Acute, prolonged, and chronic exposure to organochlorine insecticides evoke differential effects on in vitro neuronal activity and network development

Abstract

Organochlorine insecticide exposure has been associated with neurodevelopmental and neurodegenerative disorders. Moreover, both in vitro and in vivo studies have shown that exposure to organochlorine insecticides causes hyperactivity in the nervous system, and negatively affects calcium homeostasis, neurite outgrowth, and neurotransmitter (receptor) levels. Some of the in vivo effects and associations from epidemiological studies were sex-specific, highlighting the importance of investigating the effects of organochlorine exposure in both sexes. It is therefore of great importance to investigate the effects of prolonged, developmental exposure to organochlorines on the development of neuronal network activity. Here, we examined the effects of acute (30 min), prolonged (up to 48 h), and chronic (21 days) exposure to DDT, its metabolite DDE, endosulfan, dieldrin, and lindane on neuronal activity and network development in sex-separated rat primary cortical cultures using micro-electrode array (MEA) recordings. Our study showed that acute exposure to all tested organochlorines evoked a hyperexcitation, sometimes at concentrations ≤ 1 µM. Exposure to DDT, DDE, endosulfan, and dieldrin inhibited neuronal activity after prolonged exposure, while exposure to lindane had no clear effects after 24 and 48 h. Chronic exposure to all tested organochlorines inhibited neuronal network development at high micromolar concentrations. Most of these effects were observed at non-cytotoxic concentrations, except for exposure to 100 µM endosulfan. Some of the effects found in this study differed between male and female cultures, but no clear sex-specific patterns could be determined across exposure scenarios or between compounds. Together, these results show that acute, prolonged, and chronic exposure to organochlorine insecticides evoke differential effects on neuronal activity and network development. The effects found after acute exposure to DDT, endosulfan, dieldrin, and lindane occur at concentrations close to, or even below human internal exposure levels, highlighting the importance of further monitoring human exposure to organochlorine insecticides.