Developmental exposure to mixtures of environmental pollutants : Studies on metabolism, developmental processes, and reproductive organs in zebrafish and chicken embryos

Sammanfattning: Humans and wildlife are continuously exposed to mixtures of environmental pollutants. Mixture toxicity can be challenging to predict due to interactions between chemicals and thus whole-mixture approaches are crucial in toxicology. Developing organisms are generally more sensitive to chemical insult than adults and early exposure has been linked to metabolic and reproductive disorders later in life. It is thus imperative to clarify how mixtures of environmental pollutants affect early development.Within this thesis, consequences of early exposure to human-relevant chemical mixtures have been demonstrated using zebrafish and chicken embryos. The mixtures were designed previously based on negative associations with birth weight (mixture G) or anogenital distance (mixture S) in Swedish children. Mixture G consist of phthalate monoesters, perfluoroalkyl acids, and triclosan (TCS). It was assessed for effects on developmental processes (apoptosis and wnt/β-catenin signaling) and lipid metabolism in zebrafish. Two components of mixture G were assessed as single compounds: perfluorooctane sulfonate (PFOS) and TCS. Exposure to mixture G induced apoptosis, reduced wnt/β-catenin signalling, increased visceral adiposity, and reduced blood- and whole body-lipid levels in developing zebrafish. PFOS induced apoptosis but not Wnt/β-catenin signaling and TCS had similar effects on lipid levels as the mixture, although the effect of TCS on adipogenesis was not as pronounced. Mixture S, which consists of four phthalate monoesters, and a suggested bisphenol A metabolite (4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene; MBP) were assessed for disruption of reproductive organ development in chicken embryos. No effects were observed by mixture S. MBP caused feminization in male embryos (left ovotestis, feminized gonadal mRNA expression pattern, and Müllerian duct retention). MBP-exposed females displayed smaller left ovaries, malformed left Müllerian ducts, and right Müllerian duct retention.In conclusion, a mixture that has been implicated in altered intrauterine metabolism and growth in Swedish children caused developmental and metabolism disrupting effects in larval zebrafish. PFOS and TCS most likely contribute to the effects by the mixture. Furthermore, the suggested bisphenol A metabolite MBP, but not a mixture of phthalate monoesters, altered both male and female reproductive organ development in chicken embryos. The results were generated using models of both environmental and human relevance. The results in this thesis demonstrate the value of combining epidemiological and experimental studies to assess mixture toxicity.