Region- and age-specific effects of perinatal phthalate exposure on developmental cell death and adult anatomy of dorsal and ventral hippocampus and associated cognitive behaviors

Humans are exposed to phthalates, a class of endocrine-disrupting chemicals used in food packaging/processing, PVC plastics, and personal care products. Gestational exposure may lead to adverse neurodevelopmental outcomes. In a rat model, perinatal exposure to an environmentally relevant mixture and dose of phthalates leads to increased developmental apoptosis in the medial prefrontal cortex (mPFC) and a subsequent reduction in neurons and in cognitive flexibility measured in adults of both sexes (Sellinger et al., 2021b; Kougias et al., 2018b). However, whether these effects generalize to other cognitive regions, like the hippocampus, is less well understood as existing studies used single phthalates at large doses, unrepresentative of human exposure. In the current study, patterns of naturally occurring cell death were first established in the dorsal and ventral hippocampal subfields (CA3 and CA1). Both dorsal and ventral CA3 reached high levels of cell death on P2 while levels in dorsal and ventral CA1 peaked on P5 in both sexes. Exposure to a phthalate mixture (0.2 and 1 mg/kg/day) throughout gestation through postnatal day 10 resulted in subtle age- and region-specific decreases in developmental cell death, however there were no significant changes in adult neuron number or associated behaviors: the Morris water maze and social recognition. Therefore, perinatal exposure to a low dose mixture of phthalates does not result in the dramatic structural and behavioral changes seen with high doses of single phthalates. This study also adds to our understanding of the distinct neurodevelopmental effects of phthalates on different brain regions.