyl ethers and heavy metals (Rhind et al., 2002) (Ta- ble 1). They are ubiquitous, persist in the environment at low concentrations, how- ever, they appear to exert a range of adverse 174 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011 Table 1: Common environmental contaminants, sources and health effects from developmental and adult exposures (animal and human data) Contaminant Sources Selected health Selected health effects with effects with postnatal exposure prenatal exposure Bisphenol A (BPA) Industrial chemical and Oocyte chromosome ab- Altered puberty onset, al- building block for polycar- normalities, recurrent mis- tered prostate development, bonate plastic and epoxy carriage, ↓ semen quality ↓ semen quality, hormonal resins, lining of metal food (Hunt et al., 2003) changes (Herath et al., and drink cans, plastic 2004) bottles, baby toys, dental sealant, cell phones etc. Pesticides in general Many classes of insecti- Menstrual irregularities, ↓ Altered sex ratio, altered cides, fungicides, herbi- fertility, ↓ semen, quality, puberty onset, malformation cides, rodenticides and premature birth, sperm of reproductive tract, ↓ fertil- fumigants. Exposure can chromosome abnormali- ity, impaired fetal growth, occur through food, drink- ties, hormonal changes (IUGR) (Gray et al., 2001) ing water or simply from (Farr et al., 2004) domestic applications Phthalates Plasticizers (added to Altered (earlier) menarche Shortened anogenital dis- soften plastics like PVC), onset, altered oestrus tance, malformations of cosmetics, perfumes, toys, cycle, ovulatory irregulari- reproductive tract, hormonal pharmaceuticals, medical ties, ↓ semen quality, re- changes, ↓ semen quality devices, lubricants and duced fertility, fetal loss, (Couse and Korach, 2004) wood finishers endometriosis (Cobellis et al., 2003) Chlorinated hydrocarbons PCBs, DDT, dioxins/furans Menstrual irregularities, Malformations of the repro- endometriosis, reduced ductive tract, altered oestrus fertility, fetal loss, ↓ semen cycle, reduced fertility al- quality, altered puberty tered sex ratio, altered pu- onset, altered menarche berty onset, ↓ semen quality, onset delayed time to pregnancy (Venners et al., 2005) (Miller et al., 2004; Denham et al., 2005) Pharmaceuticals DES, ethynylestradiol Malformations of reproduc- tive tract, altered hormone response, menstrual irregu- larities, reduced fertility, uterine fibroids, miscarriage, - hormonal changes, reduced birth weight, fetal loss (Lau et al., 2004) Wildlife, laboratory and human studies occurrence. For instance, reduced testoster- Reproductive and developmental ab- one synthesis, plasma steroid concentra- normalities associated with EDC exposures tions and male phallus size were reported in have been well documented in wildlife. juvenile alligators from seven Florida lakes These include birds, frogs, seals, polar following EDC exposure