Developmental Toxicity

Abstract

This chapter provides an overview of the developmental toxicity resulting from exposure to perfluorinated alkyl acids (PFAAs). The majority of studies of PFAA-induced developmental toxicity have examined effects of perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA) and there is only limited information available for other members of this family of chemicals. In this chapter, there are separate overviews of the developmental toxicity of PFOS and PFOA, along with a summary of studies available for perfluorobutyrate (PFBA), perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA). In general, among the PFAAs that do produce developmental toxicity in one or more laboratory species, prenatal PFAA exposure in teratology studies typically does not result in major malformations and significant findings are often limited to the higher exposure levels. The postnatal effects in rats or mice exposed to PFAAs are typically increased mortality in the first hours or week after birth, effects on weight which may persist beyond weaning, delayed eye opening, abnormal mammary gland development, and liver hypertrophy. The role of peroxisome proliferator activated receptor-alpha (PPARα) in mediating developmental effects is discussed, including insights from genetically modified mice, PPARα knockout mice, and mice expressing the human PPARα gene. Pharmacokinetic issues are relevant to selecting an appropriate animal model for developmental studies and regarding the influence of rapid clearance on manifestation of developmental toxicity. Whether or not a particular PFAA will cause developmental toxicity depends on levels and timing of fetal exposure and is influenced by species and gender specific pharmacokinetic characteristics that impact exposure of the conceptus throughout gestation and during the lactational period. Factors influencing the pharmacokinetics and developmental outcomes include chemical characteristics of a particular PFAA (carbon chain length, functional moiety – carboxylate or sulfonate), species specific characteristics (sex and species specific expression of particular transporters in the kidney that influence clearance), timing and level of exposure to the developing fetus, and ability of the PFAA to activate PPARα (human, mouse, and rat PPARα differ in responses to PFAA, carboxylates are more effective than sulfonates, and longer carbon chain PFAA are more potent than short chain PFAA). The expression and activation of PPARα is necessary for mediating developmental effects of PFOA and PFNA, but the early postnatal deaths caused by exposure to PFOS were not dependent on expression of PPARα.