Perinatal Exposure to an Environmentally Relevant Mixture of Phthalates Results in a Lower Number of Neurons and Synapses in the Medial Prefrontal Cortex and Decreased Cognitive Flexibility in Adult Male and Female Rats

Abstract

The growth and organization of the developing brain is known to be influenced by hormones, but little is known about whether disruption of hormones affects cortical regions, like the medial prefrontal cortex (mPFC). This region is particularly important given its involvement in executive functions and implication in the pathology of many neuropsychiatric disorders. Here, we examine the long-term effects of perinatal exposure to endocrine-disrupting compounds, the phthalates, on the mPFC and associated behavior. This investigation is pertinent as humans are ubiquitously exposed to phthalates through a variety of consumer products and phthalates can readily cross the placenta and be delivered to offspring via lactation. Pregnant dams orally consumed an environmentally relevant mixture of phthalates at 0, 200, or 1000 μg/kg/day through pregnancy and for 10 days while lactating. As adults, offspring were tested in an attentional set-shifting task, which assesses cognitive flexibility. Brains were also examined in adulthood for stereological quantification of the number of neurons, glia, and synapses within the mPFC. We found that, independent of sex, perinatal phthalate exposure at either dose resulted in a reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. Interestingly, the number of synapses was correlated with cognitive flexibility, such that rats with fewer synapses were less cognitively flexible than those with more synapses. These results demonstrate that perinatal phthalate exposure can have long-term effects on the cortex and behavior of both male and female rats.Humans globally are exposed on a daily basis to a variety of phthalates, which are endocrine-disrupting chemicals. The effects of phthalate exposure on the developing brain, especially on cognitively relevant regions like the medial prefrontal cortex (mPFC), is not known. Here, we use a rat model of human prenatal exposure to an environmentally relevant mixture of phthalates and find there is an appreciable reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. These results may have serious implications for humans given the mPFC is involved in executive functions and is implicated in the pathology of many neuropsychiatric disorders.

Identifying periods of susceptibility to the impact of phthalates on children's cognitive abilities

“…Therefore, during this period, the rapidly developing brain may be more sensitive to toxic chemicals and other insults, which may play a detrimental role in neurodevelopment and adversely influence children's cognitive abilities later in life. An experimental study has shown that early-life exposure to a mixture of phthalates decreased the number of neurons and synapses in the medial prefrontal cortex and was associated with decreased cognitive flexibility in adult rats (Kougias et al, 2018), which supports our observations. Some epidemiological studies have reported inverse associations of gestational or childhood urinary concentrations of ΣDEHP, MBzP, MEP, and MCPP with children's cognitive abilities (Doherty et al, 2017;Factor-Litvak et al, 2014;Huang et al, 2015;Kim et al, 2017;Kim et al, 2018;Polanska et al, 2014).…”

Effects of diisopentyl phthalate exposure during gestation and lactation on hormone‐dependent behaviours and hormone receptor expression in rats

“…This may explain the differences between vinclozolin and DiPeP in relation to play behaviour. By contrast to our results, Kougias et al reported a reduction of periadolescent social play in male rats perinatally exposed to a phthalate mixture at 200 µg kg day ‐1 , although not in males exposed to 1000 µg kg day ‐1 . Interestingly, in an epidemiology study, Swan et al found associations between phthalate exposure during gestation and feminised play behaviour in boys.…”

“…Although doses typically used in animal studies, including our own, are three to five orders of magnitude greater than those found in humans, many epidemiological studies demonstrated associations between phthalate exposures and anti‐androgenic effects in reproductive organs . The changes in play behaviour reported by Kougias et al after developmental exposure to a low phthalate dose in rats and the epidemiological associations reported by Swan et al highlight the need to further investigate the neurobehavioural impact of phthalates at low, human‐relevant doses.…”

“…However, these alterations in the pituitary are followed by higher Esr1 expression in the hypothalamus, which was not found in the present study. On the other hand, the rat study by Kougias et al found no systematic changes in the mRNA expression of ERs and other steroid and nonsteroid hormone receptors in the hypothalamus of adult male rats perinatally exposed to low doses of a phthalate mixture …”

Phthalate exposure and neurodevelopmental outcomes in early school age children from Poland

“…As far as mechanisms of developmental neurotoxicity, experimental studies have indicated that several pathways relevant to brain development are targeted by phthalates, including dopaminergic neurotransmission (Chen et al, 2011;Dhanya et al, 2003;Tully et al, 2000;Wang et al, 2016), thyroid hormone homeostasis (Liu et al, 2015), and steroids' action through their receptors (Dombret et al, 2017). Very recent data obtained in rats also showed decreased number of neurons and synapses in the medial prefrontal cortex following developmental exposure to an environmentally relevant mixture of major phthalates (Kougias et al, 2018).…”