The intersection of neurotoxicology and endocrine disruption

Abstract

Endocrine disruption, the guiding theme of the 27th International Neurotoxicology Conference, merged into the neurotoxicology agenda largely because hormones help steer the process of brain development. Although the disruption motif first attracted public health attention because of reproductive anomalies in both wildlife and humans, the neurobehavioral implications had been planted decades earlier. They stemmed from the principle that sex differences in behavior are primarily the outcomes of differences in how the brain is sexually differentiated during early development by gonadal hormones (the Organizational Hypothesis). We also now understand that environmental chemicals are capable of altering these underlying events and processes. Among those chemicals, the group labeled as endocrine disrupting chemicals (EDCs) offers the clearest evidence of such selectivity, a consequence of their actions on the endogenous sex steroids, androgens and estrogens. Two EDCs in particular offer useful and intriguing examples. One is phthalate esters. The other is bisphenol A. Both agents are used extensively in plastics manufacture, and are pervasive in the environment. Both are produced in immense quantities. Both are found in almost all humans. Phthalates are considered to function in essence as anti-androgens, while bisphenol A is labeled as an estrogen. Their associations with brain sexual differentiation are reviewed and further questions noted. Both EDCs produce a wider spectrum of health effects, however, than would be extrapolated simply from their properties as anti-androgens and estrogens. Obesity is one example. Further complicating their assessment as health risks are questions about nonmonotonic dose-response functions and about transgenerational effects incurred via epigenetic mechanisms. All these facets of endocrine disruption are pieces of a puzzle that challenge neurotoxicologists for solutions.

Figure 1

Rachel Carson (1907–1964) lifted a nascent environmental movement into public awareness with the publication of Silent Spring (1962). It highlighted the environmental risks of pesticides such as DDT, which earlier had been overlooked.

Figure 2

Basic sketch of human sexual differentiation, depicting windows of susceptibility to endocrine-disrupting chemicals. Until about gestational week 6, the fetus in essence is sexually undifferentiated. Production of testosterone by the fetal testis, beginning at about week 7, as well as programmed gene expression, transforms the sexually undifferentiated fetus into the male form. At this sensitive juncture, anti-androgens such as phthalates can begin to exert their effects. In the rat, testosterone secretion peaks at about embryonic days 16–18.

Figure 3

The process of brain sexual differentiation as seen in rodents, the primary experimental model for studies of brain sexual differentiation. Here, masculinization is governed by estradiol, converted from testosterone by the enzyme aromatase (CYP19). In humans and other primates, dihydrotestosterone performs this function.

Figure 4

Different types of dose-response functions. Traditional toxicology assumes monotonic relationships. Endocrine disruptors often display nonmonotonic relationships. Cf., Welshons et al, 2006: Vandenberg et al 2012.

Figure 5

Polynomial model for benchmark dose ED10 value and 95% lower confidence limit for the male–female littermate differences in Fixed Ratio response rate during the fixed-ratio component of a multiple schedule (Hojo et al, 2002). Pregnant Long-Evans rats were administered TCDD doses of 0, 20, 60, or 180 ng/kg on GD 8. Male and female offspring were trained on a multiple Fixed Ratio-DRL schedule for food pellet rewards. The polynomial was calculated from a quadratic fit to the dose–effect data. A similar plot was calculated for Markowski et al. (2001) for wheel running.