Author(s): Yang Hu 1,2,3, Ruoyu Wang 1, Zou Xiang 4, Weiping Qian 5, Xiaodong Han 1,2,3,*, Dongmei Li 1,2,3,*
The production of massive amounts of chemicals is correlated with the modernization drive worldwide, which accounts for increasingly serious environmental problems. Among such chemicals, the build-up of environmental endocrine disruptors (EDCs) in the food chain has caused widespread public concern. EDCs are capable of disrupting the endocrine system leading to hormone-dependent diseases or reproductive disorders . Nonylphenol (NP) and di-n-butyl phthalate (DBP), two well-known EDCs, are high-production volume chemicals widely distributed in the environment. NP and phthalates can leach from products that contain them and accumulate in the environment . Such environmental toxicants can be taken up by humans through ingesting contaminated food or water. Recent studies suggest that environmental levels of NP may exert estrogenic effects in humans and wild animals, disturbing the balance of hormone secretion and cytokine network at the maternal-fetal interface , . Exposure to DBP, also referred to as antiandrogen, between gestation days (GD) 12 and 21 disrupts sexual development in rats, leading to decreased anogenital distance, reproductive tract malformations, seminiferous tubule degeneration, interstitial cell hyperplasia and adenoma in the testis, as well as small reproductive organs in male F1 rats . Monobutyl phthalate (MBP) , , the active monoester metabolite of DBP, can inhibit the fetal testosterone synthesis resulting in anti-androgenic effects -.
Humans and wildlife populations are exposed simultaneously to a multitude of environmental chemicals. Mixtures of chemicals have the potential to interact with each other and elicit combination effects that differ from those resulting from exposure to individual chemicals. Despite the ubiquitous coexistence of multiple EDCs in the environment, there is little evidence regarding combination effects of chemical mixtures which may present different mechanisms of action. Furthermore, the available data almost inevitably focus on the immediate implications of exposure for population dynamics, or very specific life-history stages such as embryonic development or reproduction. Apparently, there is a need to investigate the combination effects of chemicals between embryonic development and sexual maturation. During this intermediate period, also known as pre-puberty, the newborns and juveniles face considerable challenges which may negatively impact on reproduction or even survival. Antiandrogen, such as flutamide, which is capable of altering the androgen pathway, can impair sperm motility and lower the fertility potential of male rats during the prepubertal period .
Combined effects of mixtures are normally classified into additivity, synergism, or antagonism. Therefore, appropriate evaluation of the combination effects is difficult and the result may be unpredictable. On the basis of pharmacological and mathematical statistics, two concepts have been employed in this study, i.e. concentration addition (CA) and response addition (RA, also termed independent action) . CA has been used to evaluate the interaction of chemicals that have the same mechanism of toxicity in a mixture. Without compromising the overall mixture effect, one chemical can be replaced totally or in part by an equal fraction of an equieffective concentration of another . Alternatively, the combination effect of agents...