Detection of 3,3′-Dichlorobiphenyl in Human Maternal Plasma and Its Effects on Axonal and Dendritic Growth in Primary Rat Neurons

Abstract

3,3'-Dichlorobiphenyl (PCB 11), a byproduct of pigment production, is increasingly detected in environmental samples. While more highly chlorinated PCB congeners are known developmental neurotoxicants, nothing is known about the potential developmental neurotoxicity of PCB 11. To address this critical data gap, we measured PCB 11 levels in human maternal plasma and quantified the effects of PCB 11 and its major metabolites on morphometric parameters of neuronal connectivity in cultured primary neurons. Mass spectrometry analyses of plasma from 241 pregnant women enrolled in the MARBLES study (University of California, Davis) detected PCB 11 in all samples at concentrations ranging from 0.005 to 1.717 ng/ml. Morphometric analyses of primary neuron-glia co-cultures dissociated from the neocortices or hippocampi of neonatal Sprague Dawley rats exposed to vehicle or concentrations ranging from 1 attamolar (aM) to 1 micromolar (µM) of PCB 11, OH-PCB 11, or PCB 11 sulfate indicated that PCB 11 and both metabolites significantly increased axonal and dendritic growth in cortical and hippocampal pyramidal neurons. PCB 11 significantly altered neuronal morphogenesis at concentrations as low as 1 femtomolar (fM), which is ∼0.22 ng/ml. These data suggest the potential for the developing human brain to be exposed to PCB 11, and demonstrate that environmentally relevant levels of PCB 11 alter axonal and dendritic growth in neuronal cell types critically involved in cognitive and higher-order behaviors. These findings identify PCB 11 as a potential environmental risk factor for adverse neurodevelopmental outcomes in humans.

Linoleic acid‐derived metabolites constitute the majority of oxylipins in the rat pup brain and stimulate axonal growth in primary rat cortical neuron‐glia co‐cultures in a sex‐dependent manner

“…Primary cortical neuron‐glia co‐cultures were prepared from 3‐5 pups (per sex) per dissection as previously described (Wayman et al ; Sethi et al ). There were 4 independent dissections in total, resulting in 9‐12 wells per treatment per sex.…”

“…The neuron‐glia co‐culture assays were blinded to treatment but not sex. Sample size for neuron‐glia co‐culture was determined based on historical data (Sethi et al ); sample size for the lipid assays was not determined because of the lack of quantitative lipidomic data in rat pup brain. Hence, this should be considered an exploratory study.…”

Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity

“…These dendritic effects are observed in cultures exposed to PCB 11 at fM concentrations, which are within the range of PCB 11 concentrations detected in the serum of pregnant women [259]. In contrast to the HC-PCBs 95 and 136, PCB 11 and its metabolites not only increase dendritic arborization, but also enhance axonal growth [13]. Subsequent mechanistic studies indicated that the dendrite-promoting activity of PCB 11 is not blocked by pharmacological antagonism of the RyR, the AhR, or the THR [259].…”

“…The non-legacy LC-PCB, PCB 11, has recently been detected in the serum of dairy animals [257] and in commercial cow's milk in Northern California [258]. Of even greater concern, PCB 11 has also been found in serum of pregnant women living in Northern California [13,69] as well as women and their adolescent children living in the greater Chicago area and rural Iowa [6]. Analysis of PCBs in the serum of pregnant women at increased risk for having a child with an NDD revealed that the non-legacy LC-PCBs 28 and 11 were the two most abundant PCB congeners, and together they comprised almost 75% of the PCB burden in the maternal serum samples [69].…”

“…Yet, humans continue to be exposed to legacy PCBs because the differential environmental distribution of HC-PCBs vs. LC-PCBs, it is proposed that humans are primarily exposed to HC-PCBs via diet, particularly fish, and to LC-PCBs via inhalation [8]. However, it is worth noting that recent studies have documented the widespread presence of the LC-PCB congener, PCB 11, in commercial milk products in Northern California [13]; and, conversely, the HC-PCB congener, PCB 95, is the second most abundant PCB detected in the air in U.S. schools [49].…”