The annual Neurotoxicology Conference took place in Research Triangle, NC on October 30-November 2. The conference title was “Environmentally Triggered Neurodevelopmental Disorders: Focus on Endocrine Disruption and Sex Differences in Autism, ADHD, and Schizophrenia.” One day of the conference was webcast and archived, courtesy of Susan Daniels of the Office of Autism Research Coordination which supports the Interagency Autism Coordination Commmittee at NIH. View here. The conference proceedings are expected to be published in a future journal issue of Neurotoxicology.
A conference on mercury, the endocrine system and autism was conceived several years ago by SafeMinds after reading a review paper by Shirlee Tan, Jesse Meiller and Kathryn Mahaffey of the EPA, “The endocrine effects of mercury in humans and wildlife” (Crit Rev Toxicol. 2009;39(3):228-69). SafeMinds reached out to Drs. Pessah and Zoeller to move the concept forward. Dr. Cranmer, the chair of the conference, graciously adopted the theme. SafeMinds directors Lyn Redwood and Sallie Bernard attended the sessions, and SafeMinds was a co-sponsor of the event.
Findings presented at the conference on neurotoxicology provided evidence that the endocrine system is dysregulated in people on the autism spectrum and common toxins like mercury might be behind this condition. Invited scientists offered supporting data that these alterations might be reversible or prevented through a variety of interventions.
Findings of low levels of sulphate and sulphur-containing compounds like glutathione in autism may be a marker for a more fundamental alteration in selenium status leading to deficiencies in selenoenzymes, according to Nicholas Ralston of the University of North Dakota and a conference presenter. Low circulating sulphate has been a consistent finding validated in autism studies. Selenoenzymes are essential to thyroid hormone homeostasis, repair from oxidative damage in the brain and endocrine tissues, cell signalling, immune function and basic metabolic processes. Selenium is a target of mercury, which tightly binds the selenium molecule, making it unavailable for biological use and disrupting selenium biochemistry. Conversely, selenium can bind mercury, rendering it inert. Dietary selenium, especially from low-mercury deep ocean fish, can counteract the negative effects of mercury exposure.
The endocrine system has received modest attention as a contributor to autism biological differences. This conference, the 27th in a series on International Neurotoxicity, was the first to bring prominent scientists together from different fields to present on and discuss this topic. Thomas Zoeller of the University of Massachusetts, who was the autism session co-chair and an expert in endocrine system and development, defined an endocrine disruptor as “an exogenous chemical or chemical mixture that interferes with hormone signaling.”
Hormones implicated in autism include testosterone as well as oxytocin and vasopresin, which are also slow neurotransmitters or neuromodulators. The adrenal gland, part of the endocrine system, regulates catecholamines, adrenaline, norepinephrine, and dopamine. Dr. Zoeller said that measurements of hormones like thyroid in the periphery do not always reflect what is happening in the brain, since the brain creates its own. The adverse effects of an endocrine disruptor can be silent for some period, and its expression may be due to interaction with other events. The mode of action can be epigenetic, that is, caused by changes in gene regulation rather than a direct insult.
Uncovering how this critical system is changed in people with autism can help identify and understand the mechanisms of action of the environmental contributors to the autism epidemic. Isaac Pessah of the University of California-Davis and a conference co-chair, emphasized that new research confirms a “substantial shared environmental contribution and moderate heritability” for autism, with purely genetic or syndromic forms behind at most 25% of cases and the majority of cases explained by environmental factors. Thus, uncovering environmental effects is crucial to reversing the autism epidemic.
As an example of how chemical exposures can lead to an autism, Thomas Curtis of Oklahoma State University described his new animal model of environmentally-induced autism. Features of autism including social avoidance were elicited in prairie voles in a sex-specific (male) manner when these animals were given either cadmium or inorganic mercury in their drinking water. Behavioral changes were mediated by the dompamine system acting on the limbic system.
Endocrine disruptors are increasing in the home and outdoors via pollutants and household, medical and personal care products. Mercury has been found to be a potent endocrine disruptor, as well as a neuro- and immunotoxin. Besides mercury, endocrine toxicants singled out at the conference included PCBs, BPA, lead, phthalates and pesticides. Medicines like valproic acid, thalidimide, and anti-fever medications were also mentioned.
Pam Lein and Judy van de Water of the University of California-Davis explained that endocrine disruptors may alter the immune system and vice versa. Immune system changes have been linked to autism. The immune signalling system has a dual role in development in shaping the brain, for example, synapse formation or dentritic pruning.
Infections may have similar effects as and work synergistically with chemicals to disrupt endocrine homeostasis. Paul Patterson of the California Institute of Technology described his research on maternal immune response to influenza infection, which changes endocrine function of several placental growth factors. The maternal cytokines produced as a result of infection or similar stimulation has led to anxiety, altered vocalization, repetitive behaviors, reduced social interaction, OCD behaviors like increased self grooming, gastrointestinal illness and purkinje cell neuropathology in the offspring in rat studies.
The higher autism rate in males, higher testosterone levels in autism samples, and other autism features might be explained by endocrine disturbances, specifically in steroid biosynthesis. Dr. Valerie Hu of George Washington University noted that the RORA gene showed lower expression between autism and control samples. RORA regulates aramotase, which she observed to be lower in the frontal cortex of autism subjects. Aramotase is an enzyme that converts testosterone to estrogen. Aromatase deficiency gives rise to elevated testosterone or reduced estrogen. Conversely, elevated testosterone can decrease RORA function while elevated estrogen can increase RORA function. Testosterone is elevated in autism subjects. RORA effects thyroid function as well as cholesterol synthesis. Loss of RORA can reduce purkinje cells, dysregulate circadian rhythms, and reduce the brain’s protection against oxidative stress and inflammation.
Most presenters spoke of the possibility that the effects of the endocrine alterations might be reversible even if these problems arose during development. Possible treatments included enriched learning environments, deliberate infections to restart the immune system or speed up metabolism, biomedical interventions, melatonin, and meditation. Taking steps to eliminate exposures to endocrine disruptors was also suggested.
